naloxone and Pain

U.S. military veterans have been heavily impacted by the opioid overdose crisis, with drug overdose mortality rates increasing by 53% from 2010-2019. Risk for overdose among veterans is complex and influenced by ongoing interaction among physiological/biological, psychological, and socio-structural factors. A thorough understanding of opioid-related overdose among veterans, one that goes beyond simple pharmacological determinism, must examine the interplay of pain, pain treatment, and stress, as well as psychological and social experiences-before, during, and after military service. Comprehensive efforts to tackle the overdose crisis among veterans require interventions that address each of these dimensions. Promising interventions include widespread naloxone distribution and increased provision of low-threshold wrap-around services, including medications for opioid use disorder (MOUD) and holistic/complementary approaches. Interventions that are delivered by peers - individuals who share key experiential or sociodemographic characteristics with the population being served - may be ideally suited to address many of the barriers to opioid-related risk mitigation common among veterans. Community care models could be beneficial for the large proportion of veterans who are not connected to the Veterans Health Administration and for veterans who, for various reasons including mental health problems and the avoidance of stigma, are socially isolated or reluctant to use traditional substance use services. Interventions need to be tailored in such a way that they reach those more socially isolated veterans who may not have access to naloxone or the social support to help them in overdose situations. It is important to incorporate the perspectives and voices of veterans with lived experience of substance use into the design and implementation of new overdose prevention resources and strategies to meet the needs of this population. Key messagesU.S. military veterans have been heavily impacted by the opioid overdose crisis, with drug overdose mortality rates increasing by 53% from 2010-2019.The risks for overdose that veterans face need to be understood as resulting from an ongoing interaction among biological/physiological, psychological, and social/structural factors.Addressing drug overdose in the veteran population requires accessible and non-judgemental, low threshold, wraparound, and holistic solutions that recognise the complex aetiology of overdose risk for

Topics: Analgesics, Opioid; Drug Overdose; Humans; Naloxone; Opiate Overdose; Opioid-Related Disorders; Pain; Risk Factors; Veterans

Numerous G-protein-coupled receptors (GPCRs) display ligand-free basal signaling with potential physiological functions, a target in drug development. As an example, the μ opioid receptor (MOR) signals in ligand-free form (MOR-μ*), influencing opioid responses. In addition, agonists bind to MOR but can dissociate upon MOR activation, with ligand-free MOR-μ* carrying out signaling. Opioid pain therapy is effective but incurs adverse effects (ADRs) and risk of opioid use disorder (OUD). Sustained opioid agonist exposure increases persistent basal MOR-μ* activity, which could be a driving force for OUD and ADRs. Antagonists competitively prevent resting MOR (MOR-μ) activation to MOR-μ*, while common antagonists, such as naloxone and naltrexone, also bind to and block ligand-free MOR-μ*, acting as potent inverse agonists. A neutral antagonist, 6β-naltrexol (6BN), binds to but does not block MOR-μ*, preventing MOR-μ activation only competitively with reduced potency. We hypothesize that 6BN gradually accelerates MOR-μ* reversal to resting-state MOR-μ. Thus, 6BN potently prevents opioid dependence in rodents, at doses well below those blocking antinociception or causing withdrawal. Acting as a 'retrograde addiction modulator', 6BN could represent a novel class of therapeutics for OUD. Further studies need to address regulation of MOR-μ* and, more broadly, the physiological and pharmacological significance of ligand-free signaling in GPCRs.

Topics: Analgesia; Analgesics, Opioid; Humans; Ligands; Morphine; Naloxone; Naltrexone; Narcotic Antagonists; Opioid-Related Disorders; Pain; Receptors, Opioid, mu

Pain is a non-motor symptom in Parkinson's disease (PD) which commonly goes underreported. Adequate treatment for pain in PD remains challenging, and to date, no clear guidelines for management are available.. With the goal of understanding and organizing the current status of pain management in PD, we conducted a review of pharmacological and non-pharmacological treatments for pain in patients with PD. Suitable studies cataloged in PubMed and the Cochrane database up to October 31, 2019, were included prioritizing randomized controlled trials. Post-hoc analyses and open-label studies were also included.. Treatment with levodopa increases pain thresholds in patients with PD. Apomorphine did not have similar efficacy. Duloxetine provided benefit in an open-label trial. Oxycodone-naloxone PR did not have a significant improvement in pain, but per-protocol analysis showed a reduction in pain when adherence was strong. Rotigotine patch had numerical improvement on pain scales with no statistical significance. Safinamide significantly improved the "bodily discomfort" domain in the PDQ-39 questionnaire. Botulinum toxin A had a non-significant signal toward improving dystonic limb pain in PD. DBS to the subthalamic nucleus may modulate central pain thresholds, and a pilot study of cranioelectric therapy warrants future research in the area.. After optimizing dopaminergic therapy, understanding the type of pain a patient is experiencing is essential to optimizing pain control in PD. While recommendations can be made regarding the treatment options in each domain, evidence remains weak and future randomized controlled studies are needed.

Topics: Acetylcholine Release Inhibitors; Alanine; Analgesics; Antiparkinson Agents; Apomorphine; Benzylamines; Botulinum Toxins, Type A; Deep Brain Stimulation; Dopamine Agonists; Drug Combinations; Duloxetine Hydrochloride; Humans; Levodopa; Naloxone; Oxycodone; Pain; Pain Management; Pain Measurement; Pain Threshold; Parkinson Disease; Tetrahydronaphthalenes; Thiophenes

Women are being disproportionately affected by the opioid crisis, including during pregnancy. Pain and other vulnerabilities to addiction differ between men and women. Management of opioid use disorder should be gender informed and accessible across the lifespan. During pregnancy, care teams should be multidisciplinary to include obstetrics, addiction, social work, anesthesia, pediatrics, and behavioral health. Pain management for women with opioid use disorder requires tailored approaches, including integration of trauma-informed care and addressing psychosocial needs. Thus, coordinated continued care by obstetric and addiction providers through pregnancy into postpartum is key to supporting women in recovery.

Topics: Analgesics, Opioid; Chronic Pain; Drug Overdose; Female; Harm Reduction; History, 20th Century; History, 21st Century; Humans; Naloxone; Narcotic Antagonists; Opiate Substitution Treatment; Opioid-Related Disorders; Pain; Pain Management; Patient Care Planning; Patient Participation; Postnatal Care; Pregnancy; Pregnancy Complications; Prenatal Care; Prenatal Diagnosis; Psychological Trauma; Sex Factors

To review the emergency-based approach to opioid toxicity reversal in cancer-related pain patients.. A MEDLINE and PubMed search was conducted (1966 to May 2014) using the terms opioids, cancer, naloxone, respiratory depression, morphine, morphine derivatives, emergency, and anaphylaxis.. English articles in human subjects identified from the MEDLINE and PubMed search were evaluated. Citations were excluded if they addressed acute overdoses, non-cancer pain, and/or acute, non-chronic pain.. Pain is a common occurrence in the oncology population. Although toxicity from opioids is common, life-threatening toxicities are not. The use of naloxone in this particular patient population occurs frequently for any perceived opioid-related effect and can be detrimental to the oncology patient's care and quality of life. Difficulties exist when attempting to separate opioid toxicity from disease progression or metastases and, therefore, a thorough history is needed prior to complete opioid reversal in this population. Severity of the opioid intoxication should dictate reversal strategy. Dosing strategies that take into account both the treatment of the opioid-related effects as well as the negative effects reversal will have on the patient are offered. We also review the pre-hospital setting and identified the need for protocols that not only take the patient's symptoms into account, but also the patient's cancer history.. Opioid reversal protocols should be developed by a multi-disciplinary team. Each protocol should differentiate those toxicities which are life-threatening and require complete opioid reversal with toxicities that require small aliquots of naloxone to mitigate the presenting symptoms.

Topics: Analgesics, Opioid; Humans; Naloxone; Neoplasms; Pain; Quality of Life

Common opioids adverse effects include opioid-induced bowel dysfunction (OIBD), which comprises opioid-induced constipation, dry mouth, nausea, vomiting, gastric stasis, bloating, and abdominal pain. Traditional laxatives which are often prescribed for the prevention and treatment of OIBD possess limited efficacy and display adverse effects. A targeted approach to OIBD management is the use of a combination of an opioid agonist with opioid receptor antagonist or administration of purely peripherally acting opioid receptor antagonists.. A literature search with terms "oxycodone/naloxone" in the PubMed and MEDLINE database updated on 31(st) July 2013. All studies of oxycodone/naloxone (randomized, controlled trials and open, uncontrolled studies) were included. In addition, studies on pharmacokinetics and pharmacodynamics of oxycodone/naloxone were included.. A combination of prolonged-release oxycodone with prolonged-release naloxone (OXN) in one tablet with a fixed 2:1 ratio provides effective analgesia with limited disturbing effect on bowel function. Oxycodone is a valued opioid administered either as the first strong opioid or when other strong opioids have been ineffective. Naloxone is an opioid receptor antagonist that displays local antagonist effect on opioid receptors in the gastrointestinal tract and is nearly completely inactivated in the liver after oral administration. As demonstrated in controlled studies conducted in patients with chronic non-malignant and cancer-related pain OXN in daily doses up to 80 mg/40 mg provided equally effective analgesia with an improved bowel function compared to oxycodone administered alone.. OXN is an important drug for chronic pain management, prevention and treatment of OIBD.

Topics: Constipation; Drug Combinations; Gastrointestinal Tract; Humans; Naloxone; Oxycodone; Pain

Opioid receptor antagonists are well known for their ability to attenuate or reverse the effects of opioid agonists. This property has made them useful in mitigating opioid side effects, overdose and abuse. Paradoxically, opioid antagonists have been reported to produce analgesia or enhance analgesia of opioid agonists. The authors review the current state of the clinical use of opioid antagonists as analgesics.. Published clinical trials, case reports and other sources were reviewed to determine the effectiveness and safety of opioid antagonists for use in relieving pain. The results are summarized. Postulated mechanisms for how opioid antagonists might exert an analgesic effect are also briefly summarized.. Since the comprehensive review by Leavitt in 2009, few new studies on the use of opioid antagonists for pain have been published. The few clinical trials generally consist of small populations. However, there does appear to be a trend of effectiveness of low doses (higher doses antagonize opioid agonist effects). How opioid antagonists can elicit an analgesic effect is still unclear, but a number of possibilities have been suggested. Although the data do not yet support recommendation of widespread application of this off-label use of opioid antagonists, further study appears worthwhile.

Topics: Animals; Humans; Naloxone; Naltrexone; Narcotic Antagonists; Pain

Tramadol and tilidine (in combination with naloxone) are used as weak opioid analgesics in Germany. Tramadol is not scheduled in the German Narcotic Drugs Act. Tilidine is scheduled, whereas Tilidine in fixed combinations with naloxone is exempt from some of the provisions of the Narcotic Drugs Act. Recent reports on misuse of both substances led to an evaluation of their potential for misuse, abuse, and dependency by the expert advisory committee established by the German Federal Government, resident at the Federal Institute for Drugs and Medical Devices.. A subcommittee formulated key questions and identified available data sources for each of these questions. Additional information was solicited where necessary, including a survey among a panel of pharmacists, a survey in an addiction clinic, analysis of prescription patterns, and information from the boards of pharmacists of the federal states and the Federal Bureau of Criminal Investigation.. Analgesic efficiency in the treatment of acute and chronic pain has been proven for both tramadol and tilidine/naloxone. For tramadol, high evidence has been confirmed in systematic reviews, and tramadol is listed in national and international guidelines on acute and chronic pain management. Animal and human studies found a low potential for misuse, abuse, and dependency for both substances. Information from 2 tramadol safety databases allowed calculation of the incidence of abuse or dependency as 0.21 and 0.12 cases per million defined daily dosages (DDDs), with lower incidences in recent years. For tilidine/naloxone, the incidence was calculated as 0.43 cases per million DDDs for oral solution and 0.18 for slow-release tablets. In an online survey among German pharmacies as well as in the reports from state pharmacy boards, fraud attempts were repeated more frequently with tilidine/naloxone than with tramadol in the last 2 years. The Federal Bureau of Criminal Investigations reported prescription fraud only with tilidine/naloxone and predominantly in the region of Berlin. Dependency on tramadol or tilidine/naloxone is reported only rarely from addiction counseling centers. One third of the patients surveyed in an addiction clinic reported experiences with tramadol or tilidine/naloxone, but mostly with duration of less than 4 weeks and with a medical prescription based on a reasonable indication. Also, occasional illegal use of opioid analgesics as a substitute of heroin was reported. An evaluation of pooled data from statutory health insurance companies found 2.5% of persons receiving at least 1 prescription of tramadol or the combination of tilidine and naloxone in 2009 (1.6% with tramadol and 1.0% with tilidine/naloxone). High usage with more than 180 DDDs per year was found in 8.6% of patients treated with tramadol and 17.2% of patients with tilidine/naloxone.. In conclusion, the subcommittee of the expert advisory committee found a low potential for misuse, abuse, and dependency for tramadol, and a low prevalence in clinical practice. Considerable less information is available for the combination of tilidine and naloxone. However, the cumulation of evidence indicated a higher risk of misuse, abuse, and dependency for tilidine/naloxone solution, but not for slow-release tablets.

Topics: Analgesics, Opioid; Drug Therapy, Combination; Fraud; Germany; Humans; Incidence; Naloxone; Opioid-Related Disorders; Pain; Self Medication; Tilidine; Tramadol

Opioids are the drugs of choice for treating moderate-to-severe pain, especially for patients in the end stage of cancer or other advanced illnesses, and also in critical care or for the treatment of chronic pain. Side effects such as nausea, pruritus, dizziness and constipation have to be controlled in order to use these drugs to their full potential. Opioid-induced bowel syndrome and constipation caused by activation of μ-receptors in the gut can have such distressing effects that some patients prefer to forego adequate pain control. Methylnaltrexone is a μ-opioid receptor antagonist that, unlike naltrexone or naloxone, does not pass the blood-brain barrier, and therefore does not impair the centrally mediated analgesic effect of opioids. It is licensed for the treatment of opioid-induced constipation in palliative care in more than 50 countries. This article presents practically relevant pharmacological data, basic research results and evidence from clinical research about methylnaltrexone, and outlines potential future therapeutic options for this promising drug.

Topics: Analgesics, Opioid; Constipation; Humans; Naloxone; Narcotic Antagonists; Pain; Palliative Care; Quaternary Ammonium Compounds; Receptors, Opioid, mu; Treatment Outcome

Opioid substitution therapy (OST) for opioid dependence is common, and injection drug users have significant medical and psychiatric comorbidity. Many physicians will encounter OST patients in their usual practice. This article provides guidance on management of common clinical problems in this population, including OST management in hepatic failure, respiratory disease, pain management and potential drug interactions.

Topics: Analgesics; Australia; Buprenorphine; Comorbidity; Drug Interactions; Female; Humans; Liver Diseases; Mental Disorders; Methadone; Naloxone; Opiate Substitution Treatment; Pain; Pain Management; Palliative Care; Polypharmacy; Pregnancy; Pregnancy Complications; Respiratory Insufficiency; Substance-Related Disorders; Virus Diseases

Opiates such as morphine and fentanyl, a major class of analgesics used in the clinical management of pain, exert their effects through the activation of opioid receptors. Opioids are among the most commonly prescribed and frequently abused drugs in the USA; however, the prolonged use of opiates often leads to the development of tolerance and addiction. Although blockade of opioid receptors with antagonists such as naltrexone and naloxone can lessen addictive impulses and facilitate recovery from overdose, systemic disruption of endogenous opioid receptor signalling through the use of these antagonistic drugs can have severe side effects. In the light of these challenges, current efforts have focused on identifying new therapeutic targets that selectively and specifically modulate opioid receptor signalling and function so as to achieve analgesia without the adverse effects associated with chronic opiate use. We have previously reported that opioid receptors interact with each other to form heteromeric complexes and that these interactions affect morphine signalling. Since chronic morphine administration leads to an enhanced level of these heteromers, these opioid receptor heteromeric complexes represent novel therapeutic targets for the treatment of pain and opiate addiction. In this review, we discuss the role of heteromeric opioid receptor complexes with a focus on mu opioid receptor (MOR) and delta opioid receptor (DOR) heteromers. We also highlight the evidence for altered pharmacological properties of opioid ligands and changes in ligand function resulting from the heteromer formation.

Topics: Analgesia; Analgesics; Animals; Drug Antagonism; Drug Overdose; Humans; Morphine Dependence; Naloxone; Naltrexone; Narcotic Antagonists; Pain; Protein Multimerization; Protein Structure, Quaternary; Receptors, Opioid, delta; Receptors, Opioid, mu; Signal Transduction; United States

Opioids induce respiratory depression via activation of μ-opioid receptors at specific sites in the central nervous system including the pre-Bötzinger complex, a respiratory rhythm generating area in the pons. Full opioid agonists like morphine and fentanyl affect breathing with onset and offset profiles that are primarily determined by opioid transfer to the receptor site, while the effects of partial opioid agonists such as buprenorphine are governed by transfer to the receptor site together with receptor kinetics, in particular dissociation kinetics. Opioid-induced respiratory depression is potentially fatal but may be reversed by the opioid receptor antagonist naloxone, an agent with a short elimination half-life (30 min). The rate-limiting factor in naloxone-reversal of opioid effect is the receptor kinetics of the opioid agonists that requires reversal. Agents with slow dissociation kinetics (buprenorphine) require a continuous naloxone infusion while agents with rapid kinetics (fentanyl) will show complete reversal upon a single naloxone dose. Since naloxone is non-selective and will reverse analgesia as well, efforts are focused on the development of compounds that reverse opioid-induced respiratory depression without affecting analgesic efficacy. Such agents include ampakines and serotonin agonists which are aimed at selectively enhancing central respiratory drive. A novel approach is aimed at the reduction of respiratory depression from opioid-activation of (micro-)glia cells in the pons and brainstem using micro-glia cell stabilizers. Since this approach simultaneously enhances opioid analgesic efficacy it seems an attractive alternative to the classical reversal strategies with naloxone.

Topics: Analgesics, Opioid; Animals; Humans; Microglia; Naloxone; Narcotic Antagonists; Pain; Receptors, Opioid, mu; Respiration; Respiratory Center; Respiratory Insufficiency; Toll-Like Receptor 4

An 82-year-old female on hemodialysis was diagnosed with advanced breast cancer. She received 20 mg of controlled-release oral morphine per day for the relief of cancer pain. After a total dose of 30 mg was administered, she was hospitalized with disturbance of consciousness. The patient underwent hemodialysis the next day, but developed impaired consciousness and respiratory depression. On the third day of hospitalization, a continuous infusion of naloxone was started and administered for eleven days. Thereafter, she was given oxycodone during hemodialysis without any side effects. Morphine-6-glucuronide(M-6-G)can accumulate in the blood of renal failure and dialysis patients. Toxicity of M-6-G may persist even after this metabolite is removed by dialysis, causing potentially life-threatening opioid toxicity. Morphine is therefore not recommended for use in renal failure and dialysis patients. The use of fentanyl or oxycodone is recommended as an alternative opioid. It is essential that medical staff are aware that these patients have an increased risk of developing serious morphine-related toxicity.

Topics: Aged, 80 and over; Breast Neoplasms; Consciousness; Delayed-Action Preparations; Female; Humans; Morphine; Naloxone; Narcotic Antagonists; Pain; Renal Dialysis; Respiratory Insufficiency; Time Factors

There has been an alarming increase in the prescription of opiates and opioids for chronic non-cancer pain in the past 15 years. It is estimated that opiate-induced constipation (OIC) is experienced by ~40% of these patients, and that constipation and other gastrointestinal symptoms may dissuade patients from using the required analgesic dose to achieve effective pain relief. Opiates have several effects on gastrointestinal functions, and the inhibition of colonic transit and intestinal and colonic secretion results in constipation. Several different pharmacological approaches are being developed to prevent or treat OIC: prolonged release formulations that contain naloxone (a less specific opiate antagonist that is widely distributed) and a new class of peripherally restricted μ-opiate receptor antagonists, including methylnaltrexone, alvimopan, tapentadol, NKTR-118, and TD-1211. Novel patient response outcomes have been developed to facilitate demonstration of efficacy and safety of drugs in development for OIC.

Topics: Analgesics, Opioid; Constipation; Humans; Naloxone; Narcotic Antagonists; Pain; Phenols; Receptors, Opioid, mu; Tapentadol

The purpose of this case series was to review the management of burn patients who requested ultrarapid opioid detoxification under anesthesia after extended duration of narcotic use for chronic pain related to burn injury.. The treatment plan of six opioid-dependent burn patients was analyzed to assess the effectiveness of our detoxification practice to date. Demographic and clinical information was used to characterize the patient population served: age, burn size, injury severity, duration of narcotic use before detoxification intervention, and length of hospitalization stay. Daily narcotic consumption, in morphine equivalent units, was noted both before and after detoxification.. Six burn patients (average age, 31 years) underwent detoxification at the Burn Center during a hospitalization lasting between 1 day and 2 days. Average burn size was 38% total body surface area (range, 17-65); average Injury Severity Score was 30 (range, 25-38). Mean duration of narcotic use was 672 days (range, 239-1,156 days); average use of narcotics at time of detoxification was >200 units daily. Mean outpatient consumption for opioids after the intervention was minimal (<25 units/d). No complications were noted during any procedures.. The results of ultrarapid opioid detoxification under anesthesia suggests that it is safe and effective for treating opioid addiction in military burn casualties when a coordinated, multidisciplinary approach is used. Safety and effectiveness to date validate current practice and supports incorporation into clinical practice guidelines. Further clinical research is warranted to identify those patients who may benefit most from detoxification and to determine the timing of such treatment.

Topics: Adult; Analgesics, Opioid; Burns; Humans; Male; Military Personnel; Naloxone; Narcotic Antagonists; Pain; Substance Withdrawal Syndrome; United States

In Australia and New Zealand, in parallel with other developed countries, the number of patients prescribed opioids on a long-term basis has grown rapidly over the last decade. The burden of chronic pain is more widely recognised and there has been an increase in the use of opioids for both cancer and non-cancer indications. While the prevalence of illicit opioid use has remained relatively stable, the diversion and abuse of prescription opioids has escalated, as has the number of individuals receiving methadone or buprenorphine pharmacotherapy for opioid addiction. As a result, the proportion of opioid-tolerant patients requiring acute pain management has increased, often presenting clinicians with greater challenges than those faced when treating the opioid-naïve. Treatment aims include effective relief of acute pain, prevention of drug withdrawal, assistance with any related social, psychiatric and behavioural issues, and ensuring continuity of long-term care. Pharmacological approaches incorporate the continuation of usual medications (or equivalent), short-term use of sometimes much higher than average doses of additional opioid, and prescription of non-opioid and adjuvant drugs, aiming to improve pain relief and attenuate opioid tolerance and/or opioid-induced hyperalgesia. Discharge planning should commence at an early stage and may involve the use of a 'Reverse Pain Ladder' aiming to limit duration of additional opioid use. Legislative requirements may restrict which drugs can be prescribed at the time of hospital discharge. At all stages, there should be appropriate and regular consultation and liaison with the patient, other treating teams and specialist services.

Topics: Acute Disease; Analgesics; Analgesics, Opioid; Animals; Australia; Buprenorphine; Buprenorphine, Naloxone Drug Combination; Drug Tolerance; Humans; Hyperalgesia; Illicit Drugs; Methadone; Naloxone; Narcotic Antagonists; Narcotics; New Zealand; Opiate Substitution Treatment; Opioid-Related Disorders; Pain; Pain, Postoperative; Patient Discharge; Preoperative Care; Substance Withdrawal Syndrome

Despite proven analgesic efficacy, opioid use is associated with frequently dose-limiting bowel dysfunction that seriously impacts patients' quality of life (QoL). Agents used at present to manage opioid-induced constipation do not address the underlying opioid receptor-mediated cause of bowel dysfunction and are often ineffective. There is, therefore, a significant need for more effective treatment options. The combination of the strong opioid oxycodone and the opioid antagonist naloxone has the potential to prevent opioid-induced bowel dysfunction (OIBD) while maintaining analgesic efficacy.. To review the safety and efficacy of oral prolonged-release (PR) oxycodone/naloxone in the treatment of patients experiencing chronic pain.. A MEDLINE search was done (January 2002 - July 2009) for available literature for prolonged release oxycodone and naloxone in different patient groups. Results were limited to English-language and clinical trials. Data were also obtained from congress materials. WHAT KNOWLEDGE THE READER WILL GAIN: Unmet needs of opioid pain treatment in terms of OIBD, reduced QoL and low treatment compliance, leading to reduced efficacy. A data overview demonstrates the efficacy and tolerability of PR oxycodone/naloxone in the management of severe chronic pain without the burden of severe gastrointestinal adverse events. The combined formulation of a highly effective opioid and an antagonist that acts locally to reduce gastrointestinal side effects is expected to simplify pain management.. The combination of PR oxycodone/naloxone offers the potential of maintaining normal bowel function in patients requiring opioid therapy--it is a strong analgesic that is well tolerated.

Topics: Administration, Oral; Chronic Disease; Clinical Trials as Topic; Constipation; Drug Administration Schedule; Drug Therapy, Combination; Humans; Naloxone; Narcotic Antagonists; Oxycodone; Pain; Pain Measurement; Quality of Life; Receptors, Opioid; Safety

Morphine and other opioids increase tone and reduce propulsive motility in several segments of the gut, enhance absorption of fluids, and inhibit secretion. This opioid-induced bowel dysfunction may present as infrequent stools, hard stools, difficult defecation, bloating, and sense of incomplete emptying of the bowels, but also dry mouth, gastroesophageal reflux, epigastric fullness, and abdominal cramping. It afflicts about one-third of patients on opioid treatment. Lifestyle measures, such as regular toilet visits, physical activity, and fiber-rich diet, are very unlikely to be successful. Laxatives, such as bisacodyl, sodium picosulfate, sennosides, macrogols, and prucalopride, may relieve opioid-induced constipation (OIC) in a proportion of patients only. A new approach to counteract OIC is the coadministration of an opioid antagonist devoid of the potential to penetrate the brain. In the EU, an oxycodonenaloxone combination has been approved for this purpose. Both components are included in an oral extended-release preparation. Following its release, naloxone acts locally on the gut and antagonizes the inhibitory effect of the opioid. After being absorbed in parallel with oxycodone, naloxone is rapidly and completely inactivated by a high first-pass effect in the liver. In a 2:1 dose ratio it may improve OIC without interfering with the analgesic effect.

Topics: Analgesics, Opioid; Constipation; Drug Combinations; Humans; Laxatives; Morphine; Naloxone; Narcotic Antagonists; Oxycodone; Pain; Treatment Outcome

Opioid analgesics are the cornerstone of pain management for moderate-to-severe cancer pain and, increasingly, chronic noncancer pain. Despite proven analgesic efficacy, the use of opioids is commonly associated with frequently dose-limiting constipation that seriously impacts on patients' quality of life. Agents currently used to manage opioid-induced constipation (OIC), such as laxatives, do not address the underlying opioid receptor-mediated cause of constipation and are often ineffective. A significant need therefore exists for more effective treatment options. A novel approach for selectively and locally antagonizing the gastrointestinal effects of opioids involves the coadministration of a mu-opioid receptor antagonist with negligible systemic availability, such as oral naloxone. Combination therapy with prolonged-release (PR) oxycodone plus PR naloxone has been shown to provide effective analgesia while preventing or reducing constipation. The current article highlights this novel strategy in its potential to significantly improve the quality of life of patients suffering from chronic pain, affording patients the benefit of full analgesia, without the burden of OIC.

Topics: Analgesics, Opioid; Chronic Disease; Clinical Trials as Topic; Constipation; Dose-Response Relationship, Drug; Drug Therapy, Combination; Humans; Laxatives; Naloxone; Narcotic Antagonists; Oxycodone; Pain; Quality of Life

Opioids are the most effective compounds available for the relief of pain, yet there are a number of side effects that are of great concern to clinicians. For example, opioids are powerful reinforcers, and the treatment of pain using opioids could lead to the development of addiction. In addition, there is an increasing body of literature demonstrating that the repeated administration of opioids could lead to a phenomenon called opioid-induced hyperalgesia (i.e., increased sensitivity to painful stimulation). Studies examining these potential adverse effects are necessary in the development of novel analgesics. Furthermore, most studies of pain sensitivity and pain relief use reflex-based procedures to identify analgesics; however, it is argued here that operant-based procedures provide measures that are more analogous to the human condition (i.e., the mechanisms of pain are similar to those in humans) and should be useful in the assessment of novel analgesics. A series of studies examining the effects of opioids and the influence of variables such as age are discussed to demonstrate the utility of this approach.

Topics: Analgesics, Opioid; Animals; Behavior, Animal; Conditioning, Operant; Hot Temperature; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Rats; Reinforcement, Psychology

Topics: Administration, Cutaneous; Administration, Oral; Analgesics, Opioid; Anti-Inflammatory Agents, Non-Steroidal; Buprenorphine; Cyclooxygenase 2 Inhibitors; Humans; Naloxone; Osteoarthritis; Pain; Risk Factors; Tilidine; Tramadol

A meta-analysis was performed to investigate the ability of placebo administration to reduce self-report of pain and to examine whether placebo-induced pain reduction might have physiological and psychological underpinnings.. Forty-five effect sizes and 1183 participants from 12 studies were meta-analyzed for the effects of placebo and the opioid antagonist, naloxone, on self-report of pain.. Analyses showed that placebo administration was associated with a decrease in self-report of pain, and a hidden or blind injection of naloxone reversed placebo-induced analgesia. Furthermore, there were significant between-group differences for type of pain (experimental vs. postoperative/clinical) for placebo studies.. The results support the literature illustrating that the belief and expectation of analgesia induces discrete physiological changes, leading to relief from pain, and this response may be mediated by endogenous opioids. The implications of these findings are discussed in terms of the symbolic aspect of health care and mental health providers' words and context, and their potential impact on the course of illness and well-being.

Topics: Adult; Female; Humans; Male; Middle Aged; Naloxone; Narcotic Antagonists; Opioid Peptides; Pain; Pain Measurement; Placebo Effect; Placebos

Topics: Analgesics, Opioid; Animals; Immune System; Immune Tolerance; Lymphokines; Mice; Mice, Inbred BALB C; Morphine; Naloxone; Narcotic Antagonists; Narcotics; Neuroimmunomodulation; Opioid Peptides; Pain; Stress, Physiological; Th1 Cells; Th2 Cells

Nociceptin and its receptor are present in dorsal spinal cord, indicating a possible role for this peptide in pain transmission. The majority of functional studies using behavioral and electrophysiological studies have shown that nociceptin applied at spinal level produces antinociception through pre- and post-synaptic mechanisms. The spinal inhibitory effect of nociceptin is not sensitive to antagonists of opioid receptors such as naloxone. Thus, nociceptin-induced antinociception is mediated by a novel mechanism independent of activation of classic opioid receptors. This has raised the possibility that agonists of the nociceptin receptor may represent a novel class of analgesics. Supporting this hypothesis, several groups have shown that intrathecal nociceptin alleviated hyperalgesic and allodynic responses in rats after inflammation or partial peripheral nerve injury. Electrophysiological studies have also indicated that the antinociceptive potency of spinal nociceptin is maintained or enhanced after nerve injury. It is concluded that the predominant action of nociceptin in the spinal cord appears to be inhibitory. The physiological role of nociceptin in spinal nociceptive mechanisms remains to be defined. Moreover, further evaluation of nociceptin as a new analgesic calls the development of non-peptide brain penetrating agents.

Topics: Analgesics; Animals; Electrophysiology; Mice; Naloxone; Narcotic Antagonists; Nociceptin; Nociceptin Receptor; Opioid Peptides; Pain; Rats; Receptors, Opioid; Receptors, Opioid, mu; Spinal Cord; Vasodilator Agents

The authors report information about endogenous opioid peptides (EOP), receptors, antagonists and their interference with pain, stress, endocrine and immune system. A relationship between EOP and calcium homeostasis, both at extracellular and intracellular level, has been observed. In vitro, beta-endorphin exerts different actions through calcium channel functionality in epithelial cells. In rat aorta and cerebral cortex: beta-endorphin or Naloxone alternatively influence oocyte maturation through the mu-receptor gene expression and intracellular calcium concentration in granulosa and cumulus cells. Calcium channel block is removed by administrating Naloxone and calcium. In vivo, Naloxone and calcium removes EOP induced apoptosis in granulosa cells; is the most safe therapy in cow's milk fever; allow to remove ovarian follicular cysts. A negative influence of opioids on immune response after vaccination was established; EOP-related metabolic problems in post-partum cows. Abnormal intestinal motility, in which a Ca++ influence is well known, can be removed by Naloxone and calcium administration. Calcium-related function and neuromodulation must be re-evaluated since high level of EOP are involved in many pathologies through their influence on calcium activity. The use of calcium salts and Naloxone offers a safe and supplementary therapeutical possibility, active in any condition of altered endogenous opioids.

Topics: Animal Diseases; Animals; Biological Evolution; Calcium Signaling; Endorphins; Female; GTP-Binding Proteins; Hormones; Humans; In Vitro Techniques; Male; Naloxone; Narcotic Antagonists; Opioid Peptides; Pain; Rats; Receptors, Opioid; Stress, Physiological

Acupuncture is an ancient Chinese method to treat diseases and relieve pain. We have conducted a series of studies to examine the mechanisms of this ancient method for pain relief. This article reviews some of our major findings. Our studies showed that acupuncture produces analgesic effect and that electroacupuncture (EA) is more effective than manual acupuncture. Furthermore, electrical stimulation via skin patch electrodes is as effective as EA. The induction and recovering profiles of acupuncture analgesia suggest the involvement of humoral factors. This notion was supported by cross-perfusion experiments in which acupuncture-induced analgesic effect was transferred from the donor rabbit to the recipient rabbit when the cerebrospinal fluid (CSF) was transferred. The prevention of EA-induced analgesia by naloxone and by antiserum against endorphins suggests that endorphins are involved. More recent work demonstrated the release of endorphins into CSF following EA. In addition, low frequency (2 Hz) and high frequency (100 Hz) of EA selectively induces the release of enkephalins and dynorphins in both experimental animals and humans. Clinical studies suggesting its effectiveness for the treatment of various types of pain, depression, anxiety, spinally induced muscle spasm, stroke, gastrointestinal disorders, and drug addiction were also discussed.

Topics: Acupuncture Analgesia; Animals; Brain; Drug Synergism; Electric Stimulation; Electroacupuncture; Endorphins; Humans; Immune Sera; Microinjections; Morphine; Naloxone; Narcotic Antagonists; Nociceptors; Pain; Pain Management; Pain Threshold; Rabbits; Rats; Substance-Related Disorders

These studies were undertaken to investigate the site and nature of the antinociceptive effect of NSAIDs (Non-Steroidal Anti-Inflammatory Drugs) and paracetamol in the central nervous system (CNS).. Different nociceptive test models were employed: the tail-flick and hot-plate tests (thermoreceptors), the writhing test (visceral chemoreceptors) the "scratching, biting, licking" (SBL) behaviour and the colorectal distension test (mechanoreceptors). Drugs were given intraperitoneally (i.p.), intracerebroventricularly (i.c.v.), intrathecally (i.t.) or as local injection via cannulae implanted stereotactically. Nerve destruction was made by local injection of the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT). Whole brain and spinal cord contents of serotonin and 5-hydroxyindole acetic acid (5-HIAA) were analysed by high pressure liquid chromatography (HPLC).. Injections of diclofenac induced antinociception in visceral pain models (writhing test, colorectal distension test), but not in two models of somatosensory pain (tail-flick and hot-plate test). The antinociceptive effect of diclofenac (i.p., i.c.v., or i.t.) was reversed by i.p. naloxone. Naloxone also reversed the effect of diclofenac injected locally into thalamic and hypothalamic areas involved in pain transmission as well as in n. paragigantocellularis or n. raphe magnus. In addition, chemical destruction of the n. raphe region attenuated the antinociceptive effect of diclofenac. Inhibition of serotonergic transmission by pretreatment with methiothepin, ritanserin, parachlorophenylalanine (PCPA) or 5,7-DHT also reduced the antinociceptive effect of diclofenac in a visceral pain model. Pretreatment with diclofenac or ibuprofen blocked pain behaviour (SBL) after activation of excitatory amino acid receptors of the NMDA type, but not pain behaviour after activation of AMPA or substance P (SP) receptors. Paracetamol inhibited hyperalgesia after both NMDA and SP. The antinociceptive effects of diclofenac, ibuprofen and paracetamol were reversed by L-arginine, but not by D-arginine.. The antinociceptive effect of diclofenac involves a central nervous component which may be elicited from several defined areas in the CNS. Part of the antinociceptive effect seems to be mediated by descending inhibitory opioid, serotonin and/or other neurotransmitter systems interfering with visceral pain impulse traffic at the spinal level. NSAIDs and paracetamol interfere with nociception associated with spinal NMDA receptor activation. This effect involves an inhibitory action on spinal nitric oxide (NO) mechanisms. Possibly, the supraspinal antinociceptive effect of NSAIDs may be explained by an analogous action.

Topics: Acetaminophen; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arginine; Behavior, Animal; Brain; Chemoreceptor Cells; Diclofenac; Ibuprofen; Male; Mechanoreceptors; Naloxone; Nociceptors; Pain; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; Receptors, Neurokinin-1; Receptors, Serotonin; Spinal Cord; Thermoreceptors

Topics: Animals; Antibodies; beta-Endorphin; Disease Models, Animal; Endorphins; Immunity, Cellular; Inflammation; Naloxone; Neuroimmunomodulation; Neurons, Afferent; Pain; Pain Threshold; Rats; Receptors, Opioid

Placebo effects have been recognized for a long time, but the underlying mechanisms are unknown. The analgesic effect of placebo has been studied, and one hypothesis is that placebo-induced analgesia is mediated by endorphins. The opiate antagonist naloxone has been used in an attempt to prevent this analgesia. Partial antagonism has been shown, but the placebo still has a considerable analgesic effect. This means that release of endorphins cannot be the only explanation of the analgesia. Patients participating in clinical trials to compare an active drug with a placebo are informed that they may receive the latter. This information leads to a reduction of the effect of the active drug. Possibly the participating patients should not be given this information.

Topics: Analgesics; Animals; Endorphins; Ethics, Medical; Humans; Naloxone; Nociceptors; Norway; Pain; Placebo Effect; Randomized Controlled Trials as Topic

Forty cancer patients were randomly assigned to two groups (n = 20). All had incapacitating pain unresponsive to the usual non opioid analgesic drugs. An epidural catheter was set up at the level of the most painful metamere, and made to pass subcutaneously so as to exit either in the supraclacicular fossa, or on the patient's flank. At T0, the patients were given 4 mg morphine hydrochloride diluted in 10 ml normal saline. Thirty min later, patients in the naloxone group (group N) were given a 0.4 mg bolus, followed by a constant rate infusion of 5 micrograms.kg-1.h-1, of naloxone hydrochloride during 18 h. Patients in group P (placebo) were given normal saline instead. The degree of pain was studied with a visual analogue scale and analgesia was assessed by a clinician on a five point scale. These two parameters were obtained half an hour after the injection of morphine and 2, 4, 6 and 24 hours later. At the same time, the patients were questioned about adverse side-effects: nausea, vomiting, pruritus, dysuria, urinary retention. Respiratory depression was assessed clinically and biologically (blood gas measurements at the afore mentioned times). Heart rate, systolic and diastolic blood pressure were also measured. There was no statistically significant difference between the groups in quality and duration of analgesia. Pain reached its lowest level 4 h after the injection of morphine, returning to half its original value at the 24th h. This was also true for the incidence of nausea (11 in group N, 5 in group P), vomiting (3 in both groups), and urinary retention (6 in group P, 5 in group N).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Analgesia, Epidural; Chronic Disease; Double-Blind Method; Female; Humans; Male; Middle Aged; Morphine; Naloxone; Nausea; Neoplasms; Pain; Pain Measurement; Pruritus; Respiration Disorders; Urinary Retention; Vomiting

Opiates are now known to be important modulators of cardiovascular function in both the normotensive and hypertensive states. There is accumulating evidence that endogenous opiates are elevated in models of hypertension of various etiologies including genetic and renovascular hypertension. Early evidence for elevated opiates in hypertension arose from observations that hypertensive humans and rats with genetic or experimental hypertension exhibited hypoalgesia in various tests of pain sensitivity. Because pain and cardiovascular regulatory systems have in common a number of brain loci, cardiovascular effects of opiates and opiate blockade were studied. These studies have shown that opiate blockade can attenuate the development of hypertension and reduce blood pressure in chronic hypertension possibly via actions on the baroreflexes and/or by modulating the centrally mediated pressor actions of angiotensin II.

Topics: Angiotensin II; Animals; Blood Pressure; Cardiovascular System; Endorphins; Hypertension; Hypertension, Renovascular; Models, Cardiovascular; Naloxone; Narcotics; Pain; Pressoreceptors; Shock

We have attempted to dispel many of the myths and misconceptions surrounding the use of narcotic analgesics in the treatment of childhood pain. Our hope is that an improved understanding and application of effective and safe therapies will minimize the suffering of the child with acute or chronic pain.

Topics: Analgesia, Epidural; Analgesics; Child; Child, Preschool; Codeine; Fentanyl; Humans; Infant; Meperidine; Methadone; Morphine; Naloxone; Narcotics; Pain

Despite ever-increasing popularity as a quick, effective and safe means of pain control, acupuncture is still regarded with some suspicion in conventional medical circles. Nevertheless evidence is accumulating to support a firm physiological basis for its action, a fuller understanding of which will shed light on the essence of pain itself.

Topics: Acupuncture Therapy; Analgesia; Animals; Endorphins; Humans; Naloxone; Neural Pathways; Pain; Serotonin

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Arthritis; Arthritis, Experimental; Benzomorphans; beta-Endorphin; Dynorphins; Endorphins; Enkephalin, Leucine; Enkephalin, Methionine; Morphine; Naloxone; Nociceptors; Pain; Pituitary Gland, Anterior; Protein Precursors; Pyrrolidines; Rats; Receptors, Opioid; Sensory Thresholds; Spinal Cord; Thalamus

Topics: Anti-Anxiety Agents; Brain; Cholestyramine Resin; Histamine H1 Antagonists; Humans; Hypnotics and Sedatives; Naloxone; Neurons, Afferent; Pain; Pruritus; Sensory Receptor Cells; Skin; Spinal Cord; Synaptic Transmission

In the runner study, as measured by tourniquet ischemic pain, exercise stress produced hypoalgesia 20 minutes post-run, followed by hyperalgesia and euphoria at 30 minutes. The hypoalgesia and euphoria were reversed by naloxone. Exercise stress also produced a decrease in P(A), suggesting hypoalgesia to the thermal cutaneous stimulation. However, this analgesia was not naloxone reversible. Nor did exercise stress produce analgesia to cold-pressor pain. In the acupuncture study, noxious electrical stimulation of classical acupuncture sites failed to produce analgesia either during or after stimulation. However, expectation did produce a change in the pain report criterion, but only in the acupunctured arm. Noxious electrical stimulation (TENS) of the median nerve produced no analgesia outside of the related segmental area, that is, acute electrical pain did not produce generalized hypoalgesia. Thus, the effects of the stress produced by noxious electrical stimulation differ from that produced by exercise. In contrast to the results of the acute pain studies, chronic clinical pain, which combines mental stress and pain stress, produced strong hypoalgesia and anesthesia. Again, in contrast to the acute experimental pain studies, the emotional stress of mental illness produces hypoalgesia, but not anesthesia. Finally, the somatosensory system is not the only the sensory system affected by stress. Cold-pressor pain decreases visual sensitivity both during and for a few minutes following stimulation, and does not interfere with short-term (supra-digit span) memory.

Topics: Acupuncture Therapy; Acute Disease; Adult; Back Pain; Chronic Disease; Cold Temperature; Discrimination Learning; Electric Stimulation; Emotions; Female; Hormones; Hot Temperature; Humans; Ischemia; Male; Memory; Mental Disorders; Naloxone; Pain; Physical Exertion; Sensory Thresholds; Stress, Physiological; Visual Perception

Topics: Acupuncture Therapy; Animals; beta-Endorphin; Blood-Brain Barrier; Cats; Circadian Rhythm; Copulation; Electrophysiology; Endorphins; Hot Temperature; Hypophysectomy; Naloxone; Narcotics; Pain; Physical Exertion; Sexual Behavior, Animal; Stress, Physiological

Topics: Animals; Anticonvulsants; Autonomic Nervous System; Blood Pressure; Brain; Diprenorphine; Drug Tolerance; Electroconvulsive Therapy; Electroencephalography; Endorphins; Enkephalin, Leucine; Enkephalin, Leucine-2-Alanine; Enkephalins; Heart Rate; Morphine; Naloxone; Pain; Pituitary Gland; Pressoreceptors; Rats; Receptors, Opioid; Sensory Thresholds; Tritium

Topics: Acute Disease; Anesthesia; Animals; Blood Circulation; Chronic Disease; Endorphins; Halothane; Humans; Ketamine; Naloxone; Pain; Receptors, Opioid; Shock; Sleep; Thiopental

Topics: Acetates; Acetic Acid; Acupuncture Therapy; Analgesia; Animals; Electric Stimulation; Electroshock; Endorphins; Formaldehyde; Haloperidol; Hot Temperature; Hydroxydopamines; Naloxone; Oxidopamine; Pain; Potassium Chloride; Propranolol; Rats; Reserpine; Sensory Thresholds

Topics: Analgesia; Animals; Apomorphine; Catalepsy; Endorphins; Haloperidol; Mice; Naloxone; Pain; Receptors, Dopamine; Stress, Physiological

Topics: Analgesia; Animals; Cold Temperature; Deoxyglucose; Endorphins; Hyperphagia; Hypophysectomy; Hypothalamus; Morphine; Naloxone; Pain; Physical Exertion; Rats; Rats, Brattleboro; Sensory Thresholds; Stress, Physiological; Vasopressins

Topics: Analgesia; Animals; Dexamethasone; Electroshock; Endorphins; Ligation; Mice; Naloxone; Nociceptors; Pain; Physical Exertion; Sensory Thresholds; Spinal Cord; Stress, Physiological; Swimming; Temperature; Time Factors

Topics: Analgesia; Animals; Avoidance Learning; Electroshock; Injections, Spinal; Morphine; Naloxone; Naltrexone; Pain; Rats; Restraint, Physical; Sensory Thresholds; Stress, Physiological; Time Factors

This contribution reviews the practical applications of evoked potentials (EPs) in the evaluation of experimental studies on analgesic intervention in humans. It is also intended as an introduction to EP methodology, its possibilities, and its limitations, for all fellow researchers working in other fields.

Topics: Acupuncture Therapy; Analgesics; Brain; Dental Pulp; Evoked Potentials; Fentanyl; Humans; Naloxone; Nitrous Oxide; Nociceptors; Pain; Placebos

Topics: Acupuncture Therapy; Amino Acids; Analgesics, Opioid; Animals; Differential Threshold; Electric Stimulation; Endorphins; Enkephalins; Humans; Hypnosis; Naloxone; Nitrous Oxide; Pain; Receptors, Opioid

Butorphanol (Stadol) is a synthetic agonist-antagonist analgesic from the 14-hydroxymorphinan series. Animal studies display analgesia, antitussive effects, low gastrointestinal activity, limited respiratory depression, some cardiovascular and skeletal muscle actions, diuresis, slight miosis and opiate antagonism. Butorphanol is metabolized in the liver with renal excretion, yielding a half-life of 3-4 h. Pain relief is good to excellent with parenteral administration in 90% of patients with moderate to severe pain. Surgical anesthetic indications involve preoperative and preinduction supplementation, balanced anesthesia and postoperative pain. Side effects are sedation, nausea, elevated pulmonary vascular pressures and rarely CNS excitation. Limited respiratory depression exists. Butorphanol is a potent analgesic agent with a favorable side effect profile.

Topics: Anesthesia; Animals; Antitussive Agents; Butorphanol; Chemical Phenomena; Chemistry; Depression, Chemical; Diuretics; Dose-Response Relationship, Drug; Humans; Morphinans; Morphine; Naloxone; Nausea; Oxymorphone; Pain; Pulmonary Wedge Pressure; Rats; Respiration; Substance-Related Disorders

The first symposium on endorphins and behavioural processes in Britain was held by the British Psychological Society in March 1985. Against a background of the explosive history of the discovery of endogenous opioids, problems of terminology, and basic mechanisms and concepts, five papers reflect the main fields in which outstanding progress has been made: analgesia, feeding, reward mechanisms, social behaviour and aggression, and addiction. A review of the literature on endorphins and exercise stresses both the value and limitations of trying to unravel a fashionable subject. Endorphin research is multi-disciplinary and highly complex, with tricky technical and conceptual problems and inevitable lack of consensus. Investigators should be more aware of the crucial role that outcomes of behaviour experiments play in the attribution of function to opioid systems.

Topics: Analgesia; Animals; Behavior, Animal; Emotions; Endorphins; Humans; Naloxone; Pain; Physical Exertion; Substance-Related Disorders; Terminology as Topic

Topics: Adrenal Medulla; Analgesia; Animals; Behavior; Blood Pressure; Brain; Cardiovascular Physiological Phenomena; Drug Tolerance; Endocrine Glands; Endorphins; Enkephalins; Female; Humans; Morphine; Naloxone; Pain; Pituitary Gland; Pituitary Hormones, Anterior; Pregnancy; Pro-Opiomelanocortin; Protein Precursors; Protein Processing, Post-Translational; Receptors, Opioid; Shock; Spinal Cord; Stress, Physiological; Tissue Distribution

Endorphinergic neurons certainly play a role in the brain's processing of painful stimuli. Endorphins act to alter pain appreciation at many levels within the central nervous system including spinal cord, midbrain, thalamus, and cortex. The activity of this pain-suppressing system may play a role in individual differences in the experience of pain. Endorphinergic mechanisms play a major role in analgesia associated with stress and acupuncture, and perhaps mediate placebo-induced analgesia. Chronic pain influences endorphinergic function perhaps depleting endorphinergic neurons of their neurotransmitters. Endorphin function and pain sensibility are prominently affected in affective illness and schizophrenia. It may be that endorphinergic neurons play a fundamental role in selective attention--a kind of sensory filtering of information flow--in somatosensory and other sensory modalities.

Topics: Analgesia; Analgesics; Animals; Antidepressive Agents; Attention; Central Nervous System; Circadian Rhythm; Depressive Disorder; Endorphins; Humans; Mice; Naloxone; Neural Pathways; Pain; Schizophrenia; Stress, Physiological; Synaptic Transmission

Topics: Endorphins; Fentanyl; Humans; Hydrocortisone; Intraoperative Period; Morphine; Naloxone; Pain; Pain, Postoperative; Physical Exertion; Postoperative Period; Stress, Physiological; Stress, Psychological; Surgical Procedures, Operative

Topics: Analgesia; Animals; Brain Stem; Electric Stimulation; Endorphins; Humans; Morphine; Naloxone; Narcotics; Pain; Rats; Spinal Cord

Topics: Analgesia; Analgesics, Opioid; Animals; Brain; Endorphins; Enkephalins; Humans; Migraine Disorders; Naloxone; Neural Pathways; Norepinephrine; Pain; Receptors, Opioid; Sensory Thresholds; Serotonin; Spinal Cord

Topics: Animals; Anti-Anxiety Agents; Benzodiazepines; Endorphins; gamma-Aminobutyric Acid; Humans; Naloxone; Narcotics; Pain

Topics: Animals; Dopamine; Endorphins; Humans; Hypophysectomy; Naloxone; Neurotransmitter Agents; Norepinephrine; Pain; Receptors, Opioid; Serotonin

Since the discovery of endogenous opioids within the central nervous system much research has been directed towards the demonstration of a physiological control of pain operated by these substances. One way of studying this problem is to challenge the process suspected of being opioid-operated with a specific opiate antagonist, and prior experiments coupled with clinical experience suggested that naloxone was a suitable substance of this type. This short review examines the status of naloxone as an antagonist of endogenous pain control mechanisms and their neuronal correlates, but is not comprehensive. The reader is referred to refs. 4, 29 and 36 for additional detail which space does not allow to be included here.

Topics: Analgesia; Animals; Endorphins; Humans; Naloxone; Neurons; Pain; Rats; Receptors, Opioid

Topics: Animals; Endorphins; Guinea Pigs; Humans; Mice; Naloxone; Pain

Topics: Animals; Endorphins; Enkephalins; Glutamates; Naloxone; Neurons; Pain; Spinal Cord; Substance P; Substantia Gelatinosa

Part III of this review describes the impact that acupuncture, our drug culture, and the gate-control theory have had on our progress in elucidating pain mechanisms and in treating pain syndromes. Whether an analgesis is produced by morphine, acupuncture, or electrical stimulation of an appropriate brain region, the analgesia can be blocked by naloxone, a morphine antagonist. This observation, among others, suggests that similar effector mechanisms involving endogenous opiates serve all three types of analgesia. Although the gate-control theory must continually be revised to accord with new information, it has been a major impetus for stimulating fruitful research.

Topics: Acupuncture Therapy; Analgesia; Animals; Brain; Electric Stimulation Therapy; Humans; Morphine; Naloxone; Pain; Pain Management; Peripheral Nerves; Receptors, Opioid; Substance-Related Disorders; Synapses; Synaptic Transmission

Autoanalgesia (behaviorally-activated antinociception) was elicited by lesion-induced hyperemotionality or the classical conditioning of fear to the environmental stimuli associated with measuring antinociception. Both hyperemotionality and antinociception exhibited parallel decline in septal-lesioned rats with daily handling and in VMH-lesioned rats following treatment with diazepam. Autoanalgesia elicited by conditioned fear was blocked by spinal cord transection but not by diazepam. Although opiate binding experiments suggested the involvement of endorphins as mediators of autoanalgesia, hypophysectomy, morphine tolerance or very high doses of opiate antagonists failed to reduce the antinociception. Electrolytic lesions of the nucleus raphe magnus, a descending serotonergic system, did cause a significant reduction in autoanalgesia. Therefore, endorphin systems may be activated by the stress involved in autoanalgesic paradigms as a parallel system, whose functional integrity is not necessary for the expression of behaviorally-induced antinociception.

Topics: Animals; Central Nervous System; Conditioning, Classical; Diazepam; Electroshock; Emotions; Endorphins; Fear; Hypophysectomy; Hypothalamus; Male; Mice; Naloxone; Naltrexone; Norepinephrine; Pain; Raphe Nuclei; Rats; Reaction Time; Receptors, Opioid; Serotonin; Spinal Cord

Several lines of evidence suggest that the endogenous opioid peptides endorphins may play a role in the defensive response of the organism to stress. The present paper summarizes these findings as well as evidence linking endorphins to the anterior pituitary polypeptide hormone adrenocorticotropin (ACTH). Evidence is presented that endorphins may function as trophic hormones in peripheral target organs such as the adrenal medulla and the pancreas. As such they may be part of the physiological mechanisms that mediate adrenaline and glucagon release in response to stress. Endorphins (enkephalins) are also suggested to play a role in the control of the pituitary gland during stress. In such capacity they may act as hormone-releasing or inhibiting factors. Finally, endorphins appear to play a role in the behavioral concomitants of stress. In such capacity endorphins are suggested to function as modulators of neural systems that mediate the elaboration and expression of the reactive/affective components of stress. Speculations on the mode of interaction between endorphins and ACTH in the global response to stress are discussed.

Topics: Adaptation, Physiological; Adrenal Medulla; Adrenocorticotropic Hormone; Animals; Chemical Phenomena; Chemistry; Emotions; Endorphins; Epinephrine; Glucagon; Humans; Hypothalamo-Hypophyseal System; Insulin; Islets of Langerhans; Naloxone; Pain; Pituitary Gland; Pituitary-Adrenal System; Rats; Receptors, Opioid; Stress, Physiological; Stress, Psychological; Vasopressins

The present review examined the influence of endorphins in animal learning and behavior. It was suggested that in learning paradigms involving stress, the stressor elicits the release of endorphins. Given the evidence on endorphin-mediated, stress-induced analgesia, it was further suggested that the stress-induced release of endorphins modulates the aversiveness of the stressor, and as such, affects the learning based on this stressor. A number of learning paradigms, e.g., the conditioned emotional response, preference for signaled shock, conditioned taste aversions, and learned helplessness, were presented in support of this mediation of learning by the endorphins. A possible interaction between the endorphins and adrenocorticotropic hormone was offered as a physiological basis for this mediation.

Topics: Adrenocorticotropic Hormone; Animals; Avoidance Learning; Behavior, Animal; Conditioning, Classical; Cues; Electroshock; Emotions; Endorphins; Learning; Lithium; Naloxone; Pain; Rats; Receptors, Opioid; Saccharin; Sensory Thresholds; Stress, Physiological; Taste; Toxins, Biological

Extensive evidence has indicated that distinct neural systems specifically designed to inhibit sensitivity to painful stimuli exist. Recent advances suggest that the endorphins, enkephalins and the opiate receptor interact with a descending serotonergic bulbospinal system to mediate the analgesic responses to opiates and electrical stimulation. In assessing the evolutionary and behavioral significance of this pain-inhibitory system, several laboratories discovered that acute exposure to a wide variety of stressful events results in a transient analgesia. Chronic exposure to a number of these stressors results in adaptation of the analgesic response. The purpose of this review is to identify and characterize the mechanisms by which these stressors activate pain-inhibition. The relationship of stress-induced analgesia to each of the following is reviewed: (a) the role of endorphins, enkephalins and the opiate receptor; (b) the role of the descending serotonergic bulbospinal system; (c) the role of the pituitary gland; and (d) the role of hypothalamic mechanisms. Data will be discussed in terms of "opiate" and "non-opiate" pain-inhibitory mechanisms, in which some stressors act through the former and other stressors act through the latter.

Topics: Analgesia; Animals; Central Nervous System; Deoxyglucose; Drug Synergism; Drug Tolerance; Efferent Pathways; Hormones; Hypothalamus; Mesencephalon; Morphine; Naloxone; Pain; Pituitary Gland; Raphe Nuclei; Rats; Sensory Thresholds; Serotonin; Spinal Cord; Stress, Physiological; Substantia Gelatinosa

Topics: Acupuncture Therapy; Afferent Pathways; Animals; Cats; Electric Stimulation; Enkephalins; Hot Temperature; Humans; Naloxone; Nociceptors; Pain

Topics: Animals; Electric Stimulation; Endorphins; Humans; Naloxone; Pain; Receptors, Opioid

The anatomy, physiology, and pharmacology of an intrinsic neural network that monitors and modulates the activity of pain-transmitting neurons is reviewed. This system can be activated by opiate administration or by electrical stimulation of discrete brainstem sites. Evidence is presented that its pain-suppressing action is mediated in part by endogenous opiatelike compounds (endorphins). This pain suppression system is organized at three levels of the neuraxis: midbrain, medulla, and spinal cord. Activation of neurons in the midbrain periaqueductal gray matter (by electrical stimulation, opiates, and possibly psychological factors) excites neurons of the rostral medulla, some of which contain serotonin. The medullary neurons, in turn, project to and specifically inhibit the firing of trigeminal and spinal pain-transmission neurons. As part of a negative feedback loop, the output of the pain transmission neurons, i.e., pain itself, is an important factor in activating the pain-suppression system. A neural model which incorporates the experimental findings is proposed, and the clinical implications of the model are discussed.

Topics: Analgesia; Animals; Biogenic Amines; Brain; Brain Stem; Cats; Electric Stimulation; Enkephalins; Humans; Models, Neurological; Naloxone; Narcotics; Neural Inhibition; Neural Pathways; Pain; Raphe Nuclei; Rats; Serotonin; Spinal Cord; Spinal Cord Diseases; Synaptic Transmission

Topics: Afferent Pathways; Animals; Brain; Brain Mapping; Cats; Electric Stimulation; Endorphins; Enkephalins; Humans; Mice; Naloxone; Neural Inhibition; Nociceptors; Pain; Pain, Intractable; Rats; Spinal Cord; Spinothalamic Tracts; Substance P; Substantia Gelatinosa

Topics: Analgesia; Animals; Brain; Dopamine; Electric Stimulation; Humans; Medial Forebrain Bundle; Mesencephalon; Models, Neurological; Morphine; Naloxone; Norepinephrine; Pain; Serotonin; Synaptic Transmission

The cold pressor test (CPT) is widely implemented and offers a simple, experimental acute pain model utilizing cold pain. Previous trials have frequently paired the CPT with opioids in order to investigate the mechanisms underlying pharmacological analgesia, due to their known analgesic efficacy. However, opioid side effects may lead to unblinding and raise concerns about the safety of the experimental setting. Despite the established clinical efficacy of dipyrone (metamizole), its efficacy, tolerability, and safety in cold pressor pain has not been systematically addressed to date. This pooled analysis included data of 260 healthy volunteers from three randomized, placebo-controlled, double-blind substudies using the CPT following a pre-test-post-test-design. These substudies allow for comparing a single dose of 800 mg dipyrone with two different doses of the opioid tilidine/naloxone (50/4 mg and 100/8 mg, respectively). Outcomes included pain intensity ratings, pain tolerance, medication-attributed side effects, as well as changes of blood pressure and heart rate. We demonstrate that both opioid doses and dipyrone had a comparable, significant analgesic effect on cold pressor pain. However, dipyrone was associated with significantly less self-reported adverse effects and these were not significantly different from those under placebo. These results indicate that the combination of dipyrone and the CPT provides a safe, tolerable, and effective experimental model for the study of pharmacological analgesia. In combination with a CPT, dipyrone may be useful as a positive control, or baseline medication for the study of analgesic modulation.

Topics: Adult; Analgesics, Opioid; Anti-Inflammatory Agents, Non-Steroidal; Cold Temperature; Dipyrone; Double-Blind Method; Female; Healthy Volunteers; Humans; Male; Naloxone; Pain; Pain Measurement; Tilidine; Treatment Outcome; Young Adult

The endogenous opioidergic system is critically involved in the cognitive modulation of pain. Slow-breathing-based techniques are widely used nonpharmacological approaches to reduce pain. Yet, the active mechanisms of actions supporting these practices are poorly characterized. Growing evidence suggest that mindfulness-meditation, a slow-breathing technique practiced by nonreactively attending to breathing sensations, engages multiple unique neural mechanisms that bypass opioidergically mediated descending pathways to reduce pain. However, it is unknown whether endogenous opioids contribute to pain reductions produced by slow breathing. The present double-blind, placebo-controlled crossover study examined behavioral pain responses during mindfulness-meditation (n = 19), sham-mindfulness meditation (n = 20), and slow-paced breathing (n = 20) in response to noxious heat (49°C) and intravenous administration (0.15 mg/kg bolus + 0.1 mg/kg/hour maintenance infusion) of the opioid antagonist, naloxone, and placebo saline. Mindfulness significantly reduced pain unpleasantness ratings across both infusion sessions when compared to rest, but not pain intensity. Slow-paced breathing significantly reduced pain intensity and unpleasantness ratings during naloxone but not saline infusion. Pain reductions produced by mindfulness-meditation and slow-paced breathing were insensitive to naloxone when compared to saline administration. By contrast, sham-mindfulness meditation produced pain unpleasantness reductions during saline infusion but this effect was reversed by opioidergic antagonism. Sham-mindfulness did not lower pain intensity ratings. Self-reported "focusing on the breath" was identified as the operational feature particularly unique to the mindfulness-meditation and slow paced-breathing, but not sham-mindfulness meditation. Across all individuals, attending to the breath was associated with naloxone insensitive pain-relief. These findings provide evidence that slow breathing combined with attention to breath reduces pain independent of endogenous opioids.

Topics: Adult; Analgesics, Opioid; Cross-Over Studies; Humans; Mindfulness; Naloxone; Pain; Pain Management

Severe chronic postsurgical pain has a prevalence of 4-10% in the surgical population. The underlying nociceptive mechanisms have not been well characterized. Following the late resolution phase of an inflammatory injury, high-dose μ-opioid-receptor inverse agonists reinstate hypersensitivity to nociceptive stimuli. This unmasking of latent pain sensitization has been a consistent finding in rodents while only observed in a limited number of human volunteers. Latent sensitization could be a potential triggering venue in chronic postsurgical pain. The objective of the present trial was in detail to examine the association between injury-induced secondary hyperalgesia and naloxone-induced unmasking of latent sensitization. Healthy volunteers (n = 80) received a cutaneous heat injury (47°C, 420 s, 12.5 cm2). Baseline secondary hyperalgesia areas were assessed 1 h post-injury. Utilizing an enriched enrollment design, subjects with a magnitude of secondary hyperalgesia areas in the upper quartile ('high-sensitizers' [n = 20]) and the lower quartile ('low-sensitizers' [n = 20]) were selected for further study. In four consecutive experimental sessions (Sessions 1 to 4), the subjects at two sessions (Sessions 1 and 3) received a cutaneous heat injury followed 168 h later (Sessions 2 and 4) by a three-step target-controlled intravenous infusion of naloxone (3.25 mg/kg), or normal saline. Assessments of secondary hyperalgesia areas were made immediately before and stepwise during the infusions. Simple univariate statistics revealed no significant differences in secondary hyperalgesia areas between naloxone and placebo treatments (P = 0.215), or between 'high-sensitizers' and 'low-sensitizers' (P = 0.757). In a mixed-effects model, secondary hyperalgesia areas were significantly larger following naloxone as compared to placebo for 'high-sensitizers' (P < 0.001), but not 'low-sensitizers' (P = 0.651). Although we could not unequivocally demonstrate naloxone-induced reinstatement of heat injury-induced hyperalgesia, further studies in clinical postsurgical pain models are warranted.

Topics: Hot Temperature; Humans; Hyperalgesia; Infusions, Intravenous; Male; Naloxone; Narcotic Antagonists; Nociception; Pain; Young Adult

The easily performed "cough-trick" (CT) reduces pain during venipuncture (VP), although the underlying mechanism remains unclear. The aim was to investigate the pain-reducing effect of CT during VP in comparison with two distraction methods, as well as under the influence of naloxone.. 54 healthy male volunteers participated in 3 investigations. Pain during standardized VP with CT was compared to a "weak" distraction (squeezing a rubber ball; investigation 1;. Pain intensity at VP with CT was lower than under "weak" distraction (mean difference 5 mm; 95% CI: 0.5 to 9.6;. Pain-reducing effect of CT during VP is superior to that of simple motor distraction and equivalent to a complex distraction method. This might be due to the activation of segmental pain inhibitory pathways during coughing indicated through the lack of pain reduction due to CT under opioid antagonist blockage.

Topics: Adult; Attention; Cough; Cross-Over Studies; Double-Blind Method; Healthy Volunteers; Humans; Male; Naloxone; Pain; Pain Management; Phlebotomy; Young Adult

To evaluate thermal antinociception from intravenous (IV) administration of hydromorphone alone or followed by butorphanol or naloxone in cats.. Randomized, controlled, masked, crossover design.. A group of eight adult female cats.. Cats were administered six treatments of two IV injections 30 minutes apart: treatments S-S, two 0.9% saline; H-S, hydromorphone (0.1 mg kg. Data from seven cats were analyzed. There were no significant differences among treatments in baseline values, SS and within S-S over time. Compared with respective 0.5 hour values following hydromorphone administration, %MPE was significantly lower at 4-8 hours for H-S; at 3-8 hours for H-LB; at 4-8 hours for H-MB; at 6-8 hours for H-HB and at 1-8 hours for H-N. Compared with respective 0.5 hour values, TE was significantly lower at 4-8 hours for H-S; at 3-8 hours for H-LB; at 2 and 4-8 hours for H-MB; at 6 and 8 hours for H-HB and at 1-8 hours for H-N.. Butorphanol and naloxone reduced hydromorphone-induced thermal antinociception. Butorphanol preserved hydromorphone antinociceptive properties better than naloxone. Butorphanol is recommended during non-life-threatening scenarios as a partial reversal agent for hydromorphone in cats.

Topics: Administration, Intravenous; Analgesics, Opioid; Animals; Butorphanol; Cats; Cross-Over Studies; Drug Therapy, Combination; Female; Hydromorphone; Naloxone; Pain; Pain Measurement; Random Allocation; Skin Temperature

This study aimed to develop a model for pharmacodynamic and pharmacokinetic studies of naloxone antagonism under steady-state opioid agonism and to compare a high-concentration/low-volume intranasal naloxone formulation 8 mg/ml to intramuscular 0.8 mg.. Two-way crossover in 12 healthy volunteers receiving naloxone while receiving remifentanil by a target-controlled infusion for 102 min. The group were subdivided into three different doses of remifentanil. Blood samples for serum naloxone concentrations, pupillometry and heat pain threshold were measured.. The relative bioavailability of intranasal to intramuscular naloxone was 0.75. Pupillometry showed difference in antagonism; the effect was significant in the data set as a whole (p < 0.001) and in all three subgroups (p < 0.02-p < 0.001). Heat pain threshold showed no statistical difference.. A target-controlled infusion of remifentanil provides good conditions for studying the pharmacodynamics of naloxone, and pupillometry was a better modality than heat pain threshold. Intranasal naloxone 0.8 mg is inferior for a similar dose intramuscular. Our design may help to bridge the gap between studies in healthy volunteers and the patient population in need of naloxone for opioid overdose.. clinicaltrials.gov : NCT02307721.

Topics: Administration, Intranasal; Adult; Analgesics, Opioid; Cross-Over Studies; Female; Healthy Volunteers; Humans; Injections, Intramuscular; Male; Miosis; Models, Biological; Naloxone; Narcotic Antagonists; Pain; Piperidines; Pupil; Remifentanil; Young Adult

The inclusion of naloxone with oxycodone in a fixed combination prolonged-release formulation (OXN PR) improves bowel function compared with oxycodone (Oxy) alone without compromising analgesic efficacy. In a recent 5-week, randomized, double-blind comparative trial of OXN PR and OxyPR, it could be shown that the beneficial properties of OXN PR extend to doses up to 160/80 mg.. Bowel function, pain, quality of life (QoL) and safety of OXN PR up to 180/90 mg daily were evaluated in a 24-week open-label extension phase of the 5-week randomized comparative study in patients with non-malignant or malignant pain requiring opioids and suffering from opioid-induced constipation.. During treatment with a mean (SD) daily dose OXN PR of 130.7 (26.56) mg (median, maximum: 120 and 180 mg), the Bowel Function Index (BFI) decreased from 45.3 (26.37) to 26.7 (21.37) with the largest decrease seen in the first week. The average pain over the last 24 h remained stable (median Pain Intensity Scale score 4.0) and QoL was maintained throughout the study. Adverse events were consistent with the known effects of OXN PR and no new safety concerns emerged. Equivalent efficacy and safety benefits were observed in cancer patients.. The OXN PR in doses up to 180/90 mg provides effective analgesia with maintenance of bowel function during long-term treatment. The beneficial effects of such dose levels of OXN PR contribute to stable patient-reported QoL and health status despite serious underlying pain conditions, such as cancer.. In patients with pain requiring continuous opioid therapy at doses above 80 mg of oxycodone, stable and effective long-term analgesia can be achieved using OXN PR up to 180/90 mg daily without compromising bowel function and may be preferential to supplemental oxycodone.

Topics: Adult; Aged; Aged, 80 and over; Analgesics, Opioid; Constipation; Delayed-Action Preparations; Double-Blind Method; Drug Combinations; Female; Humans; Male; Middle Aged; Naloxone; Oxycodone; Pain; Pain Management; Pain Measurement; Quality of Life; Treatment Outcome; Young Adult

Mindfulness meditation, a cognitive practice premised on sustaining nonjudgmental awareness of arising sensory events, reliably attenuates pain. Mindfulness meditation activates multiple brain regions that contain a high expression of opioid receptors. However, it is unknown whether mindfulness-meditation-based analgesia is mediated by endogenous opioids. The present double-blind, randomized study examined behavioral pain responses in healthy human volunteers during mindfulness meditation and a nonmanipulation control condition in response to noxious heat and intravenous administration of the opioid antagonist naloxone (0.15 mg/kg bolus + 0.1 mg/kg/h infusion) or saline placebo. Meditation during saline infusion significantly reduced pain intensity and unpleasantness ratings when compared to the control + saline group. However, naloxone infusion failed to reverse meditation-induced analgesia. There were no significant differences in pain intensity or pain unpleasantness reductions between the meditation + naloxone and the meditation + saline groups. Furthermore, mindfulness meditation during naloxone produced significantly greater reductions in pain intensity and unpleasantness than the control groups. These findings demonstrate that mindfulness meditation does not rely on endogenous opioidergic mechanisms to reduce pain.. Endogenous opioids have been repeatedly shown to be involved in the cognitive inhibition of pain. Mindfulness meditation, a practice premised on directing nonjudgmental attention to arising sensory events, reduces pain by engaging mechanisms supporting the cognitive control of pain. However, it remains unknown if mindfulness-meditation-based analgesia is mediated by opioids, an important consideration for using meditation to treat chronic pain. To address this question, the present study examined pain reports during meditation in response to noxious heat and administration of the opioid antagonist naloxone and placebo saline. The results demonstrate that meditation-based pain relief does not require endogenous opioids. Therefore, the treatment of chronic pain may be more effective with meditation due to a lack of cross-tolerance with opiate-based medications.

Topics: Adult; Analgesics, Opioid; Analysis of Variance; Double-Blind Method; Female; Healthy Volunteers; Hot Temperature; Humans; Male; Meditation; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Psychophysics; Treatment Outcome; Young Adult

Mu-opioid-receptor antagonists have been extensively studied in experimental research as pharmacological tools uncovering mechanisms of pain modulation by the endogenous opioid system. In rodents, administration of high doses of mu-opioid-receptor antagonists after the resolution of an inflammatory injury has demonstrated reinstatement of nociceptive hypersensitivity indicating unmasking of latent sensitization. In a recent human study, pain hypersensitivity assessed as secondary hyperalgesia area (SHA), was reinstated 7 days after a mild thermal injury, in 4 out of 12 subjects after a naloxone infusion.The aims of the present study are first, to replicate our previous findings in a larger-sized study; second, to examine if high sensitizers (subjects presenting with large SHA after a thermal injury) develop a higher degree of hypersensitivity after naloxone challenge than low sensitizers (subjects presenting with restricted SHA after a thermal injury); and third to examine a dose-response relationship between 3 stable naloxone concentrations controlled by target-controlled infusion, and the unmasking of latent sensitization.Healthy participants (n = 80) underwent a screening day (day 0) with induction of a thermal skin injury (47°C, 420 seconds, 12.5 cm). Assessment of SHA was performed 1 and 2 hours after the injury. Using an enriched design, only participants belonging to the upper quartile of SHA (Q4, high sensitizers; n = 20) and the lower quartile of SHA (Q1, low sensitizers; n = 20) continued the study, comprising 4 consecutive days-days 1 to 4. Thermal skin injuries were repeated on day 1 and day 3, whereas day 2 and day 4 (7 days after day 1 and day 3, respectively) were target-controlled infusion days in which the subjects were randomly allocated to receive either naloxone (3.25 mg/kg, 4 mg/mL) or placebo (normal saline) intravenous. The primary outcome was SHA assessed by weighted-pin instrument (128 mN) 0, 1, 2, and 165 to 169 hours after the thermal injury (day 1-4). The secondary outcomes were pin-prick pain thresholds assessed by weighted-pin instrument (8-512 mN) at primary and secondary hyperalgesia areas (days 1-4).The naloxone-induced unmasking of latent sensitization is an interesting model for exploring the transition from acute to chronic pain. The results from the present study may provide valuable information regarding future research in persistent postsurgical pain states.

Topics: Adult; Burns; Cross-Over Studies; Denmark; Double-Blind Method; Humans; Hyperalgesia; Infusions, Intravenous; Male; Naloxone; Narcotic Antagonists; Pain; Pain Management; Pain Measurement; Pain Threshold

An international double-blind randomized placebo controlled study evaluated the safety and efficacy of four doses of a new sustained release naloxone capsule to treat Opioid Induced Constipation (OIC).. Forty patients taking opioids for noncancer related pain, and experiencing OIC, were randomized into 4 cohorts of 10 patients. A multiple ascending dose design was used to evaluate the safety and efficacy of 2.5 mg, 5 mg, 10 mg, and 20 mg naloxone sustained release (NSR) capsules vs placebo. Drug was given once-daily for 3 weeks followed by twice daily (bid) dosing between weeks 4 and 6.. The incidence of treatment emergent adverse events was highest in the placebo group. The incidence of adverse events among the four active treatment groups were similar. There were no serious adverse events. The number of severe events was low overall but highest in the placebo group. Significant improvements were seen in Spontaneous Bowel Movements with 5 mg, 10 mg, and 20 mg NSR capsules. Mean change in SBMs from baseline of 2.21 (P = 0.052), 2.37 (P = 0.032); 4.11 (P = 0.0005); 5.19 (<0.0001) was noted with NSR 2.5 mg, 5 mg, 10 mg, and 20 mg, respectively, when taken once daily, compared with 1.38 (P = 0.2) for patients on placebo therapy. No changes in subjective or objective measures of opioid withdrawal as measured by the Subjective Opioid Withdrawal Scale or Clinical Opioid Withdrawal Scale were observed. There was no increase in patient reported pain as measured daily using a visual analogue scale.. This Phase II study has shown that using a new sustained release formulation to deliver oral naloxone to the colon allows successful treatment of OIC without comprising the desired opioid effects.

Topics: Adult; Aged; Analgesics, Opioid; Cohort Studies; Constipation; Defecation; Delayed-Action Preparations; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Middle Aged; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Patient Satisfaction; Quality of Life; Substance Withdrawal Syndrome

Pain is a common non-motor symptom of Parkinson's disease. We investigated the analgesic efficacy of prolonged-release oxycodone-naloxone (OXN PR) in patients with Parkinson's disease and chronic, severe pain.. We did this phase 2 study in 47 secondary care centres in the Czech Republic, Germany, Hungary, Poland, Romania, Spain, and the UK. We enrolled patients with Hoehn and Yahr Stage II-IV Parkinson's disease, at least one type of severe pain, and an average 24-h pain score of at least 6 (assessed on an 11-point rating scale from 0=no pain to 10=pain as bad as you can imagine). Participants were randomly assigned (1:1) with a validated automated system (block size four) to either oral OXN PR or placebo for 16 weeks (starting dose oxycodone 5 mg, naloxone 2·5 mg, twice daily). Patients and investigators were masked to treatment assignment. The primary endpoint was average 24-h pain score at 16 weeks in the full analysis population. This study is registered with EudraCT (2011-002901-31) and ClinicalTrials.gov (NCT01439100).. We enrolled 202 patients; 93 were assigned to OXN PR and 109 to placebo; the full analysis population consisted of 88 patients versus 106 patients. Least squares mean average 24-h pain score at 16 weeks in the full analysis population was 5·0 (95% CI 4·5 to 5·5) in the OXN PR group versus 5·6 (5·1 to 6·0) in the placebo group (difference -0·6, 95% CI -1·3 to 0·0; p=0·058). Similar proportions of patients in each group had adverse events (60/92 [65%] vs 76/109 [70%]), treatment-related adverse events (52/92 [57%] vs 62/109 [57%]), and serious adverse events (5/92 [5%] vs 7/109 [6%]). Treatment-related nausea was more common in the OXN PR group than in the placebo group (16/92 [17%] vs 10/109 [9%]), as was treatment-related constipation (16/92 [17%] vs 6/109 [6%]).. The primary endpoint, based on the full analysis population at week 16, was not significant. Nonetheless, the results of this study highlight the potential efficacy of OXN PR for patients with Parkinson's disease-related pain and might warrant further research on OXN PR in this setting.. Mundipharma Research.

Topics: Aged; Analgesics, Opioid; Delayed-Action Preparations; Double-Blind Method; Drug Combinations; Female; Humans; Male; Middle Aged; Naloxone; Oxycodone; Pain; Parkinson Disease; Treatment Outcome

Endogenous opioids have been implicated in mediating (placebo) analgesia, in reward processes, and in the regulation of socially relevant emotions. To explore their potential contributions to higher cognitive functions, we used a novel task with tachistoscopically presented (for 150 ms) pairs of meaningless figures. Healthy right-handed men judged the similarities and dissimilarities between the two figures on a visual analogue scale (VAS) in two separate runs. In a double-blind, between-subjects design, subjects were administered intravenously either 0.2-mg/kg naloxone or placebo 10 min prior to the task, and VAS judgments and response latencies were measured. We found a significant interaction between substance group and type of judgment: The magnitude of the similarity judgments was lower in the naloxone than in the placebo group, while dissimilarity judgments remained uninfluenced by the treatment. Reaction latencies and mood scores, assessed before and after substance administration, did not differ between the two groups, indicating that the findings did not rely on altered motor performance or motivation. We suggest that naloxone decreased the "similarity criterion" in comparative judgments, indicating its potentially modulatory effect on visual cognition. The task introduced here could be used for the implicit study and quantification of subtle affective-cognitive processes beyond the level of mere questionnaire data.

Topics: Adult; Cognition; Double-Blind Method; Emotions; Humans; Injections, Intravenous; Judgment; Male; Naloxone; Narcotic Antagonists; Pain; Photic Stimulation; Reaction Time; Surveys and Questionnaires; Visual Perception; Young Adult

Predictors of responsiveness to opioid analgesic medications are not well understood. This study tested whether individual differences in endogenous opioid (EO) function are associated with analgesic responsiveness to morphine. In randomized, counterbalanced order over 3 sessions, 45 chronic low back pain participants and 31 healthy controls received an opioid antagonist (8 mg naloxone), morphine (0.08 mg/kg), or placebo. Participants then engaged in 2 laboratory-evoked pain tasks (ischemic and thermal). Outcomes included pain threshold, pain tolerance, and pain ratings. Indexes of EO function and morphine analgesic responsiveness were derived for each measure as the difference in pain responses between the placebo condition and naloxone or morphine condition, respectively. For all 7 pain measures across the 2 laboratory pain tasks, greater EO function was associated with significantly lower morphine analgesic responsiveness (P<0.001-P=0.02). Morphine reduced pain responses of low EO individuals to levels similar to those of high EO individuals receiving placebo. Higher placebo condition-evoked pain sensitivity was associated with significantly greater morphine analgesic responsiveness for 5 of 7 pain measures (P<0.001-P=0.02). These latter associations were significantly mediated by EO function for 4 of these 5 pain outcomes (all P values<0.05). In the laboratory-evoked pain context, opioid analgesic medications may supplement inadequate EO analgesia, with little incremental benefit in those with preexisting high EO function. Implications for personalized medicine are discussed.

Topics: Adult; Analgesics, Opioid; Cross-Sectional Studies; Double-Blind Method; Female; Humans; Hyperalgesia; Male; Middle Aged; Morphine; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Pain Threshold; Physical Stimulation; Statistics, Nonparametric; Young Adult

Previous studies suggest that the antinociceptive action of paracetamol (acetaminophen, APAP) might involve descending inhibitory pain pathways and the opioidergic system: this study explores this issue in humans with naloxone, the opioid antagonist. After ethical approval, 12 healthy male volunteers were included in this randomized, controlled, double-blind, crossover, four-arm study. They were administered intravenous paracetamol (APAP 1 g) or saline (placebo, pl) followed at 100 min with IV naloxone (Nal 8 mg) or saline, every week for 4 weeks. The amplitude of cerebral potentials evoked by thermal/painful stimuli applied on the arm was recorded nine times over 150 min, witnessing of pain integration at central level. Amplitude changes as well as areas under the curve (AUCs) over 150 min were compared for the four treatments by repeated measures ANOVA (significance 0.05). Amplitude changes were significant for APAP/pl vs. pl/pl at t150: -44% (95%CI -58 to -30) vs. -27% (95%CI -37 to -17; P < 0.05) but not vs. APAP/Nal. AUC (0-150) of APAP/pl is significantly different from pl/pl (-3452%.min (95%CI -4705 to -2199) vs. -933% min (95%CI -2273 to 407; P = 0.015) but not from APAP/Nal (-1731% min (95%CI -3676 to 214; P = 0.08) and other treatments. AUC (90-150) is not significantly different. This pilot study shows for the first time in human volunteers that naloxone does not inhibit paracetamol antinociception, suggesting no significant implication of the opioid system in paracetamol mechanism of action: this needs be confirmed on a larger number of subjects.

Topics: Acetaminophen; Adult; Analgesics, Non-Narcotic; Analysis of Variance; Cross-Over Studies; Double-Blind Method; Evoked Potentials; Humans; Injections, Intravenous; Male; Naloxone; Narcotic Antagonists; Pain; Pilot Projects; Prospective Studies; Young Adult

A 20-minute session of 10 Hz repetitive transcranial magnetic stimulation (rTMS) of Brodmann Area (BA) nine of the left dorsolateral prefrontal cortex (DLPFC) can produce analgesic effects on postoperative and laboratory-induced pain. This analgesia is blocked by pretreatment with naloxone, a μ-opioid antagonist. The purpose of this sham-controlled, double-blind, crossover study was to identify the neural circuitry that underlies the analgesic effects of left DLPFC rTMS, and to examine how the function of this circuit, including midbrain and medulla, changes during opioid blockade. Fourteen healthy volunteers were randomized to receive intravenous saline or naloxone immediately before sham and real left DLPFC rTMS on the same experimental visit. One week later, each participant received the novel pretreatment but the same stimulation paradigm. Using short sessions of heat on capsaicin-sensitized skin, hot allodynia was assessed during 3 Tesla functional magnetic resonance imaging (fMRI) scanning at baseline, post-sham rTMS, and post-real rTMS. Data were analyzed using whole-brain voxel-based analysis, as well as time series extractions from anatomically-defined regions of interest representing midbrain and medulla. Consistent with previous findings, real rTMS significantly reduced hot allodynia pain ratings. This analgesia was associated with elevated blood oxygenation-level dependent (BOLD) signal in BAs 9 and 10, and diminished BOLD signal in the anterior cingulate, thalamus, midbrain, and medulla during pain. Naloxone pretreatment largely abolished rTMS-induced analgesia, as well as rTMS-induced attenuation of BOLD signal response to painful stimuli throughout pain processing regions, including midbrain and medulla. These preliminary results suggest that left DLPFC rTMS drives top-down opioidergic analgesia.

Topics: Adolescent; Adult; Analgesia; Brain; Brain Mapping; Cross-Over Studies; Double-Blind Method; Female; Humans; Male; Middle Aged; Naloxone; Narcotic Antagonists; Pain; Pain Management; Pain Measurement; Prefrontal Cortex; Transcranial Magnetic Stimulation

Nalbuphine, an agonist-antagonist kappa-opioid, produces brief analgesia followed by enhanced pain/hyperalgesia in male postsurgical patients. However, it produces profound analgesia without pain enhancement when co-administration with low dose naloxone. To examine the effect of nalbuphine or nalbuphine plus naloxone on activity in brain regions that may explain these differences, we employed pharmacological magnetic resonance imaging (phMRI) in a double blind cross-over study with 13 healthy male volunteers. In separate imaging sessions subjects were administered nalbuphine (5 mg/70 kg) preceded by either saline (Sal-Nalb) or naloxone 0.4 mg (Nalox-Nalb). Blood oxygen level-dependent (BOLD) activation maps followed by contrast and connectivity analyses revealed marked differences. Sal-Nalb produced significantly increased activity in 60 brain regions and decreased activity in 9; in contrast, Nalox-Nalb activated only 14 regions and deactivated only 3. Nalbuphine, like morphine in a previous study, attenuated activity in the inferior orbital cortex, and, like noxious stimulation, increased activity in temporal cortex, insula, pulvinar, caudate, and pons. Co-administration/pretreatment of naloxone selectively blocked activity in pulvinar, pons and posterior insula. Nalbuphine induced functional connectivity between caudate and regions in the frontal, occipital, temporal, insular, middle cingulate cortices, and putamen; naloxone co-admistration reduced all connectivity to non-significant levels, and, like phMRI measures of morphine, increased activation in other areas (e.g., putamen). Naloxone pretreatment to nalbuphine produced changes in brain activity possess characteristics of both analgesia and algesia; naloxone selectively blocks activity in areas associated with algesia. Given these findings, we suggest that nalbuphine interacts with a pain salience system, which can modulate perceived pain intensity.

Topics: Brain; Brain Mapping; Humans; Infusions, Intravenous; Magnetic Resonance Imaging; Male; Nalbuphine; Naloxone; Nerve Net; Organ Specificity; Oxygen; Pain; Psychophysics; Young Adult

Interactions between the sympathetic nervous system and pain are manifold and still have not been sufficiently characterized. Accordingly, several possible neuronal pathways have been described as being involved in mental stress-induced analgesia. We studied the role of the endogenous opioidergic system in stress-induced analgesia in 14 healthy participants in a double-blind cross-over trial. Naloxone or placebo was applied while electrical pain stimulation was started and electrical current increased. After reaching a constant stimulation at 30 mA, a color word interference test (Stroop task) was performed in a stressful and a non-stressful version. Blood pressure, heart rate and baroreflex sensitivity were continuously recorded to assess autonomic activation. Each participant was tested with naloxone and placebo with a randomized and balanced order of trials. The major results are that the opioid-receptor antagonist naloxone prevented (1) stress-induced reduction of tonic current-induced pain, (2) attenuated the simultaneous activation of the sympathetic nervous system, and (3) reduced the counteraction of sympathetic activation by vagal baroreceptor mechanisms. Thus, the opioidergic system not only modulates nociceptive input but also the interplay with vegetative responses. We conclude that acute stress, sympathetic activation and analgesia might be linked via vagal reflexes, which are disturbed when opioid receptors are blocked. This mechanism might underlie increased perception of noxious stimuli in patients with chronic pain or mood disorders.

Topics: Adult; Analgesia; Baroreflex; Behavior; Blood Pressure; Double-Blind Method; Electric Stimulation; Female; Heart Rate; Humans; Male; Naloxone; Narcotic Antagonists; Neuropsychological Tests; Pain; Pain Measurement; Reaction Time; Regional Blood Flow; Stress, Psychological; Stroop Test; Sympathetic Nervous System; Young Adult

Naloxone can enhance the antinociceptive/analgesic effects of buprenorphine in humans and rats. The antinociceptive effects of a patented 15:1 buprenorphine:naloxone combination was investigated in cats using a thermal and mechanical nociceptive model. Twelve cats received buprenorphine 10 μg/kg, naloxone 0.67 μg/kg or a buprenorphine-naloxone combination intramuscularly in a randomised cross over study. Using thermal and mechanical analgesiometry validated in the cat, pre-treatment baselines were measured. Following test drug administration, thresholds were studied for the next 24h. Naloxone did not enhance the thermal antinociceptive effect of buprenorphine. The results from this study are in agreement with previously published work showing that naloxone antagonises the effects of clinically analgesic doses of buprenorphine. Mechanical nociceptive thresholds were not affected by buprenorphine.

Topics: Analgesics, Opioid; Animals; Buprenorphine; Cats; Cross-Over Studies; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Hot Temperature; Male; Naloxone; Narcotic Antagonists; Pain

Recent findings suggest that pain and pleasure share common neurochemical circuits, and studies in animals and humans show that opioid-mediated descending pathways can inhibit or facilitate pain. We explored the role of endogenous opioid neurotransmission in pleasure-related analgesia. μ-Opioidergic activity was blocked with 0.2 mg/kg naloxone to assess its effects on hedonic responses to pleasant emotional pictures (International Affective Picture System) and its modulating effects on heat pain tolerance. Naloxone did not alter subjective and autonomous reactions to pleasure induction or overall mood of participants. In addition, pleasure-related increases in pain tolerance persisted after reversal of endogenous μ-opioidergic neurotransmission. Subjective pain intensity and unpleasantness ratings increased after naloxone administration. These findings suggest that, in addition to opioid-sensitive circuits, mainly opioid-insensitive pain-modulating circuits are activated during pleasure-related analgesia.

Topics: Adult; Affect; Analgesia; Analgesics, Opioid; Analysis of Variance; Arousal; Autonomic Nervous System; Galvanic Skin Response; Heart Rate; Humans; Male; Naloxone; Neural Pathways; Opioid Peptides; Pain; Pain Measurement; Pain Threshold; Photic Stimulation; Pleasure; Surveys and Questionnaires; Synaptic Transmission

Elevated trait anger (TRANG; heightened propensity to experience anger) is associated with greater pain responsiveness, possibly via associations with deficient endogenous opioid analgesia. This study tested whether acute anger arousal moderates the impact of TRANG on endogenous opioid analgesia.. Ninety-four chronic low back pain (LBP) participants and 85 healthy controls received opioid blockade (8 mg of naloxone) or placebo in a randomized, counterbalanced order in separate sessions. Participants were randomly assigned to undergo either a 5-minute anger recall interview (ARI) or a neutral control interview across both drug conditions. Immediately after the assigned interview, participants engaged sequentially in finger pressure and ischemic forearm pain tasks. Opioid blockade effects were derived (blockade minus placebo condition pain ratings) to index opioid antinociceptive function.. Placebo condition TRANG by interview interactions (p values < .05) indicated that TRANG was hyperalgesic only in the context of acute anger arousal (ARI condition; p values < .05). Blockade effect analyses suggested that these hyperalgesic effects were related to deficient opioid analgesia. Significant TRANG by interview interactions (p values < .05) for both pain tasks indicated that elevated TRANG was associated with smaller blockade effects (less endogenous opioid analgesia) only in the ARI condition (p values < .05). Results for ischemic task visual analog scale intensity blockade effects suggested that associations between TRANG and impaired opioid function were most evident in LBP participants when experiencing anger (type by interview by TRANG interaction; p < .05).. Results indicate that hyperalgesic effects of TRANG are most prominent when acute anger is aroused and suggest that endogenous opioid mechanisms contribute.

Topics: Adult; Anger; Arousal; Cross-Over Studies; Double-Blind Method; Female; Humans; Low Back Pain; Male; Naloxone; Narcotic Antagonists; Opioid Peptides; Pain; Pain Measurement; Personality Inventory

Laser-evoked potentials (LEPs) are brain responses to laser radiant heat pulses and reflect the activation of Adelta nociceptors. LEPs are to date the reference standard technique for studying nociceptive pathway function in patients with neuropathic pain. To find out whether LEPs also provide a useful neurophysiological tool for assessing antinociceptive drug efficacy, in this double-blind placebo-controlled study we measured changes induced by the analgesic tramadol on LEPs in 12 healthy subjects. We found that tramadol decreased the amplitude of LEPs, whereas placebo left LEPs unchanged. The opioid antagonist naloxone partially reversed the tramadol-induced LEP amplitude decrease. We conclude that LEPs may be reliably used in clinical practice and research for assessing the efficacy of antinociceptive drugs.

Topics: Adult; Analgesics; Analgesics, Opioid; Cross-Over Studies; Double-Blind Method; Electroencephalography; Evoked Potentials; Female; Humans; Lasers; Male; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Tramadol

This pilot study tested the effectiveness of transcutaneous electric acupoint stimulation (TEAS) as an adjunctive treatment for inpatients receiving opioid detoxification with buprenorphine-naloxone at a private psychiatric hospital. Participants (N = 48) were randomly assigned to active or sham TEAS and received three 30-minute treatments daily for 3 to 4 days. In active TEAS, current was set to maximal tolerable intensity (8-15 mA); in sham TEAS, it was set to 1 mA. By 2 weeks postdischarge, participants in active TEAS were less likely to have used any drugs (35% vs. 77%, p < .05). They also reported greater improvements in pain interference (F = 4.52, p < .05) and physical health (F = 4.84, p < .01) over time. TEAS is an acceptable, inexpensive adjunctive treatment that is feasible to implement on an inpatient unit and may be a beneficial adjunct to pharmacological treatments for opioid detoxification.

Topics: Acupuncture Points; Adolescent; Adult; Analgesics, Opioid; Analysis of Variance; Buprenorphine; Chi-Square Distribution; Combined Modality Therapy; Drug Administration Schedule; Female; Health Status; Humans; Male; Middle Aged; Naloxone; Narcotic Antagonists; Opioid-Related Disorders; Pain; Patient Selection; Substance Withdrawal Syndrome; Survival Analysis; Time Factors; Transcutaneous Electric Nerve Stimulation

Ventilatory depression is a significant risk associated with the use of opioids. We assessed whether opioid-induced ventilatory depression can be selectively antagonized by an ampakine without reduction of analgesia. In 16 healthy men, after a single oral dose of 1,500 mg of the ampakine CX717, a target concentration of 100 ng/ml alfentanil decreased the respiratory frequency by only 2.9 +/- 33.4% as compared with 25.6 +/- 27.9% during placebo coadministration (P < 0.01).Blood oxygenation and the ventilatory response to hypercapnic challenge also showed significantly smaller decreases with CX717 than with placebo. In contrast, CX717 did not affect alfentanil-induced analgesia in either electrical or heat-based experimental models of pain. Both ventilatory depression and analgesia were reversed with 1.6 mg of naloxone. These results support the use of ampakines as selective antidotes in humans to counter opioid-induced ventilatory depression without affecting opioid-mediated analgesia.

Topics: Administration, Oral; Adult; Alfentanil; Analgesics, Opioid; Cross-Over Studies; Double-Blind Method; Humans; Hypercapnia; Isoxazoles; Male; Naloxone; Narcotic Antagonists; Oxygen; Pain; Respiratory Insufficiency; Young Adult

The present investigation examines baseline patient characteristics to predict dosing of buprenorphine-naloxone, a promising treatment for opioid addiction in youths.. This study of 69 opioid-dependent youths is a secondary analysis of data collected during a National Institute on Drug Abuse (NIDA) Clinical Trials Network study. Outpatients aged 15-21 were randomized to a 12-week buprenorphine-naloxone dosing condition (including 4 weeks of taper). Predictors of dosing included sociodemographic characteristics (gender, race, age, and education), substance use (alcohol, cannabis, cocaine, and nicotine use), and clinical characteristics (pain and withdrawal severity).. Most (75.4%) reported having either "some" (n=40, 58.0%) or "extreme" (n=12, 17.4%) pain on enrollment. Maximum daily dose of buprenorphine-naloxone (19.7 mg) received by patients reporting "extreme" pain at baseline was significantly higher than the dose received by patients reporting "some" pain (15.0mg) and those without pain (12.8 mg). In the adjusted analysis, only severity of pain and withdrawal significantly predicted dose. During the dosing period, there were no significant differences in opioid use, as measured by urinalysis, by level of pain.. These data suggest that the presence of pain predicts buprenorphine-naloxone dose levels in opioid-dependent youth, and that patients with pain have comparable opioid use outcomes to those without pain, but require higher buprenorphine-naloxone doses.

Topics: Adolescent; Age Factors; Buprenorphine; Data Interpretation, Statistical; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Humans; Male; Naloxone; Narcotic Antagonists; Narcotics; National Institute on Drug Abuse (U.S.); Opioid-Related Disorders; Outpatients; Pain; Pain Measurement; Socioeconomic Factors; Substance Withdrawal Syndrome; Time Factors; Treatment Outcome; United States; Young Adult

The aim of this study was to assess safety and efficacy of fixed combination oxycodone prolonged release (PR)/naloxone PR in terms of both analgesia and improving opioid-induced bowel dysfunction (OIBD) and associated symptoms, such as opioid-induced constipation (OIC), in adults with chronic non-cancer pain.. These were open-label extension studies in which patients who had previously completed a 12-week, double-blind study received oxycodone PR/naloxone PR for up to 52 weeks. The analgesia study assessed pain using the modified Brief Pain Inventory-Short Form (BPI-SF). The bowel function study assessed improvements in constipation using the Bowel Function Index (BFI).. At open-label baseline in the analgesia study (n = 379), mean score [+/- standard deviation (SD)] for the BPI-SF item 'average pain over the last 24 h' was 3.9 +/- 1.52, and this remained low at 6 months (3.7 +/- 1.59) and 12 months (3.8 +/- 1.72). Mean scores for BPI-SF item 'sleep interference', and the BPI-SF 'pain' and 'interference with activities' subscales also remained low throughout the 52-week study. In the bowel function study (n = 258), mean BFI score (+/- SD) decreased from 35.6 +/- 27.74 at the start of the extension study to 20.6 +/- 24.01 after 12 months of treatment with oxycodone PR/naloxone PR. Pain scores also remained low and stable during this study. Adverse events in both extension phases were consistent with those associated with opioid therapy; no additional safety concerns were observed.. Results from these two open-label extension studies demonstrate the long-term efficacy and tolerability of fixed combination oxycodone PR/naloxone PR in the treatment of chronic pain. Patients experienced clinically relevant improvements in OIBD while receiving effective analgesic therapy.

Topics: Aged; Analgesics, Opioid; Chronic Disease; Constipation; Defecation; Delayed-Action Preparations; Double-Blind Method; Drug Combinations; Female; Humans; Male; Middle Aged; Naloxone; Narcotic Antagonists; Oxycodone; Pain; Pain Measurement; Treatment Outcome

Previous human studies have shown that the analgesic effect of high-frequency TENS could not be reversed by low doses of naloxone. The aim of the present study was to reinvestigate the possible contribution of opioid receptors to high-frequency TENS analgesia by using low (0.02 mg/kg) and high (0.14 mg/kg) doses of naloxone. Naloxone (high and low doses) and saline were administered intravenously to young healthy adults using a triple-blind randomized cross-over design. For each visit, TENS (100 Hz, 60 μs) was applied for 25 min to the external surface of the left ankle. TENS intensity was adjusted to obtain strong but comfortable (innocuous) paresthesias. Experimental pain was evoked with a 1 cm(2) thermode applied on the lateral aspect of the left heel. Subjective pain scores were obtained before, during and after TENS. Because preliminary analyses showed that the order of presentation affected the pattern of results, only the first visit of every participant could be analyzed without fear of contamination from possible carry-over effects. These revealed that TENS maintained its analgesic properties following the injection of saline (p<.001) and the injection of a low dose of naloxone (p<.05). However, when a high dose of naloxone was administered, TENS analgesia was completely blocked (p=.20). These results suggest that high-frequency TENS involves opioid receptors. An insufficient amount of opioid antagonist likely prevented previous human studies from discovering the importance of opioid receptors in producing high-frequency TENS analgesia.

Topics: Adult; Analgesics, Opioid; Biophysics; Cross-Over Studies; Dose-Response Relationship, Drug; Female; Humans; Male; Naloxone; Narcotic Antagonists; Pain; Pain Management; Pain Threshold; Statistics, Nonparametric; Time Factors; Transcutaneous Electric Nerve Stimulation; Young Adult

The endogenous opioid system represents one of the principal systems in the modulation of pain. This has been demonstrated in studies of placebo analgesia and stress-induced analgesia, where anti-nociceptive activity triggered by pain itself or by cognitive states is blocked by opioid antagonists. The aim of this study was to characterize the effect of opioid receptor blockade on the physiological processing of painful thermal stimulation in the absence of cognitive manipulation. We therefore measured BOLD (blood oxygen level dependent) signal responses and intensity ratings to non-painful and painful thermal stimuli in a double-blind, cross-over design using the opioid receptor antagonist naloxone. On the behavioral level, we observed an increase in intensity ratings under naloxone due mainly to a difference in the non-painful stimuli. On the neural level, painful thermal stimulation was associated with a negative BOLD signal within the pregenual anterior cingulate cortex, and this deactivation was abolished by naloxone.

Topics: Adult; Behavior; Brain; Cross-Over Studies; Double-Blind Method; Hot Temperature; Humans; Male; Molecular Imaging; Naloxone; Narcotic Antagonists; Oxygen; Pain; Periaqueductal Gray; Receptors, Opioid

Two randomised 12-week, double-blind, parallel-group, multicenter studies comparing oxycodone PR/naloxone PR and oxycodone PR alone on symptoms of opioid-induced bowel dysfunction in patients with moderate/severe non-malignant pain have been conducted.. These studies were prospectively designed to be pooled and the primary outcome measure of the pooled data analysis was to demonstrate non-inferiority in 12-week analgesic efficacy of oxycodone PR/naloxone PR versus oxycodone PR alone. Patients with opioid-induced constipation were switched to oxycodone PR and then randomised to fixed doses of oxycodone PR/naloxone PR (n = 292) or oxycodone PR (n = 295) for 12 weeks (20-80 mg/day).. No statistically significant differences in analgesic efficacy were observed for the two treatments (p = 0.3197; non-inferiority p < 0.0001; 95% CI -0.07, 0.23) and there was no statistically significant difference in frequency of analgesic rescue medication use. Improvements in Bowel Function Index score were observed for oxycodone PR/naloxone PR by Week 1 and at every subsequent time point (-15.1; p < 0.0001; 95% CI -17.3, -13.0). AE incidence was similar for both groups (61.0% and 57.3% of patients with oxycodone PR/naloxone PR and oxycodone PR alone, respectively).. Results of this pooled analysis confirm that oxycodone PR/naloxone PR provides effective analgesia and suggest that oxycodone PR/naloxone PR improves bowel function without compromising analgesic efficacy.. ClinicalTrials.gov identifier: NCT00412100 and NCT00412152.

Topics: Adult; Aged; Aged, 80 and over; Analgesics, Opioid; Chronic Disease; Clinical Trials as Topic; Constipation; Delayed-Action Preparations; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Naloxone; Narcotic Antagonists; Oxycodone; Pain; Pain Measurement; Patient Discharge; Safety; Treatment Outcome; Young Adult

Opioid-induced constipation can have a major negative impact on patients' quality of life. This randomised, double-blinded study evaluated the analgesic efficacy of prolonged-release (PR) oral oxycodone when co-administered with PR oral naloxone, and its impact on opioid-induced constipation in patients with severe chronic pain. Another objective was to identify the optimal dose ratio of oxycodone and naloxone.. A total of 202 patients with chronic pain (mainly non-cancer related, 2.5% of patients had cancer-related pain) under stable oral oxycodone therapy (40, 60 or 80 mg/day) were randomised to receive 10, 20, 40 mg/day naloxone or placebo. After a 4-week maintenance phase, patients received oxycodone only for 2 weeks. Pain intensity was evaluated using a numerical analogue scale and bowel function was assessed using the bowel function index.. No loss of analgesic efficacy with naloxone was observed. Mean pain intensity scores on randomisation were comparable for placebo, 10mg, 20mg and 40 mg naloxone dose, and remained unchanged during treatment. Bowel function improved with increasing naloxone dose. Naloxone 20mg and 40 mg significantly improved bowel function at the end of the maintenance phase compared with placebo (p<0.05). Overall, the combination was well tolerated, with no unexpected adverse events. There was a trend towards an increased incidence of diarrhoea with higher doses of naloxone. The 2:1 oxycodone/naloxone ratio was identified as the most suitable for further development.. Co-administration of PR oral naloxone and PR oral oxycodone is associated with a significant improvement in bowel function compared with PR oral oxycodone alone, with no reduction in the analgesic efficacy of oxycodone.

Topics: Analgesics, Opioid; Constipation; Delayed-Action Preparations; Double-Blind Method; Female; Humans; Male; Middle Aged; Naloxone; Narcotic Antagonists; Oxycodone; Pain; Pain Measurement

This randomised, double-blind, double-dummy, parallel-group multicentre study assessed the impact of a total daily dose of 60-80 mg oral oxycodone prolonged-release (PR)/naloxone PR (OXN PR) as fixed-ratio combination for patients with opioid-induced constipation (OIC) having moderate-to-severe, non-malignant pain.. During pre-randomisation patients receiving opioids for moderate-to-severe non-malignant pain were converted to oxycodone PR (OXY PR) and titrated to an effective analgesic dose. During randomisation 265 patients on a stable OXY PR dose (60-80 mg/day) and with OIC were included in the full analysis population to receive OXN PR or OXY PR alone. Primary outcome was improvement in symptoms of constipation as measured by the Bowel Function Index (BFI). Secondary/exploratory outcomes examined analgesic efficacy and other bowel function parameters.. After 4 weeks of treatment, patients receiving OXN PR showed a significant improvement in bowel function compared with those in the OXY PR group (-14.9; 95% CI: -17.9, -11.9; p<0.0001) as measured by BFI which was seen after only 1 week of treatment continuing to the end of the study. After 4 weeks of treatment, patients receiving OXN PR had a median number of 3.0 complete spontaneous bowel movements (CSBM) per week compared with only 1.0 for OXY PR alone. Laxative intake was lower in the OXN PR than the OXY PR group. Furthermore, improvements in bowel function were achieved without loss of analgesic efficacy; pain intensity scores were comparable between the groups and consistent for duration of the study. Most frequently reported adverse events were consistent with those reported for opioid analgesics; no new or unexpected adverse reactions attributable to OXN PR used in higher doses were observed.. This study shows that the fixed-ratio combination of OXN PR is superior to OXY PR alone in terms of bowel function, while providing effective equivalent analgesia.

Topics: Analgesics, Opioid; Chronic Disease; Constipation; Delayed-Action Preparations; Drug Combinations; Female; Humans; Male; Middle Aged; Naloxone; Narcotic Antagonists; Oxycodone; Pain; Treatment Outcome

Placebo analgesia involves the endogenous opioid system, as administration of the opioid antagonist naloxone decreases placebo analgesia. To investigate the opioidergic mechanisms that underlie placebo analgesia, we combined naloxone administration with functional magnetic resonance imaging. Naloxone reduced both behavioral and neural placebo effects as well as placebo-induced responses in pain-modulatory cortical structures, such as the rostral anterior cingulate cortex (rACC). In a brainstem-specific analysis, we observed a similar naloxone modulation of placebo-induced responses in key structures of the descending pain control system, including the hypothalamus, the periaqueductal gray (PAG), and the rostral ventromedial medulla (RVM). Most importantly, naloxone abolished placebo-induced coupling between rACC and PAG, which predicted both neural and behavioral placebo effects as well as activation of the RVM. These findings show that opioidergic signaling in pain-modulating areas and the projections to downstream effectors of the descending pain control system are crucially important for placebo analgesia.

Topics: Adult; Analgesia; Analgesics, Opioid; Double-Blind Method; Humans; Male; Naloxone; Pain; Pain Measurement; Placebo Effect; Pyramidal Tracts; Receptors, Opioid; Signal Transduction; Young Adult

The Bowel Function Index (BFI) is a clinician-administered, patient-reported, 3-item questionnaire to evaluate opioid-induced constipation in cancer and non-cancer chronic pain patients. The objective of the present analysis was to evaluate the psychometric characteristics of the BFI using data from clinical studies of oral prolonged release (PR) oxycodone/naloxone.. OXN2401 was a multicenter, controlled, randomized, double-blind, parallel-group study including oral PR oxycodone combined with oral PR naloxone as well as oral PR oxycodone combined with corresponding naloxone placebo. OXN3401 and OXN3001 were 12-week multicenter, controlled, randomized, double-blind, parallel-group studies of a fixed combination of oral PR oxycodone/naloxone versus PR oxycodone. In addition, a placebo group was included in study OXN3401. BFI psychometric characteristics (reliability, reproducibility, convergent/known groups validity, and responsiveness) were evaluated.. Demographic data (n=985) were comparable and analyses indicated a high degree of internal consistency (Cronbach's alpha >0.7). Change of less than 5 points in BFI was indicative of high reproducibility. Correlations between BFI item and total scores to stool frequency were statistically significant and in the low-to-moderate range (OXN2401 -0.23 to -0.29, p < 0.001; OXN3401 range -0.26 to -0.40, p < 0.001; OXN3001 -0.14 to -0.15, p < 0.05). Data indicate that a BFI score change of ≥12 points represents a clinically meaningful change in constipation.. This publication for validation of BFI only includes data from three clinical trials. However, another publication of an additional specifically designed cross-sectional validation study is in preparation.. The BFI is a valid and reliable instrument for the assessment of opioid-induced constipation in chronic pain patients. Psychometric analyses from clinical trials support the BFI's psychometric properties.

Topics: Analgesics, Opioid; Chronic Disease; Constipation; Delayed-Action Preparations; Diagnostic Self Evaluation; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Naloxone; Narcotic Antagonists; Oxycodone; Pain; Reproducibility of Results; Severity of Illness Index; Surveys and Questionnaires

Patients with sickle cell disease experience painful crises that often require hospitalization for a continuous infusion of morphine that may cause significant pruritus. We conducted a pilot study to determine the feasibility of simultaneous continuous co-infusion of naloxone with morphine, test novel assessment instruments for pruritus, and explore whether pruritus could be reduced while maintaining effective analgesia. Patients with sickle cell disease and painful crisis requiring continuous infusion morphine received continuous co-infusion of naloxone at 0.25 (low dose) or 1.0 mcg/kg x hr (high dose). Pain scores were obtained using the FACES scale and a 100-mm visual analog scale (VAS). Itching was quantified by a modified VAS score. Evaluable data were obtained on 16 patients. Simultaneous co-infusion of naloxone and morphine was feasible, did not seem to reduce the analgesic efficacy of morphine, and was associated with no adverse effects. The high dose group reported a lower median "VAS worst itch" score than the low dose group (4.8 vs. 7.3, P = 0.08). Simultaneous continuous infusion of naloxone with morphine in pediatric patients with sickle cell disease and pain crisis was feasible and well tolerated. A quantitative pruritus score allowed us to systematically measure pruritus. Further evaluation by randomized, placebo-controlled study of 1 mcg/kg x hr naloxone in this setting is required.

Topics: Adolescent; Anemia, Sickle Cell; Child; Drug Therapy, Combination; Female; Humans; Hyperalgesia; Infusions, Intravenous; Male; Morphine; Naloxone; Narcotic Antagonists; Narcotics; Nausea; Pain; Pain Measurement; Pilot Projects; Pruritus; Vomiting

Opioid-induced constipation can have a major negative impact on patients' quality of life. This randomised clinical trial evaluated patient assessment of the efficacy and tolerability of oral prolonged-release (PR) oxycodone when co-administered with oral naloxone PR.. Two hundred and two patients with chronic cancer- or non-cancer-related pain undergoing stable oxycodone PR therapy (40, 60 or 80 mg/day) were randomised to one of four intervention groups: 10, 20 or 40 mg/day naloxone PR or placebo. Following a 4-week maintenance phase, patients were followed-up for 2 weeks in which time they received oxycodone PR only. At the end of the maintenance phase, patients and investigators were asked to assess treatment efficacy and tolerability, as well as preference for the titration or maintenance phase.. Patient and investigator global assessment of efficacy and tolerability improved with increasing naloxone dose. Efficacy was ranked as 'good' or 'very good' by 50.0%, 67.4% and 72.5% of patients in the 10, 20 and 40 mg naloxone PR dose groups, respectively, compared with 43.5% of patients in the placebo group. Patient assessment of tolerability was similar between treatment groups and placebo, being ranked as 'good' or 'very good' by 83.3%, 79.1% and 82.5% of patients in the 10, 20 and 40 mg/day naloxone PR dose groups, respectively, compared with 71.7% of patients in the placebo group. The maintenance treatment phase was preferred by patients in the naloxone groups. A 2 : 1 dose ratio of oxycodone to naloxone was also assessed. Efficacy was ranked as 'good' or 'very good' by 70.4% of patients treated with the 2 : 1 dose ratio compared with 43.5% of patients receiving placebo. Tolerability of the 2 : 1 dose ratio was ranked as being 'good' or 'very good' by 81.5% of patients compared with 71.1% for the placebo group and patients preferred the maintenance phase.. The co-administration of oral naloxone PR with oxycodone PR improves patient assessment of analgesic opioid therapy for severe chronic pain, in terms of both efficacy and tolerability.

Topics: Adolescent; Adult; Aged; Analgesics, Opioid; Chronic Disease; Constipation; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Naloxone; Narcotic Antagonists; Oxycodone; Pain; Pain Measurement; Patient Satisfaction; Prospective Studies; Severity of Illness Index; Treatment Outcome

We compared the effects of systemic morphine on normal (heat and cold) pain and paradoxical burning pain evoked by the simultaneous application of innocuous warm and cold stimuli to the skin. Twelve healthy volunteers participated in a randomised, double-blind, cross-over study to compare the effects of intravenous administration of morphine (0.025 or 0.1mg/kg) or placebo (saline). Stimuli were applied to the palm of the right hand with a thermode ("thermal grill") composed of six bars, whose temperatures were controlled by Peltier elements. For each session, we measured the heat and cold pain thresholds and then successively measured the intensity of: (i) paradoxical pain evoked by a combination of non-noxious warm and cold stimuli; (ii) "normal" pain evoked by suprathreshold heat or cold stimuli; (iii) non-painful sensations evoked by warm or cold stimuli at temperatures used to produce paradoxical pain. Measurements were performed before 20min after the administration of morphine or placebo and 5min after the administration of the morphine antagonist, naloxone. The administration of 0.1mg/kg of morphine, but not 0.025mg/kg, induced a significant and naloxone-reversible reduction of paradoxical pain intensity, which was directly correlated with the reduction of normal cold pain. No differences were observed for non-painful thermal sensations. The paradoxical burning pain evoked by a thermal grill can be modified pharmacologically by analgesics and share some mechanisms with normal pain. This unique experimental "illusion of pain" may represent a new model to test analgesics in healthy volunteers.

Topics: Adult; Cold Temperature; Cross-Over Studies; Double-Blind Method; Female; Hand; Hot Temperature; Humans; Illusions; Injections, Intravenous; Male; Morphine; Naloxone; Narcotic Antagonists; Narcotics; Nausea; Pain; Pain Measurement; Pain Threshold; Receptors, N-Methyl-D-Aspartate; Receptors, Opioid; Young Adult

Opioid therapy is frequently associated with treatment-limiting constipation. Naloxone is an opioid antagonist with low oral systemic bioavailability. This Phase III clinical trial assessed the safety and efficacy of an oral fixed-ratio combination of oxycodone prolonged-release (PR) and naloxone PR compared with oxycodone PR in relieving opioid-induced constipation.. This double-blind, multicenter trial was conducted in specialist and primary care centers in four European countries in an out-patients setting. The study included 322 adult patients with moderate-to-severe, noncancer pain requiring opioid therapy in a range of >or=20 mg/day and

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Ambulatory Care; Analgesics, Opioid; Constipation; Delayed-Action Preparations; Double-Blind Method; Drug Combinations; Europe; Female; Humans; Male; Middle Aged; Naloxone; Narcotic Antagonists; Outpatients; Oxycodone; Pain; Primary Health Care

Based on experiments in rats, serotonin receptor 5-hydroxytryptamine (5-HT)(1A) agonists have been proposed as a potential therapeutic strategy for the selective treatment of opioid-induced respiratory depression. We investigated the clinical applicability of this principle in healthy volunteers. Twelve subjects received 0.43 mg/kg morphine (30 mg for 70 kg body weight) administered intravenously (i.v.) over approximately 2 h. At the start of the morphine infusion, they received in a randomized, double-blind cross-over design 60 mg p.o. buspirone or placebo. Respiratory depression (hypercapnic challenge) and pain (electrical stimuli: 5 Hz sinus 0-20 mA; chemical stimuli: 200 ms gaseous CO(2) pulses applied to the nasal mucosa) were assessed at baseline, at the end of the morphine infusion, and a third time after antagonizing the opioid effects by i.v. administration of 2 mg naloxone. The linear relationship between the minute ventilation and the CO(2) concentration in the inspired air of 1.07+/-0.27 l/mm Hg CO(2) at baseline conditions became shallower (0.45+/-0.23 l/mm Hg CO(2)) after morphine administration (P<0.001), indicating respiratory depression, which was significantly reversed by naloxone (0.95+/-0.43 l/mm Hg CO(2); P=0.001). Co-administration of buspirone had no effect on morphine-induced respiratory depression (slope 0.45+/-0.23 l/mm Hg CO(2) under morphine plus placebo versus 0.38+/-0.25 l/mm Hg CO(2) under morphine plus buspirone; P=0.7). Significant morphine-induced analgesia was observed in both pain models and was reversed by naloxone but unaffected by buspirone. Buspirone significantly increased the nausea induced by morphine (P=0.011). Oral co-administration of a high dose of the clinically available 5-HT(1A) agonist buspirone cannot be advised as a remedy for opioid-induced respiratory depression. This is indicated by its lack of anti-respiratory depressive effects and by the buspirone-associated increase of morphine-induced nausea.

Topics: Adult; Analgesics, Opioid; Buspirone; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Injections, Intravenous; Male; Morphine; Naloxone; Narcotic Antagonists; Nausea; Pain; Respiratory Insufficiency; Serotonin 5-HT1 Receptor Agonists

The purpose of the current study was to determine if exercise-induced muscle pain is modulated by central neural mechanisms (i.e. higher brain systems). Ratings of muscle pain perception (MPP) and perceived exertion (RPE), muscle sympathetic nerve activity (MSNA), arterial pressure, and heart rate were measured during fatiguing isometric handgrip (IHG) at 30% maximum voluntary contraction and postexercise muscle ischaemia (PEMI). The exercise trial was performed twice, before and after administration of naloxone (16 mg intravenous; n = 9) and codeine (60 mg oral; n = 7). All measured variables increased with exercise duration. During the control trial in all subjects (n = 16), MPP significantly increased during PEMI above ratings reported during IHG (6.6 +/- 0.8 to 9.5 +/- 1.0; P < 0.01). However, MSNA did not significantly change compared with IHG (7 +/- 1 to 7 +/- 1 bursts (15 s)(-1)), whereas mean arterial blood pressure was slightly reduced (104 +/- 4 to 100 +/- 3 mmHg; P < 0.05) and heart rate returned to baseline values during PEMI (83 +/- 3 to 67 +/- 2 beats min(-1); P < 0.01). These responses were not significantly altered by the administration of naloxone or codeine. There was no significant relation between arterial blood pressure and MSNA with MPP during either IHG or PEMI. A second study (n = 8) compared MPP during ischaemic IHG to MPP during PEMI. MPP was greater during PEMI as compared with ischaemic IHG. These findings suggest that central command modulates the perception of muscle pain during exercise. Furthermore, endogenous opioids, arterial blood pressure and MSNA do not appear to modulate acute exercise-induced muscle pain.

Topics: Adult; Analgesics, Opioid; Blood Pressure; Brain; Codeine; Exercise; Female; Hand Strength; Heart Rate; Humans; Male; Muscle, Skeletal; Naloxone; Narcotic Antagonists; Narcotics; Pain; Perception; Sympathetic Nervous System

The level within the central nervous system where non-steroidal anti-inflammatory drugs (NSAIDs) produce analgesia and the mechanisms by which they mediate this effect are still uncertain. This study assessed the central analgesic effects of ketoprofen, phenylbutazone, salicylic acid and tolfenamic acid in sheep implanted with indwelling intrathecal (i.t.) catheters and submitted to mechanical noxious stimulation. The sheep received i.t. cumulative concentrations (0.375-200 microM; 100 microL) as well as a single intravenous (i.v.) dose (3, 8, 10 and 2 mg/kg, respectively) of each NSAID. The sheep were also given i.t. naloxone (5.49 mM; 100 microL) and atipamezole (4.03 mM; 100 microL) prior to i.v. ketoprofen. None of the i.t. NSAIDs increased mechanical thresholds. Intravenously, only ketoprofen and tolfenamic acid raised the pain thresholds. The hypoalgesic effect of i.v. ketoprofen was prevented by i.t. naloxone or atipamezole. Although NSAIDs had no direct effect on the spinal cord, their analgesic action appeared to be spinally mediated.

Topics: Adrenergic alpha-Antagonists; Animals; Anti-Inflammatory Agents, Non-Steroidal; Dose-Response Relationship, Drug; Female; Imidazoles; Injections, Intravenous; Injections, Spinal; Ketoprofen; Naloxone; Narcotic Antagonists; ortho-Aminobenzoates; Pain; Phenylbutazone; Receptors, Adrenergic, alpha-2; Receptors, Opioid; Salicylic Acid; Sheep

The aim of this study was to compare safety and efficacy of catheter-mediated femoral nerve block analgesia with systemic pain therapy in patients with proximal femoral fractures in the pre-operative and post-operative setting using a protocol for coordinating pain management.. In a prospective randomised trial of patients attending the emergency department, 100 individuals were selected with a clinically diagnosed proximal femoral fracture. Patients were divided into two equal groups A and B. Group A (n=50) received a catheter-mediated femoral nerve block with 1% prilocaine (40 ml) and post-operatively 0.2% ropivacaine (30 ml) 6 hourly. Group B (n=50) initially received intravenous metamizol (1 g) and a fixed combination of oral tilidine (100 mg) + naloxone (8 mg). Patients aged 90 years or more received a reduced dose (tilidine 75 mg + naloxone 6 mg). In the post-operative period regular oral ibuprofen (400 mg, 8 hourly) in addition to oral tilidine (50 mg) + naloxone (4 mg) was given as required for break through pain. Pain intensity was measured using a verbal rating scale (VRS) from 1 to 5: pain free (=1), mild pain (=2), moderate pain (=3), severe pain (=4), excruciating pain (=5). Pain scores were recorded at rest (R), during passive anteflection (30 degrees) of the hip (PA) on arrival and at 15 and 30 min after initial administration of analgesia. Thereafter, recordings were made 4 times a day up to the third post-operative day.. Pain scores were comparable for both groups on admission (VRS in R 2.50 vs. 2.46; VRS during PA 4.30 vs. 4.34). Significant pain relief was achieved in both groups following initial administration of analgesia, but the total pain scores in group A were significantly lower than in group B (VRS in R 1.22 vs. 1.58, p<0.01 and VRS during PA 2.66 vs. 3.26; p<0.001). No difference was noted between the two groups during the first 3 post-operative days. No severe complications occurred as a result of analgesia, however, the catheter was dislodged in 20% of patients in group A resulting in the need for systemically administered analgesia.. All patients presenting with proximal femoral fractures should receive adequate analgesia within the emergency department even prior to radiographic imaging. Femoral nerve block should be considered as the method of choice. The insertion of a femoral nerve block catheter has the dual advantage of early analgesia permitting repeated clinical examination in addition to continued post-operative pain management. The cumbersome logistics inherent in this technique within the clinical setting limits its practical application. An initial single-shot regional nerve block followed by a systemic post-operative analgesia protocol was considered an appropriate alternative. The execution of safe, consistent and appropriate regional nerve block anaesthesia is reliant on formal guidelines and protocols as agreed by the multidisciplinary teams involved with patient-directed pain management and good clinical practice.

Topics: Acute Disease; Aged; Aged, 80 and over; Amides; Analgesics, Opioid; Anesthetics, Local; Catheterization; Female; Femoral Neck Fractures; Femoral Nerve; Humans; Male; Methimazole; Middle Aged; Models, Organizational; Naloxone; Narcotic Antagonists; Nerve Block; Pain; Pain Measurement; Pain, Postoperative; Prilocaine; Prospective Studies; Ropivacaine; Tilidine

There is some evidence from in vitro, animal, and postoperative clinical studies that low doses of opioid antagonists combined with morphine increase analgesia. The theoretical model of this effect posits that ultra-low doses of opioid antagonists selectively antagonize excitatory, but not inhibitory, opioid receptor-mediated signaling. To determine whether this effect occurs in emergency department patients presenting with severe acute pain, we conducted a randomized, double-blind placebo-controlled trial to assess the relative analgesic effect of morphine administered with 3 different doses of naloxone versus morphine alone. Patients received 0.1 mg/kg morphine intravenously (IV) over 2 min plus one of 3 different doses of naloxone (0.1 ng/kg, 0.01 ng/kg, or 0.001 ng/kg) or normal saline. A 0 to 10 numerical rating scale (NRS) was used to measure pain intensity at baseline and every 30 min up to 4 hours. One hundred fifty-six patients with a median NRS of 10 (IQR: 8-10) were studied. There were no clinically or statistically significant differences in the mean pain intensity of patients in the 4 treatment groups over the 4-hour study period, nor were there differences in the administration of additional analgesics or incidence of side effects.. Ultra-low doses of naloxone in the 0.001 ng/kg to 0.1 ng/kg range do not enhance the analgesia provided by morphine alone among emergency department patients with acute, severe pain. This suggests that naloxone in these doses is not an effective adjunct to morphine for control of acute pain.

Topics: Acute Disease; Adult; Aged; Analgesics, Opioid; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Emergency Service, Hospital; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Morphine; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Treatment Failure

We previously developed a spatial summation model and demonstrated that spatial summation of pain involves the activation of both excitatory and inhibitory systems. The aim of this study was to determine whether the endogenous pain inhibitory systems recruited by the spatial summation model are opioid-mediated by verifying if they could be blocked by the opioid antagonist naloxone. Twenty healthy volunteers (10 men, 10 women) participated in a randomized, four-session, cross-over study. Each session consisted of pain perception ratings (visual analog scale) taken during the immersion of different surfaces of the arm in circulating noxious cold water (12 degrees C). The arm was arbitrarily divided into eight segments from fingertips to shoulder. Two sessions were increasing (from fingertips to shoulder) and two sessions were decreasing (from shoulder to fingertips). All sessions consisted of eight consecutive 2-min immersions separated by 5-min resting periods. Intravenous injections of naloxone hydrochloride (0.14 mg/kg) or saline (NaCl, 0.9%) were administered under double-blind conditions. We found that during the control session (saline injection) there was a significant difference in pain intensity ratings between the increasing and decreasing sessions. The decreasing session resulted in lower pain intensity. As previously demonstrated, this lowering of the perception curve seems to be due to a large recruitment of inhibitory systems at the beginning of the decreasing session as opposed to a gradual recruitment during the increasing session. However, during the opioid inhibition session (naloxone injection) no differences were found between the increasing and decreasing sessions. Naloxone inhibited the endogenous pain inhibitory systems activated by the spatial summation model, suggesting that these systems have an opioid-mediated component, as previously reported for diffuse noxious inhibitory controls.

Topics: Adult; Analysis of Variance; Arm; Body Surface Area; Cold Temperature; Cross-Over Studies; Double-Blind Method; Female; Humans; Male; Naloxone; Narcotic Antagonists; Narcotics; Neural Inhibition; Pain; Pain Measurement; Pain Threshold; Perception

When selecting the appropriate long-acting opioid to treat cancer pain, both analgesic efficacy and safety need consideration. Generally, opioids are well tolerated. However, of opioid-typical adverse events, respiratory depression is especially important because of the risk of a fatal outcome. Although all potent opioid analgesics act via the micro-opioid receptor system, they differ in how they affect respiratory control. Recently, the respiratory effects of fentanyl (1 7 microg/kg) and buprenorphine (0.7-9 microg g/kg) were compared in healthy opioid-naïve volunteers. Fentanyl produced dose-dependent depression of respiration with apnoea at doses > or = 3 microg/kg, while buprenorphine caused depression that levelled at approximately 50% of baseline with doses > or = 2 microg/kg. These findings indicate the occurrence of a ceiling in the respiratory depression induced by buprenorphine but not by fentanyl. Surprisingly few studies have addressed the clinically important ability to reverse the respiratory effects of opioids. A recent assessment of the naloxone dose required to reverse 0.2 mg intravenous buprenorphine-induced respiratory depression in healthy opioid-naïve volunteers, found that the accumulated naloxone dose causing 50% reversal of respiratory depression was 1.20 +/- 0.32 mg/70 kg (given in 30 min); 80% reversal was observed at 2.50 +/- 0.60 mg/70 kg (given in 30 min). At greater buprenorphine doses, full reversal is observed when the duration of naloxone infusion is increased. These findings indicate the need for a continuous rather than bolus administration of naloxone to reverse the respiratory effects of buprenorphine. In conclusion, buprenorphine is more favourable compared with fentanyl in respect to ventilatory control. Buprenorphine causes limited respiratory depression with a ceiling effect at higher doses, while fentanyl causes dose-dependent respiratory depression with apnoea at high dose levels. In the rare instance of respiratory depression, reversal is possible with a sufficient and continuous infusion of naloxone.

Topics: Analgesics, Opioid; Apnea; Buprenorphine; Dose-Response Relationship, Drug; Double-Blind Method; Fentanyl; Humans; Naloxone; Narcotic Antagonists; Neoplasms; Pain; Respiratory Insufficiency

It has been demonstrated clearly that sweet-tasting solutions given before a painful intervention can reduce pain among newborns. There is no fully accepted explanation for this effect, but activation of endogenous opioids has been suggested as a possible mechanism. The aim of this study was to obtain deeper knowledge of the underlying mechanism by investigating whether administration of an opioid antagonist would reduce the effect of orally administered glucose at heel stick among term newborns.. A randomized, placebo-controlled, double-blind trial with a validated, neonatal, pain-rating scale.. The trial included 30 term newborns undergoing heel stick, who were assigned randomly to 1 of 2 groups, ie, group I, with naloxone hydrochloride (opioid antagonist) 0.01 mg/kg administered intravenously before oral administration of 1 mL of 30% glucose, or group II, with a corresponding amount of placebo (saline solution) administered intravenously before oral administration of glucose.. Pain-related behavior during blood sampling was measured with the Premature Infants Pain Profile. Crying time and heart rate were also recorded.. The 2 groups did not differ significantly in Premature Infant Pain Profile scores during heel stick. The median crying time during the first 3 minutes was 14 seconds (range: 0-174 seconds) for the naloxone group and 105 seconds (range: 0-175 seconds) for the placebo group. There was no significant difference in heart rate between the 2 groups.. Administration of an opioid antagonist did not decrease the analgesic effect of orally administered glucose given before blood sampling.

Topics: Administration, Oral; Analgesia; Crying; Double-Blind Method; Female; Glucose; Heart Rate; Humans; Infant, Newborn; Injections, Intravenous; Male; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Phlebotomy; Prospective Studies; Receptors, Opioid

A study was conducted to determine whether changes in expected pain levels, desire for pain relief, or anxiety contribute to an increase in placebo analgesia over time as well as to determine whether placebo analgesic effects of IBS patients are related to endogenous opioid mechanisms. Twenty-six women with IBS were exposed to rectal stimulation (35 or 55 mmHg for 30 s) and tested under natural history (NH), rectal placebo (RP) and rectal lidocaine (RL) conditions. During all conditions, 16 patients were given saline intravenously (to test for a placebo effect) and 10 patients were given naloxone intravenously (to test naloxone antagonism of the placebo effect) on a double blind basis. Patients rated expected pain level, desire for pain relief and anxiety at 2 and 22 min after the onset of NH, RP, and RL conditions and they rated actual pain intensity at 5-min intervals for 40 min. There was a large and significant placebo effect (P<0.001) that increased over time. Ratings of expected pain levels, desire for pain relief and anxiety decreased over time and contributed to more variance in placebo and lidocaine responses during the last half of the session. These changes suggest that a reduction in negative emotions may be central to placebo effects. There was no significant difference between psychological mediators (desire, expectation, anxiety) or the placebo effect in the saline and naloxone groups, indicating that neither the psychological mediators nor the placebo analgesic effect were associated with endogenous opioids in this clinically related paradigm.

Topics: Adult; Analgesia; Anesthetics, Local; Anxiety; Attitude to Health; Female; Humans; Irritable Bowel Syndrome; Lidocaine; Naloxone; Narcotic Antagonists; Opioid Peptides; Pain; Pain Measurement; Placebo Effect; Predictive Value of Tests; Sodium Chloride

We investigated naloxone effects in a model of electrically induced pain and hyperalgesia. In a double-blind, placebo-controlled, cross-over study, 15 volunteers underwent four 150-minute sessions of high-current-density electrical stimulation of their forearms. After 60 minutes, naloxone or placebo was given intravenously (increasing plasma concentrations of 0.1, 1, and 10 ng/mL; 30 minutes each) in 3 of the 4 sessions. Pain ratings and areas of mechanical hyperalgesia were assessed at regular intervals during all sessions. The low doses of naloxone did not cause any significant change of pain rating of areas of hyperalgesia. In terms of intrasession effects, pain ratings and areas of hyperalgesia significantly decreased during the sessions to 62% (pain rating), 70% (area of punctuate hyperalgesia), and 82% (area of allodynia) of the initial values. Naloxone (10 ng/ml) reversed these decreases. In terms of between-session effects, the time course of pain ratings remained constant from session to session. In contrast, the areas of punctate hyperalgesia successively decreased to 60% of initial value at the fourth repetition. The session effect was not reversed by naloxone. High-current-density electrical stimulation provokes central sensitization, but in addition inhibitory systems are activated that are only partly naloxone-sensitive.. Endogenous inhibitory systems are of major importance for clinical pain conditions, but are not reflected in traditional human pain models. Here we show activation of a naloxone-sensitive short-term and a naloxone-insensitive long-term inhibitory system in a new model of electrically induced pain and hyperalgesia.

Topics: Adult; Electric Stimulation; Female; Humans; Hyperalgesia; Male; Naloxone; Narcotic Antagonists; Neural Inhibition; Opioid Peptides; Pain; Physical Stimulation

In the present study the effects of intravenously administered corticotropin-releasing hormone (CRH) on the release of proopiomelanocortin (POMC) derivatives such as adrenocorticotropic hormone (ACTH), beta-lipotropin (beta-LPH) and beta-endorphin (beta-END) as well as direct effects of CRH on pain sensitivity were examined. In 16 healthy volunteers we studied the effects of 100 microg intravenously administered CRH in absence or presence of 12 mg naloxone on heat or pressure pain sensitivity, using a double-blind, cross-over and placebo-controlled design. To evaluate analgesic effects of CRH via release of POMC derivatives, we determined plasma concentrations of beta-END-immunoreactive material (IRM), authentic beta-END (beta-END(1-31)) and beta-LPH IRM, in parallel with heat and pressure pain tolerance thresholds before and 15 and 30 min after treatment with CRH (or placebo), and 5 min after naloxone (or placebo) administration which was administered 40 min after CRH (or placebo) injection. CRH increased levels of beta-END IRM, beta-END(1-31) and beta-LPH IRM. As compared to beta-END IRM levels measured by a commercial RIA kit, the beta-END(1-31) levels determined by a highly specific two-site RIA, proved to be remarkably small. Furthermore, CRH did not induce increases of heat pain tolerance thresholds, but of pressure pain tolerance thresholds, which, however, were not reversible by naloxone. Neither beta-END nor beta-LPH IRM nor beta-END(1-31) levels correlated with heat or pressure pain tolerance thresholds. We conclude that CRH does not modulate heat, but pressure pain; POMC derivatives like beta-END IRM, beta-END(1-31) or beta-LPH do not mediate this effect.

Topics: Adrenocorticotropic Hormone; Adult; beta-Endorphin; beta-Lipotropin; Corticotropin-Releasing Hormone; Cross-Sectional Studies; Female; Hot Temperature; Humans; Injections, Intravenous; Male; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Pain Threshold; Pressure

Fentanyl is commonly used for spinal analgesia during labour but it is associated with a high incidence of pruritus. This randomised, double-blind, placebo-controlled study was performed to evaluate the effect of prophylactic ondansetron on the incidence and severity of pruritus among parturients receiving intrathecal fentanyl as part of combined spinal-epidural analgesia. Seventy-three women were randomised to receive either saline placebo (group P, n = 25), ondansetron 4 mg (group O4, n = 23) or ondansetron 8 mg (group O8, n = 25) intravenously before intrathecal fentanyl 25 micrograms and bupivacaine 2 mg. The incidence and severity of pruritus were measured using a verbal rating and a visual analogue scale, and by the requirement for rescue anti-pruritic medication (naloxone). The overall incidence of pruritus was 95% (group P 100%, group O4 95%, group O8 90%). There were no significant differences between groups for severity of pruritus or requirement for treatment (naloxone given to 45%, 28% and 35% of groups P, O4 and O8 respectively). Secondary outcomes such as the incidence of headache, pain and nausea were not significantly different between groups. We conclude that prophylactic ondansetron 4 or 8 mg intravenously was ineffective in reducing the incidence or severity of intrathecal fentanyl-induced pruritus during labour.

Topics: Adult; Analgesia, Obstetrical; Analgesics, Opioid; Double-Blind Method; Female; Fentanyl; Humans; Injections, Intravenous; Injections, Spinal; Naloxone; Narcotic Antagonists; Ondansetron; Pain; Postoperative Nausea and Vomiting; Pregnancy; Pruritus; Serotonin Antagonists

To investigate whether the introduction of methadone into the skin of the human forearm produces wheals, cutaneous vasodilatation or thermal hyperalgesia and, if so, to determine whether these responses are mediated by opioid receptors.. Healthy adults.. In Experiment 1 (N = 11), the increase in local blood flow (monitored with a laser Doppler flowmeter) was greater after the iontophoresis of methadone than saline (mean increase +/- S.D. 12.6 +/- 8.8 versus 2.2 +/- 1.9 times greater than baseline, p < 0.01). Flushing did not spread into surrounding skin and wheals did not form. In Experiment 2, pre-treatment with naloxone (N = 12) prevented increases in blood flow to methadone whereas saline pre-treatment (N = 14) did not. The heat pain threshold was lower at the site of methadone administration than at an untreated site (42.8 +/- 2.3 degrees C versus 44.6 +/- 1.7 degrees C, p < 0.001), and this effect was inhibited by naloxone pre-treatment. However, naloxone pre-treatment also antagonized an inhibitory effect of methadone on the pain generated by a 7-second pulse of 45 degrees C heat. In Experiment 3 (N = 11), the iontophoresis of methadone was repeated after an interval of 1.5 h. Vasodilatation to methadone persisted after the second iontophoresis, and sensitivity to heat was greater at a site of methadone administration than at a site of saline administration or an untreated control site.. Stimulation of mu-opioid receptors dilated cutaneous blood vessels, and evoked local thermal analgesia and hyperalgesia at different stimulus intensities. However, stimulation of mu-opioid receptors did not produce wheals or flares.

Topics: Administration, Cutaneous; Adolescent; Adult; Female; Flushing; Hot Temperature; Humans; Hyperalgesia; Iontophoresis; Male; Methadone; Middle Aged; Naloxone; Pain; Pain Measurement; Regional Blood Flow; Skin

Most published studies suggesting that epidural fentanyl acts predominantly at spinal sites administered the drug as a bolus injection, whereas most studies suggesting that it acts predominantly at supraspinal sites administered the drug as an infusion. In this study we tested the hypothesis that the mode of administration (bolus versus infusion) of epidural fentanyl determines its site of action. Ten healthy volunteers were enrolled in this randomized, double-blinded, cross-over study. On separate study days fentanyl was administered into the epidural space as a bolus (0.03 mg followed by 0.1 mg 210 min later) and as an infusion (0.03 mg/h followed by 0.1 mg/hr 210 min later for 200 min). Using a thermal and electrical experimental pain model, the heat ( degrees C) and electrical current (mA) causing maximum tolerable pain were assessed repetitively over a period of 420 min. The analgesic efficacy measures were obtained at a lumbar and a cranial dermatome. Plasma fentanyl concentrations were determined throughout the study. Epidural bolus administration of fentanyl resulted in segmental analgesia (leg > head), whereas the epidural infusion of fentanyl produced nonsegmental analgesia (leg = head). There was a significant linear relationship between the analgesic effect and the plasma concentration of fentanyl for the epidural infusion but not for the epidural bolus administration of fentanyl. These findings support our hypothesis and might explain the apparent conflict in the literature regarding the site of action of epidural fentanyl.. In an experimental pain study in volunteers, epidural fentanyl caused segmental analgesia when administered as a bolus and nonsegmental systemic analgesia when administered as a continuous infusion. This finding may help resolve the long-standing controversy surrounding the site of action of epidural fentanyl.

Topics: Adult; Algorithms; Analgesia, Epidural; Analgesics, Opioid; Area Under Curve; Cross-Over Studies; Double-Blind Method; Electric Stimulation; Female; Fentanyl; Hot Temperature; Humans; Infusion Pumps; Infusions, Parenteral; Injections; Male; Naloxone; Narcotic Antagonists; Pain; Pain Measurement

In contrast to an expected preventive analgesic effect, clinical observations suggest that intraoperatively applied opioids can induce postoperative hyperalgesia. We tested the development of post-infusion hyperalgesia in a newly developed experimental model of electrically induced pain and secondary mechanical hyperalgesia. In a double-blind, placebo controlled, cross-over study, 13 subjects received either saline placebo, remifentanil (0.05 or 0.1 microg/kg/min) or naloxone (0.01 mg/kg). Remifentanil dose-dependently reduced pain and mechanical hyperalgesia during the infusion, but upon withdrawal, pain and hyperalgesia increased significantly above control level (p<0.01 and p<0.05, respectively). Naloxone infusion similarly resulted in increased pain (anti-analgesia) (p<0.001) and mechanical hyperalgesia (p<0.01). Increased pain ratings following withdrawal of remifentanil significantly correlated to anti-analgesia evoked by the mu-opioid antagonist naloxone (p<0.01) and was of similar magnitude, suggesting inhibition of endogenous opioids as an underlying mechanism. In contrast, hyperalgesia after remifentanil was more pronounced than hyperalgesia after naloxone administration and did not correlate to the observed anti-analgesic effects, suggesting the involvement of additional receptors systems other than the endorphin system.

Topics: Adult; Analgesics, Opioid; Cross-Over Studies; Dermis; Electric Stimulation; Humans; Hyperalgesia; Male; Naloxone; Narcotic Antagonists; Pain; Piperidines; Receptors, Opioid, mu; Remifentanil; Sodium Chloride

Patients with silent myocardial ischemia have similar prognosis but fewer primary care and emergency care visits than patients with angina pectoris. Silent myocardial ischemia has been associated with an increased pain threshold because of an increased endogenous opioid receptor activity. In this double-blind, placebo-controlled study, we tested whether patients with silent myocardial ischemia would have less sensitivity to the ischemic pain messenger adenosine compared with angina pectoris patients and healthy controls. In addition, we tested whether this effect might be due to an increased opioid receptor activity.. Thirteen male patients with silent myocardial ischemia (mean age 58 +/- 10 years with BMI 25 +/- 3) were compared with 10 male patients with angina pectoris (mean age 57 +/- 9 years with BMI 29 +/- 5). Healthy volunteers (mean age 52 +/- 7 years with BMI 25 +/- 3, n = 10), acted as controls. Increasing doses of adenosine were injected rapidly into an antebrachial vein in a double-blind, randomized order. Central chest pain was provoked and quantified using psychophysical methods. The procedure was repeated after an injection of 0.4 mg of the non-selective opioid antagonist, naloxone.. Patients with silent myocardial ischemia exhibited higher pain threshold than patients with angina pectoris and healthy volunteers. After naloxone, healthy volunteers and patients with angina pectoris tended to have more pain than patients with silent myocardial ischemia.. In conclusion, patients with silent myocardial ischemia had a decreased sensitivity to adenosine-provoked chest pain compared with patients with angina pectoris. The decreased pain sensitivity was not related to opioid receptor activity.

Topics: Adenosine; Angina Pectoris; Blood Pressure; Double-Blind Method; Heart Rate; Humans; Male; Middle Aged; Myocardial Infarction; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Pain Threshold; Time Factors

Learning processes such as respondent or Pavlovian conditioning are believed to play an important role in the development of chronic pain, however, their influence on the inhibition of pain has so far not been assessed in humans. The purpose of this study was the demonstration of Pavlovian conditioning of stress-induced analgesia in humans and the determination of its opioid mediation. In a differential classical conditioning paradigm two different auditory stimuli served as conditioned stimuli and mental arithmetic plus white noise as unconditioned stimulus. Subsequent to four conditioning trials naloxone or placebo was applied in a double-blind fashion on two test days. Both pain threshold and pain tolerance showed conditioned stress-induced analgesia. Pain tolerance was affected by naloxone whereas pain threshold was not. The data of this study show that stress analgesia can be conditioned in humans and that it is at least partially mediated by the endogenous opioid system. Learning processes also influence pain inhibitory processes in humans and this effect might play a role in the development of chronic pain.

Topics: Adult; Central Nervous System; Conditioning, Psychological; Humans; Male; Naloxone; Narcotic Antagonists; Neural Inhibition; Neural Pathways; Neuropsychological Tests; Opioid Peptides; Pain; Pain Measurement; Pain Threshold; Perception; Stress, Psychological

We have previously shown that fibromyalgia (FMS) patients have enhanced temporal summation (windup) and prolonged decay of heat-induced second pain in comparison to control subjects, consistent with central sensitization. It has been hypothesized that sensory abnormalities of FMS patients are related to deficient pain modulatory mechanisms. Therefore, we conducted several analyses to further characterize enhanced windup in FMS patients and to determine whether it can be centrally modulated by placebo, naloxone, or fentanyl. Pre-drug baseline ratings of FMS and normal control (NC) groups were compared with determine whether FMS had higher pain sensitivity in response to several types of thermal tests used to predominantly activate A-delta heat, C heat, or cold nociceptors. Our results confirmed and extended our earlier study in showing that FMS patients had larger magnitudes of heat tap as well as cold tap-induced windup when compared with age- and sex-matched NC subjects. The groups differed less in their ratings of sensory tests that rely predominantly on A-delta-nociceptive afferent input. Heat and cold-induced windup were attenuated by saline placebo injections and by fentanyl (0.75 and 1.5 microg/kg). However, naloxone injection had the same magnitudes of effect on first or second pain as that produced by placebo injection. Hypoalgesic effects of saline placebo and fentanyl on windup were at least as large in FMS as compared to NC subjects and therefore do not support the hypothesis that pain modulatory mechanisms are deficient in FMS. To the extent that temporal summation of second pain (windup) contributes to processes underlying hyperalgesia and persistent pain states, these results indirectly suggest that these processes can be centrally modulated in FMS patients by endogenous and exogenous analgesic manipulations.

Topics: Adult; Analgesics, Opioid; Cold Temperature; Female; Fentanyl; Fibromyalgia; Hot Temperature; Humans; Hyperalgesia; Middle Aged; Naloxone; Narcotic Antagonists; Nociceptors; Pain; Placebos; Psychophysics

Opioid receptors occur in locations of strategic importance within the central nervous system for modulation of pain. Is pain reduced by ongoing inhibition mediated by activation of these receptors? Experiments to date in which the opioid-receptor antagonist, naloxone, is administered during a painful event have yielded unclear results. Topically applied capsaicin can be used to induce tonic pain of moderate to severe intensity without tissue injury and is an ideal stimulus for studying acute pain modulation. We therefore conducted a placebo-controlled double-blind crossover study to investigate the effects of naloxone on capsaicin-induced pain (five men, four women, aged 29 +/- 5 years). Capsaicin (10%) was applied topically and subjects rated pain every 2 min. The subjects were told that any drug given to them could increase, decrease, or not change their pain sensation. Pain plateaued after 20 min. At 26 min subjects received either naloxone or placebo in double-blind fashion. At 56 min subjects received the alternative (placebo or naloxone). In a second session the order of presentation was reversed. The naloxone induced a significant increase in pain compared both to baseline (P < 0.01) and placebo (P < 0.01). The peak effect, reached at 12-20 min after naloxone delivery, was 59% greater than placebo. This experiment suggests that acute pain is actively suppressed by endogenous opioid-receptor activation.

Topics: Administration, Topical; Adult; Analysis of Variance; Capsaicin; Cross-Over Studies; Double-Blind Method; Drug Synergism; Female; Humans; Hyperalgesia; Male; Naloxone; Narcotic Antagonists; Pain; Psychophysics; Receptors, Opioid

335 patients (51% female, 49% male, mean age 56 years) with chronic pain and multimorbidity have been included in a multi-center 2-years' study with slow release Tilidine/Naloxone for efficacy and safety which included detailed laboratory examinations. 316 patients had already been treated with analgesics. 159 patients (47.5%) finished the study as planned, 176 patients finished the study earlier.. Parameters of quality of life such as persistent pain, sleep, mood and activity have improved. Tolerance has not been observed. In 85 patients (25%) adverse events had occurred (nausea, vomiting, dizziness) which are related to the study-medication. Constipation was documented in only 4 patients. After 2 years of therapy with Tilidine/Naloxone there has been no relevant changes in laboratory findings. There has been no sign of organ damage or interactions with concomitant medication.. Tilidine/Naloxone is an effective and safe analgesic (WHO II) suitable for the longterm treatment of patients with chronic pain.

Topics: Adult; Aged; Aged, 80 and over; Analgesics, Opioid; Chronic Disease; Comorbidity; Delayed-Action Preparations; Dose-Response Relationship, Drug; Drug Combinations; Drug Therapy, Combination; Female; Humans; Long-Term Care; Male; Middle Aged; Naloxone; Pain; Pain Measurement; Quality of Life; Tilidine; Treatment Outcome

The most common side effect of opioid therapy is constipation. It is often difficult to treat and is believed to be primarily a peripheral effect. Single large doses of oral naloxone have been shown to be efficacious in reversing opioid-induced constipation. However, they often cause the unwanted side effect of analgesia reversal. This study evaluated the effects on constipation and analgesia of low doses of oral naloxone given three times daily. Patients taking stable doses of opioids with complaints of constipation were recruited for this double-blind, randomized, placebo-controlled study. Patients were given 4 mg or 2 mg of oral naloxone, or placebo, three times daily. Stool frequency and symptoms related to constipation were recorded daily. Patients also recorded the daily amount of analgesics required to maintain pain control. Nine patients were recruited for the study. All the patients who received oral naloxone had some improvement in their bowel frequency. Three of the patients also experienced reversal of analgesia, including one who had complete reversal of analgesia. This study demonstrates that reversal of analgesia still occurred despite dividing the oral naloxone into very low doses relative to the total dose of opioid used. Patients using high doses of opioids appear to be the most vulnerable to the analgesic effect of oral naloxone.

Topics: Administration, Oral; Adult; Aged; Analgesia; Analgesics, Opioid; Chronic Disease; Constipation; Double-Blind Method; Female; Humans; Male; Middle Aged; Naloxone; Narcotic Antagonists; Pain; Pilot Projects

Opioid-related constipation is one of the most frequent side effects of chronic pain treatment. Enteral administration of naloxone blocks opioid action at the intestinal receptor level but has low systemic bioavailability due to marked hepatic first-pass metabolism. The aim of this study was to examine the effects of oral naloxone on opioid-associated constipation in an intraindividually controlled manner. Twenty-two chronic pain patients with oral opioid treatment and constipation were enrolled in this study. Constipation was defined as lack of laxation and/or necessity of laxative therapy in at least 3 out of 6 days. Laxation and laxative use were monitored for the first 6 days without intervention ('control period'). Then, oral naloxone was started and titrated individually between 3x3 to 3x12 mg/day depending on laxation and withdrawal symptoms. After the 4-day titration period, patients were observed for further 6 days ('naloxone period'). The Wilcoxon signed rank test was used to compare number of days with laxation and laxative therapy in the two study periods. Of the 22 patients studied, five patients did not reach the 'naloxone period' due to death, operation, systemic opioid withdrawal symptoms, or therapy-resistant vomiting. In the 6 day 'naloxone' compared to the 'control period', the mean number of days with laxation increased from 2.1 to 3.5 (P<0.01) and the number of days with laxative medication decreased from 6 to 3.8 (P<0.01). The mean naloxone dose in the 'naloxone period' was 17.5 mg/day. The mean pain intensity did not differ between these two periods. Moderate side effects of short duration were observed in four patients following naloxone single dose administrations between 6 and 20 mg, resulting in yawning, sweating, and shivering. Most of the patients reported mild or moderate abdominal propulsions and/or abdominal cramps shortly after naloxone administration. All side effects terminated after 0.5-6 h. This controlled study demonstrates that orally administered naloxone improves symptoms of opioid associated constipation and reduces laxative use. To prevent systemic withdrawal signs, therapy should be started with low doses and patients carefully monitored during titration.

Topics: Administration, Oral; Analgesics, Opioid; Cathartics; Chronic Disease; Constipation; Humans; Naloxone; Narcotic Antagonists; Neoplasms; Pain

Preemptive analgesia (PA) is effective in animal models but its clinical effectiveness remains controversial. We examined the effect of preexisting pain on PA. Subjects were recruited from patients needing orthopedic surgery. Some had presurgical pain (fracture surgery and arthritic surgery), while others had no presurgical pain (removal surgery for a tumor, nail or plate). Epidural morphine or a saline control was given preemptively before surgery and maintained until skin closure. Following skin closure, naloxone or placebo was injected intravenously to erase the aftereffects of the morphine. After total recovery, the PCA pump was set to inject epidural morphine. Pain intensity after surgery was measured by a visual analogue scale (VAS), and the amount of morphine used within 48h after surgery. PA was significantly effective for removal surgery, but ineffective for fracture or arthritic surgery. For the fracture and arthritic surgery PA treatment groups, there was a significant correlation between pre- and postsurgical (6h) spontaneous pain, while the corresponding control groups showed no significant correlation. Postsurgical VAS values in the fracture and arthritic surgery control groups increased significantly compared with presurgical VAS values. PA was effective when presurgical pain was absent, but ineffective when presurgical pain was present. We propose that central sensitization is already established by presurgical pain, and preserved until the termination of surgery. The ineffectiveness of PA did not depend on whether the pain was acute (fracture surgery) or chronic (arthritic surgery).

Topics: Adult; Aged; Analgesia; Double-Blind Method; Female; Humans; Infusion Pumps; Injections, Epidural; Male; Middle Aged; Morphine; Naloxone; Orthopedics; Pain; Pain Measurement; Postoperative Care; Postoperative Period; Preoperative Care

Several studies have demonstrated the presence of opioid inducible receptors on peripheral nerves and peripheral antinociceptive effects of opioids. However, the effects of peripheral opioid administration in man are controversial. Our study used a randomized, double-blind, placebo-controlled, three-way crossover design in a human model of acute inflammatory pain (heat injury). We studied 18 healthy volunteers who each received morphine locally (2 mg), morphine systemically (2 mg), or placebo on three separate study days. The subjects received morphine infiltration subcutaneously (s.c.). 1 h before heat injury (47 degrees C, 7 min) and naloxone infiltration s.c. (0.2 mg) 2.5 h after the heat injury. Hyperalgesia to mechanical and heat stimuli were examined using von Frey hairs and thermodes, and pain was rated using a visual analogue scale. The burns produced significant hyperalgesia, but local morphine infiltration neither reduced pain during the burn, nor primary or secondary hyperalgesia to mechanical and heat stimuli after the burn. In conclusion, peripherally applied morphine had no acute antinociceptive effects in this human model of acute inflammatory pain.

Topics: Administration, Cutaneous; Adult; Analgesics, Opioid; Burns; Cross-Over Studies; Double-Blind Method; Female; Humans; Male; Middle Aged; Morphine; Naloxone; Narcotic Antagonists; Nociceptors; Pain; Pain Measurement

The purpose of this study was to investigate whether placebo analgesia is mediated by the release of beta-endorphin. In addition to subjective pain reports, we included an objective physiological parameter of nociception reflected by the opioid sensitive nociceptive R-III reflex. Placebo consisted of strong suggestions of pain relief and an intravenous injection of saline. Forty minutes after placebo, either the opioid antagonist naloxone or saline was administered intravenously without subjects noticing (hidden). Sixty healthy males, aged 18-30 years, voluntarily participated in this study. Subjects were randomized into one of four groups: group 1 received placebo and hidden naloxone, group 2 received hidden naloxone only, group 3 received placebo and hidden saline and group 4 received hidden saline only. Pain was induced by electrical stimulation of the sural nerve and evaluated with a visual analogue scale (VAS). In addition, changes in the magnitude of the nociceptive R-III reflex activity were assessed. We determined to what extent R-III reflex activity and subjective pain reports were decreased by placebo and we investigated whether these placebo-induced changes in reflex activity and subjective pain reports were naloxone reversible. Furthermore, we measured the degree of association between pain relief as measured on VAS and changes in R-III reflex activity. Finally, the role of beta-endorphin was assessed by measuring plasma endorphin levels before and after the administration of placebo. This study could not demonstrate a placebo effect as measured on VAS and R-III responses. The administration of placebo did not appear to have an effect on the release of beta-endorphins. Consistently, the antagonizing effects of naloxone were negligible. A subgroup analysis of those who did show a placebo response as indicated on the VAS did not support the supposition that beta-endorphin is released due to placebo suggestion. It is suggested that intensified stimuli and a more effective procedure to induce placebo analgesia (e.g. conditioning) may produce a proper placebo effect.

Topics: Adolescent; Adult; beta-Endorphin; Humans; Male; Naloxone; Narcotic Antagonists; Nociceptors; Pain; Placebo Effect; Placebos; Reflex; Spinal Cord

We investigated the mechanisms underlying the activation of endogenous opioids in placebo analgesia by using the model of human experimental ischemic arm pain. Different types of placebo analgesic responses were evoked by means of cognitive expectation cues, drug conditioning, or a combination of both. Drug conditioning was performed by means of either the opioid agonist morphine hydrochloride or the nonopioid ketorolac tromethamine. Expectation cues produced placebo responses that were completely blocked by the opioid antagonist naloxone. Expectation cues together with morphine conditioning produced placebo responses that were completely antagonized by naloxone. Morphine conditioning alone (without expectation cues) induced a naloxone-reversible placebo effect. By contrast, ketorolac conditioning together with expectation cues elicited a placebo effect that was blocked by naloxone only partially. Ketorolac conditioning alone produced placebo responses that were naloxone-insensitive. Therefore, we evoked different types of placebo responses that were either naloxone-reversible or partially naloxone-reversible or, otherwise, naloxone-insensitive, depending on the procedure used to evoke the placebo response. These findings show that cognitive factors and conditioning are balanced in different ways in placebo analgesia, and this balance is crucial for the activation of opioid or nonopioid systems. Expectation triggers endogenous opioids, whereas conditioning activates specific subsystems. In fact, if conditioning is performed with opioids, placebo analgesia is mediated via opioid receptors, if conditioning is performed with nonopioid drugs, other nonopioid mechanisms result to be involved.

Topics: Adult; Analgesia; Analgesics, Opioid; Conditioning, Operant; Cues; Double-Blind Method; Endorphins; Female; Humans; Ischemia; Male; Middle Aged; Morphine; Naloxone; Narcotic Antagonists; Pain; Placebos

Hyperactivity of endogenous opioid systems has been postulated to mediate the associations between defensive/repressive coping styles, enhanced stress responsivity, and reduced immunocompetence. Study 1 examined whether repressive/defensive coping would be associated with greater sensitivity to opioid antagonism. Judgments of the painfulness of ascending series of electrocutaneous stimulation applied to the forearm were determined before and after the administration of naloxone and placebo in 38 men and 42 women. All subjects were healthy with a mean age of 32.9 years. Naloxone (10 mg i.v.) and placebo were administered in double-blind fashion and counterbalanced. Subjects were classified as High- and Low-defensive and repressive copers on the basis of scores on the Marlowe-Crowne Social Desirability Scale and the Balanced Inventory of Desirable Responding, respectively. High Self-Deception was associated with naloxone-induced hyperalgesia, whereas no effects of naloxone on pain ratings were observed in low-Self-Deceptive subjects. In Study 2, resting plasma beta-endorphin levels were found to be positively correlated with defensiveness in men (n = 26), but not women (n = 44). Study 3 examined 82 healthy subjects (mean age = 28.7 years). Beta-endorphin/defensiveness correlations were found to be greater following, compared to prior to, electrical nociceptive stimulation in men (n = 49), but unrelated in women (n = 33). These findings are consistent with the hypothesized endorphinergic dysregulation associated with repressive/defensive coping styles and are discussed in terms of the immuno-regulatory implications of such a dysregulation.

Topics: Adaptation, Psychological; Adolescent; Adult; Affect; Analysis of Variance; beta-Endorphin; Defense Mechanisms; Double-Blind Method; Female; Health Status; Humans; Male; Middle Aged; Naloxone; Narcotics; Pain; Pain Measurement; Repression, Psychology; Stress, Psychological

The analgesic efficacy and safety of single oral doses of two centrally acting compounds, the combination of 50 mg tilidine and 4 mg naloxone (Valoron N) and 50 mg tramadol (Tramal), were compared to 25, 50 and 75 mg of the non-steroidal antiinflammatory bromfenac in experimental pain.. It was a placebo-controlled double-blind 6-way crossover study design with 12 human volunteers. Acute pain was generated by electrical tooth pulp stimulation. Treatment effects were determined by recording somatosensory-evoked potentials and by subjective pain rating.. The tilidine/naloxone combination clearly was the most potent medication in this study, followed by bromfenac 75 mg, which produced an early pain relief. Tramadol produced poor analgesia, as did bromfenac 25 and 50 mg. There was no dose-response relationship for bromfenac. Control of plasma levels revealed pronounced interindividual differences in peak plasma concentrations for bromfenac, but not for tramadol. Tilidine/naloxone exerted adverse effects in 9, tramadol in 3 volunteers. Under medication with 25 and 50 mg bromfenac, respectively, only one subject reported adverse effects. No adverse effects were experienced with 75 mg bromfenac or placebo.. The results support previous conclusions about the analgesic efficacy of tilidine/naloxone and tramadol in experimental pain. Moreover, the findings suggest that 75 mg bromfenac might be suitable for fast but short relief of pain of non-inflammatory genesis.

Topics: Adult; Analgesics; Area Under Curve; Benzophenones; Bromobenzenes; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Drug Combinations; Drug Therapy, Combination; Evoked Potentials, Somatosensory; Female; Humans; Male; Naloxone; Pain; Tilidine; Tramadol

Wake-up tests may be necessary during scoliosis surgery to ensure that spinal function remains intact.. Intra- and postoperative wake-up tests were performed together with somatosensory cortical evoked potentials (SCEPs) monitoring in 40 patients randomized to either midazolam (M) or propofol (P) infusions for scoliosis surgery. Other anaesthetic medication was similar in both groups. At the surgeon's request, N2O was turned off and midazolam or propofol infusions were discontinued. In the M group, flumazenil was given in refracted doses. Patients were asked to move hands and feet. The test was repeated immediately after the end of surgery.. The median intraoperative wake-up times were 2.9 min in the M group and 16.0 min in the P group. The respective postoperative wake-up times were 1.8 and 13.9 min. The quality of both intra- and postoperative arousals was significantly better in the M group. Twelve patients in the P group could not be awakened intraoperatively within 15 min and were given naloxone. One of these patients woke up violently and dislodged the endotracheal tube. Another patient in the P group had explicit recall of the test, but no pain. Five patients in the M group became resedated in the recovery room. Cost of anaesthetic drugs was similar in both groups. Satisfactory intraoperative SCEPs were recorded from 17 patients in each group. There were no neurological sequelae.. Wake-up tests can be conducted faster and better with midazolam-flumazenil sequence compared with propofol.

Topics: Adolescent; Adult; Anesthesia Recovery Period; Anesthesia, Intravenous; Anesthetics, Intravenous; Antidotes; Arousal; Child; Drug Costs; Evoked Potentials, Somatosensory; Female; Flumazenil; Humans; Intraoperative Care; Intubation, Intratracheal; Male; Memory; Midazolam; Monitoring, Intraoperative; Naloxone; Narcotic Antagonists; Pain; Postoperative Care; Propofol; Prospective Studies; Psychomotor Performance; Scoliosis; Spinal Cord; Wakefulness

Pain sensitivity decreases with increasing resting blood pressure. This blood pressure-pain interaction may be mediated by endogenous opioids which have been shown to affect both blood pressure and nociception. To test this hypothesis, we measured mean arterial blood pressure (MAP), central venous pressure (CVP), heart rate (HR), muscle sympathetic nerve activity (MSNA), serum catecholamines, and individual pain rating scales during 2 min periods of noxious mechanostimulation (skin fold pinching) in nine young (26 +/- 2 year), male normotensive (NT) subjects and in 12 age and weight matched males with borderline hypertension (BHT). Measurements were performed before and after the i.v. administration of naloxone (0.15 mg/kg) and placebo in a randomized double-blind cross-over trial. In the pre-naloxone trials, pain led to similar changes in MAP, CVP, MSNA and plasma catecholamines in the two groups except for a higher increase in HR in the BHT group as compared to the NT group (3 +/- 1 vs. 1 +/- 1 bpm; P < 0.005). Opioid blockade with naloxone increased MSNA responses to pain in the NT group (from 5 +/- 1 to 9 +/- 1 bursts/min, and, from 100 +/- 23 to 204 +/- 36 units/min, respectively; P < 0.05) but did not significantly affect the MSNA response to pain in the BHT group. Pain induced responses of MAP, CVP, and catecholamines were not altered by naloxone in either group. Overall, there was a highly significant inverse correlation between pain perception and resting blood pressure which was not significantly affected by naloxone. The BHT subjects exhibited a lower pain perception compared to the NT subjects (P < 0.005). Naloxone increased pain rating in the NT group (from 194 +/- 9 to 218 +/- 13; P < 0.005) but not in the borderline hypertensive group (160 +/- 8 vs. 168 +/- 10; P = 0.36). Except for a decreased HR response in the BHT group, placebo had no effect on the responses to pain. Our data do not indicate a major role of the endogenous opioid system for the blood pressure-pain interaction in man. Endogenous opioids affect pain perception and sympathetic nerve activity responses to pain in normotensive men but their activity seems to be attenuated in borderline hypertensive subjects. Therefore, the lower pain sensitivity in human essential hypertension is probably mediated by non-opioid mechanisms.

Topics: Adult; Cross-Over Studies; Double-Blind Method; Hemodynamics; Humans; Hypertension; Male; Naloxone; Narcotic Antagonists; Pain; Pain Threshold; Reference Values; Sympathetic Nervous System

Having a differential sensitivity to morphine can distinguish migraine suffers from healthy people who are headache-exempt. The aim of the present study was to investigate whether such an abnormal response to morphine challenge is entirely dependent on opioid receptor activation. A role for excitatory amino acids and gamma-aminobutyric acid has been proposed on the basis of the effect of diazepam. As opposed to naloxone, this gamma-aminobutyric acid agonist was found to inhibit the adverse effects of low doses of morphine in migraine sufferers, while at the same time being able to almost abolish morphine-induced miosis in subjects who underwent a short-lasting chronic pretreatment. The capacity of diazepam either to control the adverse effects of morphine or to induce well-being in subjects known to suffer from a central neurogenic pain such as migraine, is noteworthy even regarding the clinical treatment of other painful conditions, such as deafferentation pain, which is known to be not satisfactorily treated by using morphine.

Topics: Adult; Cross-Over Studies; Diazepam; Double-Blind Method; Excitatory Amino Acids; gamma-Aminobutyric Acid; Humans; Migraine Disorders; Morphine; Naloxone; Narcotic Antagonists; Narcotics; Pain; Receptors, Opioid

The influence of anxiety on acute pain sensation was investigated, studying the relative contribution of endogenous opioids and attentional mechanisms. Thirty-six spider phobics received mildly painful electrical stimulation, while anxiety and focus of attention were manipulated within subjects. The opioid antagonist naloxone or placebo was administered between subjects to examine an analgesia owing to anxiety-induced endorphinergic activity. In contrast to earlier findings, attention towards pain failed to increase pain as opposed to distraction from pain, probably owing to a less effective attention manipulation. Furthermore, despite high levels of anxiety, subjective pain ratings were not influenced by anxiety, although heart rate responses were slightly inhibited. Accordingly, there was no increase in subjective or physiological pain responses as a result of naloxone, nor did beta-endorphin plasma levels rise during anxiety. The results suggest that phobic anxiety does not induce an opioid-mediated analgesia. Curiously, naloxone itself effected a dose-dependent analgesia compared to placebo during both high and low anxiety, which is compatible with the assumption of agonist properties of naloxone in the absence of opioid activity.

Topics: Adolescent; Adult; Analgesia; Analysis of Variance; Animals; Anxiety; Attention; beta-Endorphin; Cross-Over Studies; Female; Humans; Longitudinal Studies; Naloxone; Pain; Pain Measurement; Phobic Disorders; Spiders; Stress, Physiological

Although evidence is lacking, clinical experience suggests that pain stimulation acts as a respiratory stimulant and antagonises opioid-induced respiratory depression. The present study examined the effects of experimental pain stimulation on the ventilatory response to CO2 and morphine-induced respiratory depression. Pain was induced by a modification of the Tourniquet Pain Technique and changes in ventilatory parameters were registered through monitoring of the CO2 response of tidal volume, minute ventilation, respiratory rate and mouth occlusion pressure. The ventilatory parameters were obtained before and during pain stimulation and repeated after the administration of morphine and finally after naloxone. In the present investigation experimental pain-stimulated respiration and attenuated morphine-induced respiratory depression. Only changes in the intercept values of the CO2 response were observed. The slopes of the CO2-response curves were not affected. These observations suggested that both pain stimulation and morphine administration altered the threshold of the respiratory centre to CO2 stimulation. Naloxone administration was the only intervention altering the sensitivity of the respiratory centre to CO2. These results suggest that pain stimulates respiration and attenuates morphine-induced respiratory depression.

Topics: Adult; Carbon Dioxide; Humans; Male; Morphine; Naloxone; Pain; Pain Measurement; Physical Stimulation; Respiration; Respiratory Insufficiency; Tourniquets

Topics: Angina Pectoris; Electric Stimulation; Electrocardiography, Ambulatory; Evoked Potentials, Somatosensory; Humans; Male; Median Nerve; Middle Aged; Myocardial Infarction; Myocardial Ischemia; Naloxone; Neural Conduction; Pain; Pain Threshold; Parietal Lobe; Placebos; Reaction Time; Spinal Cord; Ulnar Nerve

Elevated resting blood pressure is associated with decreased pain sensitivity in both animals and humans. Recent evidence suggests that this relationship may be mediated by endogenous opioid peptides in hypertensives, but the precise mechanism has not been investigated in normotensives. We examined the effect of opioid receptor blockade with naloxone on the relationship between resting blood pressure and pain sensitivity in normotensive humans. Sixteen young adults were given cold pressor and handgrip challenges after treatment with either naloxone or saline in a placebo-controlled, within-subject design. Multiple regression procedures indicated that resting systolic blood pressure was a significant predictor of cold pain ratings even after the effects of naloxone were statistically controlled. The interaction between systolic blood pressure and opioid blockade was non-significant. These data suggest that the relationship between resting blood pressure and pain sensitivity in normotensive humans is mediated, at least in part, by non-opioid mechanisms.

Topics: Adolescent; Adult; Blood Pressure; Cold Temperature; Endorphins; Humans; Male; Naloxone; Pain; Pain Measurement; Regression Analysis; Stress, Psychological

The putative central analgesic activity of diclofenac was investigated in a human experimental pain model using intraneural electrical stimulation in the median nerve. Since pain is induced proximal to the peripheral nociceptors, the model can be used to test central analgesic properties of i.a. pharmacological interventions performed during series of repeated stimulations. A single intravenous dose of 50 mg diclofenac or saline was administered during an ongoing series of painful intraneural stimulations in a double-blind cross-over study in 10 healthy volunteers. Neither diclofenac nor saline caused any significant change in the level of pain experienced during stimulation. Thus, no central analgesic effect of diclofenac could be demonstrated in this model. The stability of individual visual analogue scale (VAS) scores throughout the experimental sessions, also after administration of the potent peripheral analgesic agent diclofenac, underlines the validity of intraneural stimulation as a central pain model in humans.

Topics: Adolescent; Adult; Diclofenac; Double-Blind Method; Electric Stimulation; Electrophysiology; Female; Humans; Laser-Doppler Flowmetry; Male; Median Nerve; Middle Aged; Naloxone; Pain; Pain Measurement; Regional Blood Flow; Skin

To evaluate the safety of high-dose IV narcotics in patients requiring analgesia for painful emergency department procedures.. Prospective multicenter clinical trial.. Five adult urban EDs.. All patients received IV meperidine (1.5 to 3.0 mg/kg) titrated to analgesia followed by a painful procedure. Vital signs and alertness scale were recorded at regular intervals, and patients were observed for four hours. Adverse events were monitored and documented. Comparisons between baseline and postanalgesia intervals were made with a repeated measures ANOVA (Dunnett's test).. Although statistically significant changes in vital signs and alertness scale occurred, they were not clinically significant. Opiate reversal with naloxone was not needed in any patient, and no significant respiratory or circulatory compromise occurred.. This study of 72 patients demonstrates that high-dose narcotic analgesia is appropriate, well tolerated, and safe when used in selected patients before painful procedures in the ED. Narcotic antagonists and resuscitation equipment nonetheless should be available to maximize safety.

Topics: Adolescent; Adult; Analysis of Variance; Blood Pressure; Body Temperature; Consciousness; Emergency Service, Hospital; Female; Heart Rate; Hospitals, Urban; Humans; Infusions, Intravenous; Male; Meperidine; Middle Aged; Naloxone; Pain; Prospective Studies; Respiration; Resuscitation

To investigate the role of the opioid system in the pathophysiology of silent ischemia through opiate antagonism with naloxone, and to determine the reproducibility of resting and postexercise beta-endorphin levels in predominantly asymptomatic patients with coronary artery disease.. Randomized, double-blind, placebo-controlled crossover trial.. A University hospital referral center.. Ten patients with prior evidence of silent exercise-induced ischemia were studied.. An infusion of saline placebo or naloxone at two dose regimens of 0.015 mg/kg or 0.15 mg/kg before supine exercise testing during three separate occasions for each patient.. Plasma beta-endorphin was measured at rest, immediately after exercise, and 5 min poststress. Timing and severity of angina and exercise hemodynamics were also determined.. Seven of 10 patients reported no angina, whereas the other three experienced angina with placebo and after administration of naloxone at both doses. The severity and duration of angina was consistently noted to decrease in these patients after naloxone administration, especially after low-dose naloxone relative to placebo. There were no apparent correlations between beta-endorphin levels and the characteristics of angina in these three patients, nor between beta-endorphin and hemodynamic responses in all patients in the study.. (a) naloxone failed to precipitate angina in this population of patients with silent ischemia; (b) naloxone appears to exert an analgesic effect at low doses; and (c) a variability of 5 pM at rest and 13 pM after exercise might be expected in predominantly asymptomatic patients due to random variation, which is comparable with results found in normal subjects.

Topics: Aged; Angina Pectoris; beta-Endorphin; Electrocardiography; Exercise Test; Female; Hemodynamics; Humans; Male; Middle Aged; Myocardial Ischemia; Naloxone; Pain; Receptors, Opioid; Reproducibility of Results

Intravenous naloxone has been claimed to produce pain relief in opioid-resistant central post-stroke pain (CPSP, 'thalamic syndrome'). In a double-blind trial, carried out in 20 patients with established CPSP, naloxone (up to 8 mg in 20 ml vehicle) was tested against normal saline; each patient was randomly given naloxone or saline and the other substance 2 or 3 weeks later. VAS and verbal pain scores were obtained immediately before and after naloxone or saline injection, and subjective ratings followed for 2 weeks. Three patients obtained transient pain relief with naloxone, 4 with saline, and another 4 with both. Statistical tests failed to show any influence of giving naloxone first or second. In all cases except one, pain relief had disappeared by the evening of the day on which the test was performed; one case, following naloxone, continued to experience pain relief until the following morning. We therefore conclude that intravenous naloxone is of no value in alleviating the pain of CPSP.

Topics: Adult; Aged; Cerebrovascular Disorders; Double-Blind Method; Female; Humans; Male; Middle Aged; Naloxone; Pain; Pain Measurement

Although the analgesic effects observed during the application of vibration may be attributable to neuronal inhibition of the pain pathways, this does not account for the fact that pain relief sometimes persists for a long time after the end of vibration treatment. Two experiments were carried out in order to determine whether pain relief might involve the release of endogenous opioids. In the first experiment, we studied the effects of injecting either a morphine antagonist, naloxone (0.4 mg), or a placebo, on the analgesia resulting from vibratory stimulation in 12 patients suffering from acute or chronic pain. In the second experiment, the Met-enkephalin and beta-endorphin levels were determined before and after 30 min vibratory stimulation in the cerebrospinal fluid of 8 patients suffering from chronic pain and 1 control subject, all of whom had been fitted with a ventriculo-peritoneal drain which made it possible to collect samples of cerebrospinal fluid painlessly. The results of these experiments show, on the one hand, that the effects of naloxone on the vibration-induced analgesia did not differ from those of the placebo and, on the other hand, that no increase in the Met-enkephalin or beta-endorphin levels occurred concomitantly with pain relief. It will therefore be necessary to investigate other mechanisms as possible means of explaining the post-vibratory analgesic effects.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Analgesia; beta-Endorphin; Female; Humans; Male; Middle Aged; Naloxone; Pain; Pain Measurement; Radioimmunoassay; Vibration

We have studied if 2 Hz electroacupuncture alleviates chronic nociceptive pain and if so whether the alleviation was related to the release of endogenous opioids. Thirty-two patients suffering from osteoarthritis were subjected to electroacupuncture, with or without pretreatment with naloxone or diazepam. The effect of the different experimental procedures was assessed using scales for the intensity (sensory component) and unpleasantness (affective component) of pain. Electroacupuncture induced a significant alleviation of pain. This alleviation was more significant on the affective scales (p less than 0.01) than on the sensory scales (p less than 0.05). After pretreatment with diazepam or naloxone, the subsequent pain alleviating effect was reduced. These data indicate that acupuncture induced analgesia may partly be mediated through endogenous opioids which are affected by pretreatment with diazepam or naloxone.

Topics: Acupuncture Analgesia; Aged; Animals; Chronic Disease; Combined Modality Therapy; Diazepam; Electroacupuncture; Endorphins; Humans; Middle Aged; Naloxone; Osteoarthritis; Pain; Pain Management; Pain Measurement; Receptors, Opioid

Hypnosis and acupuncture can alleviate experimentally induced pain but the mechanism of analgesia remains unclear for both techniques. Experimental pain was induced by cold pressor test (CPT) in 8 male volunteers. Analgesic effect of hypnosis (HA) and acupuncture (AA) was assessed before and after double-blind administration of placebo or naloxone, in a prospective, cross-over study. We found that pain intensity was significantly lower with HA as compared with AA, both with naloxone (P less than 0.001) and placebo (P less than 0.001). Within HA or AA groups, pain scores did not differ significantly when naloxone or placebo was administered. During AA, however, pain scores were similar to control values when naloxone was given (P = 0.05) but decreased significantly with placebo (P less than 0.002). Analog scales for pain intensity and pain relief showed a good correlation (r = 0.94). Plasma levels of beta-endorphins did not change significantly in any combination. Heart rate, peripheral arterial blood pressure and skin conductance were very insensitive indices to assess pain intensity or relief, as well as intensity of acupuncture stimulation or depth of hypnotic trance. We conclude: (1) HA and AA can significantly reduce pain from CPT, and HA is more effective than AA: (2) HA and AA are not primarily mediated by the opiate endorphin system; and (3) plasmatic levels of beta-endorphins are not significantly affected by either HA or AA nor by naloxone or placebo administration.

Topics: Acupuncture Analgesia; Adult; Affect; Analgesia; beta-Endorphin; Blood Pressure; Heart Rate; Humans; Hypnosis; Male; Naloxone; Pain; Pain Management; Pain Measurement; Reference Values; Skin Physiological Phenomena

Experimental pain thresholds (electrical intracutaneous finger and dental pulp stimulation) and plasma hormone levels (beta-endorphin, cortisol, and catecholamines) were measured in ten healthy sportive men before, during, and after progressively more strenuous physical exercise. In a double-blind study conducted on two different days, 20 mg of the opioid-antagonist naloxone or placebo was administered prior to exercise. A significant pain threshold elevation was found during exercise for finger (ANOVA, P less than 0.004) and dental pulp stimulation (P less than 0.01). Pain threshold elevation was most pronounced during maximal exertion, at which time the subjects reported the greatest subjective fatigue. Thresholds remained elevated 10-15 min after the end of exercise, and, 60 min after exercise, thresholds returned to baseline values. The subjective magnitude estimation of suprathreshold stimuli was significantly reduced (P less than 0.0001) 5-10 min after exercise. Plasma beta-endorphin, cortisol, and catecholamines increased significantly (P less than 0.0005, all values) during exercise. Plasma beta-endorphin levels did not correlate significantly with pain thresholds (r = -0.37, NS). Naloxone failed to affect pain thresholds, although beta-endorphin and cortisol increased significantly more (P less than 0.02) during exercise after naloxone. It is concluded that short-term, exhaustive physical exercise can evoke a transient elevation in pain thresholds. This exercise-induced elevation in pain threshold does not, however, appear to be directly related to plasma endorphin levels.

Topics: Adult; Analysis of Variance; beta-Endorphin; Bicycling; Double-Blind Method; Epinephrine; Exercise; Humans; Hydrocortisone; Male; Middle Aged; Naloxone; Norepinephrine; Pain; Sensory Thresholds

Forty cancer patients were randomly assigned to two groups (n = 20). All had incapacitating pain unresponsive to the usual non opioid analgesic drugs. An epidural catheter was set up at the level of the most painful metamere, and made to pass subcutaneously so as to exit either in the supraclacicular fossa, or on the patient's flank. At T0, the patients were given 4 mg morphine hydrochloride diluted in 10 ml normal saline. Thirty min later, patients in the naloxone group (group N) were given a 0.4 mg bolus, followed by a constant rate infusion of 5 micrograms.kg-1.h-1, of naloxone hydrochloride during 18 h. Patients in group P (placebo) were given normal saline instead. The degree of pain was studied with a visual analogue scale and analgesia was assessed by a clinician on a five point scale. These two parameters were obtained half an hour after the injection of morphine and 2, 4, 6 and 24 hours later. At the same time, the patients were questioned about adverse side-effects: nausea, vomiting, pruritus, dysuria, urinary retention. Respiratory depression was assessed clinically and biologically (blood gas measurements at the afore mentioned times). Heart rate, systolic and diastolic blood pressure were also measured. There was no statistically significant difference between the groups in quality and duration of analgesia. Pain reached its lowest level 4 h after the injection of morphine, returning to half its original value at the 24th h. This was also true for the incidence of nausea (11 in group N, 5 in group P), vomiting (3 in both groups), and urinary retention (6 in group P, 5 in group N).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Analgesia, Epidural; Chronic Disease; Double-Blind Method; Female; Humans; Male; Middle Aged; Morphine; Naloxone; Nausea; Neoplasms; Pain; Pain Measurement; Pruritus; Respiration Disorders; Urinary Retention; Vomiting

In man, heterotopic painful thermal conditioning stimuli induce parallel decreases in the spinal nociceptive flexion (RIII) reflex and the concurrent sensation of pain elicited by electrical stimulation of the sural nerve at the ankle. Such phenomena may be related to the diffuse noxious inhibitory controls (DNIC) which were initially described in the rat and subsequently documented in humans. In nine subjects in the present study, a 2-min application of a moderately noxious temperature (46 degrees C) to the contralateral hand strongly depressed the RIII reflex elicited in the biceps femoris muscle by electrical stimulation of the sural nerve at 1.2 times the reflex threshold. These depressive effects were maximal during the 2nd min of the conditioning period, showing an almost complete inhibition of the RIII reflex which gradually recovered its baseline value 6-9 min after the end of the conditioning period. Using a double-blind, cross-over design, it was found that these inhibitory effects were completely blocked 5 min after naloxone hydrochloride administration (0.4 mg i.v.) whereas the administration of saline was totally ineffective. The lifting of the inhibitions was compatible with the short duration of the pharmacological effects of naloxone in that the inhibitions were observed again 50 min after the naloxone injection. During all the experimental sessions, heart and respiratory rates remained stable at their control levels. It is concluded that the loop subserving DNIC which ascends from--and redescends to--the spinal cord involves an opioidergic link in man as in experimental animals. Possible implications for hypoalgesia based on the principles of counter-irritation or elicited by naloxone are discussed.

Topics: Adult; Autonomic Nervous System; Conditioning, Operant; Electric Stimulation; Female; Heart Rate; Hot Temperature; Humans; Male; Naloxone; Pain; Physical Stimulation; Receptors, Opioid; Reflex; Respiration; Sensory Thresholds

The effect of acupuncture on sensory thresholds was studied in 6 healthy subjects. The modes of acupuncture studied were: 1. manual stimulation, 2. electrical stimulation at 2 Hz, 3. electrical stimulation at 80 Hz. Superfiscial-acupuncture was used as placebo. Insertions of needles or application of electrodes were bilateral, at St 7 (intrasegmental) or Li 4 (extrasegmental). The study showed that manual or electro-acupuncture were effective when used intrasegmentally, raising pain threshold values 1.1 to 1.4 times that prior to stimulation. The pain threshold elevation obtained was not significantly related to plasma levels of beta-endorphin, ACTH or prolactin. Other sensory thresholds, thermal, vibrotactile and electrotactile were unaffected by such conditioned stimulation. Superfiscial-acupuncture had no significant effect on the sensory thresholds tested.

Topics: Acupuncture Analgesia; Acupuncture Therapy; Adolescent; Adult; beta-Endorphin; Blood Pressure; Electroacupuncture; Evaluation Studies as Topic; Female; Heart Rate; Humans; Male; Naloxone; Pain; Pain Measurement; Sensory Thresholds; Thermosensing; Touch

In the present study involving healthy test subjects, tilidin/naloxone (Valoron N; VAL) proved to have an analgesic effect roughly twice as pronounced as that of tramadol (TRA). Moreover, the analgesic effect of VAL showed a significantly more rapid onset than did that of TRA. This finding reflects the difference in rate of action of the active substances. In accordance with these findings, VAL is thus the most powerful analgesic presently available on the German market on simple prescription.

Topics: Clinical Trials as Topic; Cyclohexanecarboxylic Acids; Cyclohexanols; Double-Blind Method; Drug Combinations; Humans; Naloxone; Pain; Pain Measurement; Random Allocation; Tilidine; Tramadol

The analgesic efficiency of ketamine and pethidine was compared in experimental ischemic pain and postoperative pain after oral surgery. Naloxone 1.6 mg or placebo was given 5 min before the analgesic drug. The subjects recorded their pain on a visual analogue scale. Both ketamine 0.3 mg/kg and pethidine 0.7 mg/kg were effective as analgesics against the two types of pain studied. Naloxone prevented the analgesic effect of pethidine, but had no effect on ketamine analgesia. The results are in accordance with the hypothesis that the analgesic effect of ketamine is mediated by a non-opioid mechanism, possibly involving PCP-receptor-mediated blockade of the NMDA-receptor-operated ion channel.

Topics: Adult; Female; Humans; Ischemia; Ketamine; Meperidine; Naloxone; Pain; Pain, Postoperative; Visual Pathways

It has been hypothesized that, in the absence of acute or chronic pain, a tonically active system exists involving opioid peptides, which ensures a certain level of pain insensitivity. Although various studies have failed to support this concept, it has been reported that in conditions of both experimentally induced and clinical pain, high doses of the opioid antagonist naloxone induced a state of hyperalgesia and thus seemed to set off this hypothetical system. Lower doses were, however, without effect or even acted as analgesics. This study investigated the effect of 5 and 20 mg naloxone i.v., compared to placebo, on the perception of pain in healthy humans. Pain was induced by two methods, using electrical and thermal stimulation of the skin, which have previously been shown to be sensitive to the effects of opioid as well as of non-steroidal anti-inflammatory analgesics. Each of 12 males and 12 females participated in 3 experimental sessions, in which the treatments were administered double-blind according to a Latin square design. Threshold and tolerance to electrically induced pain and threshold to thermally induced pain were measured at 30 min intervals for 90 min before and 90 min after drug administration. Electrical stimuli were square wave constant current impulses of linearly increasing intensity; thermal stimuli were of constant intensity and variable duration. Threshold and tolerance to electrically induced pain were not altered by either dose of naloxone, whereas the threshold to thermally induced pain was significantly higher after both 5 and 20 mg naloxone than after placebo, the effects of the two naloxone doses not differing from each other.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Electric Stimulation; Female; Hot Temperature; Humans; Male; Naloxone; Nociceptors; Pain; Pain Measurement; Sensory Thresholds; Skin

In a double-blind study, eight patients with symptomatic myocardial ischaemia and nine with asymptomatic myocardial ischaemia were compared during physical exercise under naloxone (6 mg i.v.) or placebo. Plasma beta-endorphin, cortisol and catecholamines were measured before exercise, during maximal exercise, and 10, 20 and 60 min after exercise. A tourniquet pain test (on the forearm, under control of transcutaneous PO2), and an electrical pain test (intracutaneous electrode placed in the finger with the electrical stimulus under computer control and two-interval forced-choice psychophysical technique) were performed before exercise as well as immediately after, and 60 min after exercise. Plasma beta-endorphin levels increased significantly (P less than 0.01) during exercise in symptomatic and asymptomatic patient groups; every patient showed an increase on beta-endorphins during and after exercise. However, the increase found in beta-endorphins during and after exercise was significantly larger (P less than 0.01) in asymptomatic than in symptomatic patients. After naloxone, this difference was no longer evident. Angina pectoris during exercise was reported with less latency in symptomatic patients (P less than 0.05) and occurred in two of nine asymptomatic patients following naloxone. The time course of plasma cortisol levels exhibited the same pattern as beta-endorphins with the same significant differences between symptomatic and asymptomatic groups. Electrical pain thresholds, though on average higher in asymptomatic patients (2.21 mA vs. 0.79 mA), were not affected by exercise or naloxone. Asymptomatic patients required more time to reach pain thresholds in the tourniquet pain test (P less than 0.02). After exercise, tourniquet pain thresholds were significantly lower (P less than 0.01) under naloxone compared with placebo.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Angina Pectoris; Catecholamines; Coronary Disease; Endorphins; Exercise; Humans; Hydrocortisone; Injections, Intravenous; Male; Middle Aged; Naloxone; Pain; Pain Measurement; Time Factors

This study was designed to examine the effects of aspirin, naloxone and placebo treatment on serum beta-endorphin concentration and joint pain in patients with rheumatoid arthritis (RA). Ten patients with definite or classical RA were studied. All treatments were administered in a randomized sequence. On each study day, the following measurements were carried out at specified time intervals: serum beta-endorphin concentration, serum salicylate concentration and joint pain score on a visual analogue horizontal scale. We conclude that in patients with rheumatoid arthritis suffering from chronic joint pain, serum beta-endorphin does not appear to play a role in pain relief.

Topics: Arthritis, Rheumatoid; Aspirin; beta-Endorphin; Clinical Trials as Topic; Double-Blind Method; Drug Therapy, Combination; Humans; Naloxone; Pain; Pain Measurement; Placebos; Random Allocation

Pain relief following stimulation of the periaqueductal gray matter (PAG) or periventricular gray matter (PVG) in man has been ascribed to stimulation-induced release of endogenous opioid substances. Forty-five patients were studied and followed for at least 1 year after placement of chronic stimulating electrodes in the PAG or PVG to determine if pain relief due to stimulation could be ascribed to an endogenous opioid mechanism. Three criteria were assessed: the development of tolerance to stimulation; the possibility of cross-tolerance to morphine; and reversibility of stimulation-induced pain relief by the opiate antagonist naloxone. Sixteen patients (35.6%) developed tolerance to stimulation, that is, they obtained progressively less effective pain relief. Twelve (44.4%) of 27 patients undergoing stimulation of the thalamic sensory relay nuclei for treatment of chronic pain (a presumably non-opioid mechanism) also developed tolerance. Morphine sulfate was administered in a blind, placebo-controlled protocol to 10 patients who had become tolerant to PAG-PVG stimulation and none showed evidence of cross-tolerance. Fifteen of 19 patients, already tolerant to morphine at the time of PAG-PVG electrode implantation, experienced excellent pain relief by stimulation, also indicating a lack of cross-tolerance. Twenty-two patients who experienced excellent pain relief from chronic PAG-PVG stimulation received intravenous naloxone in a double-blind, placebo-controlled protocol. Pain intensity as assessed by the visual analog scale was increased to the same degree by both placebo and naloxone. Eight patients showed no increase in pain intensity with either placebo or naloxone. Although tolerance to PAG-PVG stimulation developed in these patients, the frequency of tolerance was similar to that seen in patients undergoing thalamic sensory nuclear stimulation. Since the latter technique presumably relieves pain by a non-opioid mechanism, the development of tolerance to PAG-PVG stimulation does not, in itself, confirm an opioid mechanism. Cross-tolerance between PAG-PVG stimulation and morphine was not seen and cross-tolerance to PAG-PVG stimulation in patients already tolerant to morphine was rare. The pain-relieving effect of PAG-PVG stimulation was reversed to an approximately equal degree by naloxone and placebo. The authors do not believe that, in most patients, pain relief elicited by PAG-PVG stimulation depends on an endogenous opioid mechanism. It appears tha

Topics: Cerebral Aqueduct; Cerebral Ventricles; Chronic Disease; Electric Stimulation Therapy; Endorphins; Humans; Naloxone; Pain; Pain Management; Placebos; Sensory Thresholds

Previous studies have shown that muscle exercise and low frequency transcutaneous nerve stimulation (TNS) give rise to an analgesic effect in humans and animals. Endorphin has been proposed to mediate this analgesia. In this investigation, the effect of muscle exercise and low frequency TNS, on dental pain thresholds was studied and the possible involvement of endorphinergic mechanisms was investigated using naloxone as an antagonist. Dental pain thresholds were measured in 11 volunteers following leg or arm exercise and after low frequency TNS of the hands or face. After exercise (20 min) or stimulation (30 min) either 0.8 mg naloxone (2 ml) or saline (2 ml) was injected i.v. in a double-blind fashion. Pain thresholds were measured repetitively before and after exercise or stimulation. Both leg and arm exercise increased pain threshold. Stimulation of the hands also increased pain threshold, but less than arm exercise. A marked increase in pain threshold was seen after face stimulation. These changes in pain threshold were unaffected following injections of either naloxone or saline, except for an early and short-lasting reduction when naloxone was injected following arm exercise. The increases in pain threshold following muscle exercise and after low frequency TNS, showed similarities suggesting that a common mechanism might be involved. The pain threshold increase after arm exercise could only be partially mediated by endorphinergic mechanisms.

Topics: Adult; Anesthesia, Dental; Double-Blind Method; Electric Stimulation Therapy; Humans; Muscle Contraction; Naloxone; Nociceptors; Pain; Physical Exertion; Sensory Thresholds; Sodium Chloride; Tooth; Transcutaneous Electric Nerve Stimulation

Sixty patients suffering from moderate to severe pain following either orthopaedic or gynaecological surgery were treated with intramuscular buprenorphine (0.3 mg) or an intramuscular combination of buprenorphine (0.3 mg)/naloxone (0.2 mg) and the analgesic efficacy and safety of the two treatments was compared. The evaluation of efficacy showed that both treatments provided good analgesia which was apparent at the first assessment time (10 minutes) and continued for approximately 10 hours. Only seven patients suffered from unwanted side-effects with only drowsiness/sleepiness and nausea being reported by more than one patient. Over-all analysis of the results showed that there were no significant differences between the two treatments with regard to efficacy and safety.

Topics: Adolescent; Adult; Aged; Analgesia; Buprenorphine; Drug Therapy, Combination; Female; Humans; Kinetics; Male; Middle Aged; Morphinans; Naloxone; Pain; Postoperative Complications

Forty-eight patients received either naloxone (10 mg), fentanyl (0.1 mg), diazepam (0.3 mg/kg), or saline solution placebo, and then underwent surgical removal of impacted third molars under local anesthesia. Placebo resulted in significantly elevated levels of immunoreactive beta-endorphin (i beta-END), norepinephrine, and anxiety during surgery. Patients receiving naloxone had significantly greater intraoperative i beta-END and pain as compared with those receiving placebo. The naloxone effect on intraoperative pain was a result of a difference in perceived unpleasantness. Both the fentanyl and diazepam groups had significantly lower intraoperative i beta-END and anxiety levels as compared with the placebo group. Norepinephrine levels increased significantly in response to surgical stress in all groups except the diazepam group. Postoperative circulating levels of i beta-END and norepinephrine and pain increased significantly from the 1 to 3-hour postoperative period for all groups, with the exception of stable norepinephrine levels observed in patients receiving diazepam. Results indicate that opiate antagonists stimulate and agonists suppress the release of i beta-END, possibly by affecting the patient's perceived level of pain and anxiety. In addition, the association of intraoperative hyperalgesia with naloxone predosing suggests that endogenous opioid peptides inhibit the perception of intraoperative pain even in the presence of concurrent local anesthesia.

Topics: Diazepam; Double-Blind Method; Drug Evaluation; Endorphins; Fentanyl; Humans; Intraoperative Period; Molar, Third; Naloxone; Pain; Premedication; Tooth, Impacted

The analgesic effects of a repetitive stress induced by anticipation of pain (noxious footshock) were studied on both the threshold of a nociceptive flexion reflex and the corresponding pain sensation after a 4-day-treatment of diazepam vs placebo (cross-over and double-blind study) in normal volunteers. During diazepam, the stressor stimulus produced a weaker depression on both nociceptive reflex and pain sensation than that observed during placebo. Furthermore, the reversal effect by naloxone was much more marked during placebo than during diazepam. These data clearly suggest a possible moderating action of benzodiazepine brain type receptors upon the endogenous opiate systems involved in the phenomenon of stress-induced analgesia in humans.

Topics: Adult; Analgesia; Diazepam; Differential Threshold; Dose-Response Relationship, Drug; Double-Blind Method; Electroshock; Female; Foot; Humans; Male; Naloxone; Nociceptors; Pain; Reflex; Stress, Physiological

Two double blind cross-over studies were performed using a submaximal effort tourniquet test (SETT) in healthy volunteers to investigate the role of endogenous opioids in placebo analgesia. In the first study IV naloxone significantly inhibited analgesia, miosis and sedation produced by the opioid dipipanone 10 mg in 12 subjects. In the second naloxone, which did not produce hyperalgesia, failed to inhibit significant placebo analgesia in 12 subjects. The results do not support the involvement of endogenous opioids in ischemic limb pain or placebo analgesia under these conditions.

Topics: Adult; Analgesia; Analgesics, Opioid; Codeine; Endorphins; Female; Humans; Male; Methadone; Middle Aged; Naloxone; Pain; Pain Management; Placebos

Topics: Abdomen; Adult; Aged; Chronic Disease; Double-Blind Method; Female; Humans; Infusions, Parenteral; Middle Aged; Naloxone; Pain

In this study we describe the use of high-frequency transcutaneous electrical nerve stimulation (TENS) (100 Hz) and low-frequency TENS (lf-TENS) (2 Hz trains) as compared with placebo-TENS (p-TENS) in a group of 21 patients suffering from primary dysmenorrhea. Naloxone, a relatively pure opiate antagonist, was an additional test administered to 6 volunteer patients who had experienced an alleviation of pain with TENS. As will be seen, 14 out of 21 patients receiving high-frequency TENS (hf-TENS) experienced a pain reduction exceeding 50% of its original intensity. During lf-TENS or p-TENS, only 7 and 5 patients, respectively, obtained pain relief exceeding 50%. In 4 out of 6 volunteer patients, the relief of pain obtained with lf-TENS was counteracted by naloxone, whereas the relief experienced with hf-TENS in the same patients was, in general, unaffected by naloxone.

Topics: Adolescent; Adult; Clinical Trials as Topic; Dysmenorrhea; Electric Stimulation Therapy; Female; Humans; Naloxone; Pain; Pain Management; Transcutaneous Electric Nerve Stimulation; Verapamil

In a multicenter study 153 in- and outpatients suffering from severe pain were treated for three weeks with capsules containing 50 mg 1-(m-methoxyphenyl)-2-(dimethylaminomethyl)-cyclohexan-1-ol (tramadol, Tramal). The daily dosage was limited to 400 mg. At the end of the third week the patients received in a randomized double-blind manner 1.6 mg naloxone or saline (both i.m.) to evaluate the risk of developing dependence during the 3-week tramadol treatment (precipitation test). A total of 109 patients completed the trial. Development of tolerance was not observed as was evident from a constant daily tramadol dose associated with constant analgesia. The median net withdrawal scores for the naloxone treated group (mean = 0, Xmin = 0, Xmax = 13) and for the saline treated group (mean = 0, Xmin = 0, Xmax = 5) indicate absence of dependence. The outcome of the study thus suggests that tramadol under the conditions described does not induce dependence.

Topics: Administration, Oral; Adult; Aged; Cyclohexanols; Double-Blind Method; Drug Administration Schedule; Female; Humans; Injections, Intramuscular; Male; Middle Aged; Naloxone; Pain; Precipitin Tests; Random Allocation; Substance Withdrawal Syndrome; Substance-Related Disorders; Tramadol

The effects of intense exercise on pain perception, mood, and plasma endocrine levels in man were studied under naloxone and saline conditions. Twelve long-distance runners (mean weekly mileage = 41.5) were evaluated on thermal, ischemic, and cold pressor pain tests and on mood visual analogue scales (VAS). Blood was drawn for determination of plasma levels of beta-endorphin-like immunoreactivity (BEir), growth hormone (GH), adrenocorticotrophic hormone (ACTH), and prolactin (PRL). These procedures were undertaken before and after a 6.3 mile run at 85% of maximal aerobic capacity. Subjects participated on two occasions in a double-blind procedure counterbalanced for drug order: on one day they received 2 i.v. injections of naloxone (0.8 mg in 2 ml vehicle each) at 20 min intervals following the run; on the other day, 2 equal volume injections of normal saline (2 ml). Sensory decision theory analysis of the responses to thermal stimulation showed that discriminability, P(A), was significantly reduced post-run under the saline condition, a hypoalgesic effect; response bias, B, was unaffected. Ischemic pain reports were significantly reduced post-run on the saline day, also a hypoalgesic effect. Naloxone reversed the post-run ischemic but not thermal hypoalgesic effects. Joy, euphoria, cooperation, and conscientiousness VAS ratings were elevated post-run; naloxone attenuated the elevation of joy and euphoria ratings only. Plasma levels of BEir, ACTH, GH, and PRL were significantly increased post-run. The results show that long-distance running produces hypoalgesia and mood elevation in man. The effects of naloxone implicate endogenous opioid neural systems as mechanisms of some but not all of the run-induced alterations in mood and pain perception.

Topics: Adrenocorticotropic Hormone; Adult; Affect; beta-Endorphin; Endorphins; Growth Hormone; Hormones; Humans; Male; Naloxone; Pain; Physical Exertion; Prolactin; Running; Sensory Thresholds

The effect of fentanyl (opioid agonist) and naloxone (morphine antagonist) on the amplitude, area and latency of the P300 auditory potential was studied in patients undergoing minor surgical procedures. Fentanyl (5.0 micrograms/kg), naloxone (3.0 micrograms/kg) and isotonic saline (for control) were injected intravenously through a catheter just before surgery, and following a single-blind procedure and three different pharmacological paradigms with three consecutive conditions each: (1) initial baseline (C), saline (S) and late baseline (C'); (2) C, fentanyl (F) and C'; (3) C, naloxone (N) and C'. Fentanyl significantly reduced the amplitude and area with no changes in the latency of small (S) and large (L) P300 potentials. Concomitantly, fentanyl increased the number of omitted counts of the target tones of the "odd ball" P300 test and the spatial threshold of the two point discrimination test in patients with small and large P300 potentials. Naloxone significantly increased the amplitude and area and decreased the latency of the small P300 potential and decreased the amplitude and area with no changes in latency of the large P300 potentials. Concomitantly, naloxone decreased the number of omitted counts of the patients with small but not large P300 potentials and decreased the spatial threshold in patients with both small and large P300 potentials. Neither fentanyl nor naloxone produced systematic changes in the evaluation of pain and hearing of patients with small and large P300 potentials. Although dramatic changes in pulse, blood pressure, respiration and EEG were found in some cases immediately after the administration of fentanyl and naloxone, these changes were not consistent and were not present at the time other tests were performed.

Topics: Adult; Electroencephalography; Evoked Potentials, Auditory; Female; Fentanyl; Humans; Male; Naloxone; Pain; Sensory Thresholds

The effect of 8 mg IV naloxone on pain appreciation was studied with electric shocks administered to the left forearm of 20 normal volunteers. Pain sensitivity was assessed with a psychophysical task and with evoked potentials (EP) to the pain stimuli which were found sensitive to opiate agonists and antagonists in previous experiments. Naloxone-induced hyperalgesia before and after 20 min of intermittent shock was assessed in a 3-day placebo crossover experiment designed to provide control comparisons of time effects. EP amplitude enhancement with naloxone was significantly greater following 20 min of shocks than preceding them, while pain judgments were not significantly affected. Thus, naloxone increases pain sensitivity, especially after prolonged pain stimulation. This finding is consistent with endorphin mediation of stress-induced analgesia and raises the question of whether this type of response decrement over time is related to the phenomena of habituation.

Topics: Adult; Electric Stimulation; Evoked Potentials, Somatosensory; Female; Humans; Male; Morphine; Naloxone; Pain; Time Factors

The hypothesis that the alleviation of chronic pain with hypnosis is mediated by endorphins was tested. Six patients with chronic pain secondary to peripheral nerve irritation were taught to control the pain utilizing self-hypnosis. Each subject was tested at 5-min intervals during four 1-h sessions for the amount of reduction of pain sensation and suffering associated with hypnosis while being given, in a random double-blind crossover fashion, an IV injection of either 10 mg naloxone or a saline placebo through an indwelling catheter. The patients demonstrated significant alleviation of the pain with hypnosis, but this effect was not significantly diminished in the naloxone condition. These findings contradict the hypothesis that endorphins are involved in hypnotic analgesia.

Topics: Adult; Aged; Chronic Disease; Double-Blind Method; Endorphins; Female; Humans; Hypnosis, Anesthetic; Male; Middle Aged; Naloxone; Pain; Pain Management; Time Factors

Twelve normal male volunteers received saline control, low-dose naloxone, and high-dose naloxone infusions during three weekly sessions. The sessions were 16 hr long: 1 hr for predrug assessments, 8 hr during which either naloxone or saline was infused in a double-blind procedure, and a 7-hr postdrug observation period. The 8-hr infusions of naloxone had no effect on experimental ischemic arm pain. In addition, the ischemic arm pain procedure did not significantly increase either plasma levels of cortisol or immunoreactive beta-endorphin, suggesting that the procedure was not stressful. The high-dose naloxone infusion resulted in a slightly aversive mood state and prevented the normal circadian decrease in cortisol levels. Both doses of naloxone increased systolic blood pressure and prevented the normal diurnal increase in temperature. The 8-hr infusions of naloxone did not result in changes in pain, mood, or physiological indices beyond what was present within a few hours after starting the infusion.

Topics: Adult; Affect; Analgesics; Attention; Cardiovascular System; Humans; Male; Memory; Naloxone; Pain; Respiration; Wakefulness

In recent papers (8, 12, 13) it has been shown that the analysis of event related brain potentials has become a powerful tool in attempts to quantify pain experience in man. However, the following conditions have to be fulfilled when cerebral potentials are used to measure experimentally induced pain, as well as pain relief under pharmacological treatments: 1) randomization of stimulus intensities to minimize effects of habituation within and between sessions (3), 2) randomization of interstimulus intervals with a minimum distance of about 15 seconds to avoid overlapping effects, and 3) control of the power spectral density of brain activity immediately before the stimulus is applied. In searching for pain related cerebral potentials a principal component analysis was utilized. The grand mean of all evoked potentials (analysis period 500 ms) was built, and the brain potentials were decomposed into basic waveforms for the different experimental conditions (painful-nonpainful; different kinds of skin stimuli). Two components were found as correlates of the painfulness in a sample of 8 healthy untreated subjects (4). In order to demonstrate the usefulness and sensitivity of the here described methods to quantify analgesic effects in man, the opioide tilidine and the opiate antagonist naloxone were orally administered in different combinations. In detail, the 5 treatments: tilidine (100 mg), naloxone (32 mg), tilidine (100 mg) + naloxone (8 mg), tilidine (100 mg) + naloxone (32 mg), and placebo, were given double blind (3 replications of 5 X 5 Latin squares) in 15 healthy subjects, each participating in 5 sessions with exactly 3 days intervals.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Analgesics; Brain; Drug Evaluation; Evoked Potentials; Humans; Naloxone; Pain; Tilidine

A double-blind randomized placebo-controlled study was carried out in 8 healthy volunteers to determine whether the analgesic and other actions of meptazinol could be reversed by naloxone or hyoscine. Heart rate, blood pressure, respiratory rate, pupil diameter, forearm ischaemic exercise tolerance and dental pain threshold were measured before and up to 45 minutes after intramuscular meptazinol 100 mg or placebo, when 'reversal' was attempted with intravenous naloxone 2 mg, hyoscine 1.6 mg or placebo. Meptazinol caused mild pupillary constriction which is unlikely to be clinically significant. Forearm ischaemic exercise tolerance failed to show any analgesic effect of meptazinol. Measurement of dental pain threshold strongly suggested reversal of meptazinol analgesia by naloxone but not by hyoscine, but inter-subject variation in analgesic response was great and these results require confirmation in a group pre-selected for consistent response.

Topics: Adult; Analgesics; Azepines; Dental Pulp; Humans; Ischemia; Male; Meptazinol; Naloxone; Pain; Physical Exertion; Sensory Thresholds; Time Factors

The effects of the opioid tilidine and the opiate antagonist naloxone on somatosensory evoked potentials (SSEP) and pain ratings (E), elicited by electrical skin stimuli with randomized intensities, were investigated for different, orally administered tilidine and naloxone combinations in a double-blind Latin square design in 15 healthy humans. A high correlation between SSEP amplitudes and E was found for all treatments investigated. Tilidine (100 mg) decreased both SSEP amplitudes and E by about 25% compared to the placebo. No significant differences were found between the analgesic effects of tilidine and TN8 (tilidine 100 mg; naloxone 8 mg). The effects of both treatments were significantly different from those of the naloxone, placebo and TN32 treatments (tilidine 100 mg; naloxone 32 mg), indicating a marked naloxone-induced reversal of tilidine analgesia. Naloxone (32 mg) increased the SSEP amplitudes. No naloxone-induced hyperalgesia was seen in the pain ratings.

Topics: Adult; Analysis of Variance; Cyclohexanecarboxylic Acids; Evoked Potentials, Somatosensory; Humans; Male; Naloxone; Pain; Sensory Thresholds; Tilidine

The effect of ceruletide (CRL), a synthetic decapeptide analogue of cholecystokinin, on rest pain and arterial blood flow was evaluated in 8 patients with advanced, occlusive atherosclerosis of the lower extremities. CRL 1, 2, or 4 ng kg-1 or placebo were infused intravenously in random order, and in a double-blind fashion. Pain relief, assessed by a scoring system, was significantly better (p less than 0.01) following the 2 and 4 ng kg-1 doses of CRL (2.71 and 2.66, respectively) than following placebo (0.75). Arterial blood flow was not affected by either CRL in any dose or by placebo. Pretreatment with naloxone, a pure opioid antagonist, abolished the analgesic effect of CRL. Following the 2 ng dose of CRL, beta-endorphin levels were significantly elevated from a basal value of 125 +/- 15 pg/ml to 191 +/- 35 pg/ml 5 h after CRL administration (p less than 0.05). Circulating levels of ACTH, prolactin and GH were not affected by CRL. It is concluded that CRL was effective in relieving ischaemic rest pain, and that the mechanism was related to the release of endogenous opioids.

Topics: Adrenocorticotropic Hormone; Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal; Arteriosclerosis; beta-Endorphin; Ceruletide; Endorphins; Female; Gas Gangrene; Humans; Leg; Leg Ulcer; Male; Middle Aged; Naloxone; Pain; Rest

Schizophrenics treated with high doses of diazepam (150-200 mg/day) showed marked analgesia besides certain antipsychotic effects. Euphoria was noticed in some of the patients. We hypothesized that influence on the endorphin metabolism might contribute to these clinical effects. Therefore, we measured pain threshold by three different methods before and during diazepam treatment. All patients exhibited a 1.5- to 2-fold increase of pain perception. Further, using a double-blind design, the opiate antagonist naloxone (30 mg i.v.) was administered. A significant decrease but not a complete block of the euphoric state and of analgesia was achieved. It is, therefore, concluded that other pharmacological properties of diazepam might be involved in the diazepam-induced euphoria and analgesia in man.

Topics: Adult; Analgesia; Diazepam; Endorphins; Euphoria; Female; Humans; Male; Middle Aged; Naloxone; Pain; Schizophrenia

The effects of a repetitive stress (expectation of severe pain) on the threshold of a nociceptive flexion reflex of the lower limb (Rlll, Bi) were investigated in normal subjects. A progressive and significant rise of the Rlll, Bi Threshold was observed as the stress was repeated several times over a 60 to 90 minutes' period. This effect was entirely reversed by naloxone, with fall of the threshold below initial values. In a double-blind test, the injection of a placebo had no significant effect on the reflex threshold when compared with control values. These results are in agreement with those reported in animals. They provide experimental evidence for an involvement of endogenous opiate systems in the mechanism of stress in normal subjects.

Topics: Adult; Electrophysiology; Female; Humans; Male; Naloxone; Pain; Reflex; Stress, Physiological; Time Factors

Topics: Acute Disease; Adult; Aged; Brain Ischemia; Cerebral Infarction; Double-Blind Method; Female; Hemiplegia; Humans; Morphine; Naloxone; Pain

The possible reversal of nitrous oxide analgesia by naloxone was investigated. Two studies were conducted in 21 healthy male subjects, who responded to ischemic pain produced by tourniquet applied to the upper arm for 15 min, while breathing air or nitrous oxide, 33 per cent. Using a double-blind procedure, the subjects received intravenous injections of naloxone and saline solution on different days. In eight subjects, naloxone, 8 mg, administered without nitrous oxide, had no effect on pain report. However, unlike saline solution, naloxone, 8 mg, decreased significantly the analgesia induced by nitrous oxide. In 13 subjects, naloxone, 4 mg, also decreased significantly the effect of nitrous oxide analgesia in comparison with saline solution. Naloxone showed its reversal effect mainly on sensory response rating obtained during the painful stages of ischemia, between 11 and 15 min. The results suggest that analgesia induced by nitrous oxide may be partly related to the opiate receptor--endorphin system in man.

Topics: Analgesia; Arm Injuries; Drug Antagonism; Humans; Ischemia; Male; Naloxone; Nitrous Oxide; Pain; Tourniquets

Topics: Adult; Clinical Trials as Topic; Endorphins; Humans; Hypnosis, Anesthetic; Male; Naloxone; Pain

In this study the hypothesis that hypnotic analgesia under conditions of stress is mediated through a neurochemical mechanism involving the release of opioid peptides in the CNS was investigated. Ten highly hypnotizable subjects participated in a 2 x 2 factorial design, which involved hypnotic analgesia, stress and double blind administration of naloxone (an opiate antagonist) or placebo. Analysis of post-hypnosis results indicates that hypnotic analgesia was significantly reversed by the interactive effects of stress and naloxone. It is inferred that stress may be the common psychological denominator of the various analgesic methods which effectively engage this endogenous pain inhibitory system. Additional analyses of anxiety measures reveals no significant association between trait and state anxiety, but significant relationships between state anxiety and time tolerance to ischemic pain. These results suggest that anxiety remains a definitional problem and that previous conceptualizations may not have satisfactorily explained the affect's adaptive function.

Topics: Adult; Anxiety; Female; Humans; Hypnosis, Anesthetic; Male; Memory; Naloxone; Pain; Stress, Psychological

Sixteen healthy subjects participated in an investigation of the interactive effects of naloxone and personal expectations of control, stress, and anxiety, on time tolerance to ischemic pain. Control and anxiety levels provided no significant naloxone-saline discriminations, but there was a significant interaction between stress levels and naloxone-induced reduction in tolerance to ischemia. This finding suggests that activity in the opiate system may be a function of the modifying influences of variable attitudes to environmental stress. A primary analgesic role for the endorphins is challenged, however, by the findings that tolerance levels failed to reveal naloxone reactors and stress levels were not significantly associated with differences in tolerance. The latter, on the other hand, correlated significantly with control and anxiety levels, indicating that further research is needed to clarify the complex relationship between these three variables and their effects on the modulation of pain perception.

Topics: Adult; Attitude; Female; Humans; Ischemia; Male; Naloxone; Pain; Sex Factors; Stress, Psychological

To test the possibility of endorphin release in clinical pain states naloxone was given, alternate with saline, in a double-blind study to 10 patients with chronic neuralgia or low back pain. There was no significant alteration of the levels of spontaneous pain or heat pain thresholds. The results suggest that the endorphin system does not offer protection of any importance in chronic pain.

Topics: Adult; Back Pain; Clinical Trials as Topic; Double-Blind Method; Endorphins; Female; Hot Temperature; Humans; Male; Middle Aged; Naloxone; Pain; Sensory Thresholds

Topics: Adult; Analgesia; Clinical Trials as Topic; Dose-Response Relationship, Drug; Double-Blind Method; Endorphins; Female; Humans; Male; Naloxone; Pain; Postoperative Period; Receptors, Opioid; Time Factors

Topics: Adult; Analgesia; Clinical Trials as Topic; Endorphins; Humans; Hypnosis; Injections, Intravenous; Naloxone; Pain; Suggestion; Time Factors

In 30 human subjects, experimental pain was produced by either ischemia or cold-water immersion. In a double-blind procedure, intravenous doses of up to 10 milligrams of naloxone hydrochloride in saline were indistinguishable from similarly administered saline alone. There were no effects on subjective pain ratings, finger plethysmograph recordings, or responses to mood-state questionnaires. These laboratory procedures do not activate any functionally significant pain-attenuating or mood-altering effect of endorphins.

Topics: Clinical Trials as Topic; Double-Blind Method; Emotions; Endorphins; Female; Humans; Male; Naloxone; Pain; Surveys and Questionnaires

Topics: Analgesics; Clinical Trials as Topic; Cyclohexanols; Humans; Naloxone; Pain; Placebos; Substance Withdrawal Syndrome; Substance-Related Disorders; Time Factors

Topics: Adolescent; Adult; Clinical Trials as Topic; Double-Blind Method; Female; Humans; Male; Naloxone; Pain; Tooth, Impacted

Topics: Circadian Rhythm; Evoked Potentials; Female; Humans; Male; Naloxone; Pain; Somatosensory Cortex

The hypothesis that painful stimuli activate the endogenous opioid (endorphin) system in humans was tested by examining the effect of the opiate antagonist naloxone on experimentally induced ischemic pain and on subjective mood ratings. Intravenous injections of saline or naloxone hydrochloride (2 and 10 mg) were administered under double-blind conditions to 12 subjects. Naloxone did not affect the pain ratings. However, a significant dose-related effect of naloxone on tension-anxiety was found, suggesting that the endorphins. like exogenously administered opiates, may have antianxiety properties.

Topics: Adult; Anxiety; Arm; Clinical Trials as Topic; Emotions; Female; Humans; Ischemia; Male; Naloxone; Pain; Surveys and Questionnaires

Previous research implicates an endogenous central pain inhibitory mechanism in opiate analgesia, analgesia produced by focal electrical stimulation of the brain, and acupuncture analgesia. This investigation evaluates the possibility that analgesia produced by hypnosis is also mediated by such a mechanism. Results suggest that hypnotic analgesia is unlikely to involve this central pain inhibitory mechanism since hypnotic analgesia is not altered by naloxone hydrochloride, a specific narcotic antagonist. Results further demonstrate that the hypnotic procedure used produces an unusually effective and reliable increase in pain threshold. This finding generalizes to the control of clinical dental pain, and suggests that hypnotic pain control is a more widespread phenomenon in the population than has been thought.

Topics: Adolescent; Adult; Clinical Trials as Topic; Double-Blind Method; Electric Stimulation; Evaluation Studies as Topic; Female; Humans; Hypnosis, Dental; Male; Naloxone; Nociceptors; Pain; Tooth

Topics: Adult; Clinical Trials as Topic; Dose-Response Relationship, Drug; Double-Blind Method; Electroshock; Evoked Potentials; Female; Humans; Male; Naloxone; Pain; Somatosensory Cortex

Topics: Adolescent; Adult; Anesthesia, Dental; Clinical Trials as Topic; Double-Blind Method; Electronarcosis; Endorphins; Humans; Male; Naloxone; Pain; Trigeminal Nerve

Topics: Blood Pressure; Carbon Dioxide; Depression, Chemical; Drug Synergism; Humans; Injections, Intravenous; Levallorphan; Male; Naloxone; Narcotic Antagonists; Narcotics; Pain; Placebos; Psychological Tests; Pupil; Reaction Time; Respiration

Topics: Adolescent; Adult; Aged; Analgesia; Blood Pressure; Body Weight; Clinical Trials as Topic; Doxapram; Drug Interactions; Heart Rate; Humans; Middle Aged; Morphine; Naloxone; Pain; Postoperative Care; Respiration; Time Factors

The effects of intravenous naloxone on several of the actions of intravenous morphine (mean dose 30 mg/70 kg) were studied in six volunteer subjects. Naloxone produced a well defined reversal of the respiratory depression, analgesia, and miotic and subjective effects of the morphine. The agonist action of morphine outlasted the antagonist action of a single dose of naloxone. The effect of repeated doses of naloxone was also short-lived, but continuous infusions were effective in maintaining reversal.

Topics: Arousal; Blood Pressure; Carbon Dioxide; Catheterization; Constriction; Humans; Male; Morphine; Naloxone; Nausea; Pain; Pupil; Respiration

Topics: Analysis of Variance; Clinical Trials as Topic; Drug Interactions; Humans; Injections, Intramuscular; Injections, Subcutaneous; Male; Naloxone; Pain; Pentazocine; Placebos; Substance Withdrawal Syndrome; Substance-Related Disorders; Time Factors

The phenomenon of alcohol analgesia and tolerance can facilitate misuse and lead to the development of alcohol use disorder (AUD). Numerous alcohol-induced behaviors are genetically influenced; however, it is unknown if alcohol analgesia has a genetic contribution. Rodent studies have shown that alcohol responses differ vastly between two widely studied inbred strains of mice, C57BL/6 J (B6) and DBA/2 J (D2). Here, we used B6 and D2 mice as an initial behavioral genetic analysis of acute alcohol-induced antinociception.. The antinociceptive effect of orally-administered alcohol was characterized using the hot plate test in B6 and D2 mice of both sexes. Using the opioid receptor antagonist naloxone, the involvement of the opioid system was assessed. Locomotor activity and blood alcohol concentrations were also measured. Ovariectomized mice were used to evaluate the influence of ovarian sex hormones on alcohol-induced antinociception.. Alcohol induced an antinociceptive effect in B6 and D2 male mice in a time- and dose-dependent manner. In addition, D2 male mice were more sensitive to the antinociceptive effect of alcohol than B6 male mice. However, locomotion is not impeded by the tested doses of alcohol in B6 mice. Female D2 and B6 mice failed to show significant antinociceptive effects in alcohol dose-response studies. In addition, alcohol-induced antinociception was still not evident in ovariectomized female mice. Male mice of both strains developed tolerance to this effect after repeated administration of alcohol. Strain differences were found in blood alcohol concentration. Finally, no difference was found in the blockade of alcohol antinociception by 2 mg/kg naloxone.. Our results indicate that the antinociceptive effects of alcohol in the hot plate test are influenced by strain and sex. These findings support further genetic analysis of alcohol-induced antinociception to identify operative mechanisms and better assess the contribution of this phenotype to AUD.

Topics: Alcoholism; Analgesics, Opioid; Animals; Blood Alcohol Content; Ethanol; Female; Male; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Naloxone; Narcotic Antagonists; Pain

Open-label placebos, or placebos without deception, have been found to induce analgesia, a challenging concept that need to be investigated in detail. In particular, what we need to know is the mechanism through which analgesia is induced when no deception is involved. In this study, we show for the first time that open-label placebo analgesia can be reversed by the opioid antagonist naloxone, as already shown for deceptive placebos. To do this, we used the tourniquet technique to induce experimental ischemic arm pain. The open-label placebo challenge started when pain scores reached 7 on a 0 to 10 rating scale. Although 59.4% of the subjects did not respond to the open-label placebo, 40.6% showed a substantial response. On the basis of the natural history control group, a placebo responder reported pain scores equal to or less than 7 after 9 minutes from the open-label placebo administration. In these responders, we found that a hidden injection of 10 mg naloxone could reverse placebo analgesia compared with a hidden injection of saline solution. At least 2 control groups showed that naloxone per se was not hyperalgesic, thus ruling out naloxone-induced hyperalgesia as a confounding variable. In light of the need to better understand open-label placebo effects, these findings represent the first experimental evidence that nondeceptive placebo analgesia may be mediated by the same mechanisms as deceptive placebo analgesia, namely the endogenous opioid systems.

Topics: Analgesia; Humans; Naloxone; Narcotic Antagonists; Pain; Pain Management; Placebo Effect

Rhus genus is commonly known as sumac and widely used in the folk medicine. Rhus virens is a plant commonly used to treat diabetes or pain in the northern territory of Mexico. Even though R. virens is used in the folk medicine there is still a lack of evidence about the pharmacological effect of this species.. The aim of this study was to determine the antinociceptive, anti-inflammatory and antioxidant effect of R. virens through a bio-guided chemical separation.. The aqueous, methanolic, and hexane extract of R. virens were obtained and tested in the formalin test, TPA-induced ear edema, and DPPH, ABTS, and FRAP assay. Also, possible interaction of pain pathways was studied using naloxone, bicuculline, L-NAME, ODQ, and glibenclamide in the formalin test in mice.. Rhus virens methanolic extract (30 mg/kg, p.o.) produced higher antinociceptive activity in both the early and late phases of the formalin test (35.0 and 52.9%, respectively). Also, pre-administration with naloxone, bicuculline, L-NAME, ODQ and glibenclamide prevented the antinociceptive effect of R. virens in the early phase of the formalin test. Meanwhile, only naloxone and bicuculline prevented the antinociceptive effect on the late phase of the formalin test. Chemical separation of methanolic extract allowed to isolate 1,2,3,4,6-penta-O-galloyl-glucopyranose (PGG), it was tested in the formalin test, producing an antinociceptive effect on the late phase of the formalin test. On the other hand, topical application of the derivatives of R. virens methanolic extract produced an anti-inflammatory effect in the TPA-induced ear edema, being PGG an anti-inflammatory molecule. Lastly, radical scavenging activity was higher in the extracts of higher polarity, comparable to the standard used Camellia sinensis.. In conclusion, R. virens produce an antinociceptive, anti-inflammatory and free-radical scavenging activity. The antinociceptive effect could be related to the opioidergic, GABAergic, and NO-GMPc-K + ATP channels pathways. These effects could be partially produced by the presence of PGG.

Topics: Adenosine Triphosphate; Analgesics; Animals; Anti-Inflammatory Agents; Antioxidants; Bicuculline; Edema; Glyburide; Hexanes; Mice; Naloxone; NG-Nitroarginine Methyl Ester; Pain; Plant Extracts; Plant Leaves; Rhus

Opioid-induced constipation (OIC) may occur in up to 81% of critically ill patients and can lead to many complications. Opioid antagonists are a reasonable approach and may be used for managing OIC.. The purpose of this study was to assess the efficacy of enteral naloxone (NLX) versus subcutaneous methylnaltrexone (MNTX) for the management of OIC in critically ill patients.. A retrospective analysis was conducted on adult patients who received NLX or MNTX and a continuous opioid infusion for at least 48 hours. The primary end point was time to resolution of constipation, defined as hours to first bowel movement (BM) after the first dose of an opioid antagonist. Reversal of analgesia was assessed by comparing the total number of morphine milligram equivalents (MME) 24 hours preopioid and postopioid antagonist administration. Univariate and multivariate analyses were conducted to assess treatment response within 48 hours.. The time to first BM was shorter with enteral NLX. Both NLX and MNTX appear to be effective for the management of OIC without causing reversal of analgesia. Future controlled, prospective trials comparing these agents are warranted.

Topics: Adult; Analgesics, Opioid; Constipation; Critical Illness; Humans; Naloxone; Naltrexone; Narcotic Antagonists; Opioid-Induced Constipation; Pain; Prospective Studies; Quaternary Ammonium Compounds; Retrospective Studies

The nucleus of the solitary tract (NTS) contains pro-opiomelanocortin (POMC) neurons that are 1 of the 2 major sources of β-endorphin in the brain. The functional role of these NTS POMC neurons in nociceptive and cardiorespiratory function is debated. We have shown that NTS POMC optogenetic activation produces bradycardia and transient apnoea in a working heart-brainstem preparation and chemogenetic activation with an engineered ion channel (PSAM) produced opioidergic analgesia in vivo. To better define the role of the NTS POMC neurons in behaving animals, we adopted in vivo optogenetics (ChrimsonR) and excitatory/inhibitory chemogenetic DREADD (hM3Dq/hM4Di) strategies in POMC-Cre mice. We show that optogenetic activation of NTS POMC neurons produces time-locked, graded, transient bradycardia and bradypnoea in anaesthetised mice that is naloxone sensitive (1 mg/kg, i.p.), suggesting a role of β-endorphin. Both optogenetic and chemogenetic activation of NTS POMC neurons produces sustained thermal analgesia in behaving mice that can be blocked by naloxone. It also produced analgesia in an inflammatory pain model (carrageenan) but not in a neuropathic pain model (tibial nerve transection). Inhibiting NTS POMC neurons does not produce any effect on basal nociception but inhibits stress-induced analgesia (unlike inhibition of arcuate POMC neurons). Activation of NTS POMC neuronal populations in conscious mice did not cause respiratory depression, anxiety, or locomotor deficit (in open field) or affective preference. These findings indicate that NTS POMC neurons play a key role in the generation of endorphinergic endogenous analgesia and can also regulate cardiorespiratory function.

Topics: Analgesia; Animals; beta-Endorphin; Bradycardia; Mice; Naloxone; Neurons; Pain; Pro-Opiomelanocortin; Solitary Nucleus

Medications for opioid use disorder (MOUD) are a life-saving intervention; thus, it is important to address barriers to successful initiation. Spasticity affects many patients with spinal cord injury and can be painful and physically debilitating. Chronic painful conditions can lead to the illicit use of non-prescribed opioids, but fear of pain is a barrier to the initiation of MOUD. In this case report, we describe the novel use of botulinum toxin A injections to treat abdominal spasticity and facilitate Acute Pain Service-led buprenorphine/naloxone initiation in a patient with opioid use disorder and severe abdominal spasticity due to spinal cord injury.. A patient with C4 incomplete tetraplegia and opioid use disorder complicated by abdominal spasticity refractory to oral antispasmodics and self-treating with intravenous heroin was referred to the Acute Pain Service for inpatient buprenorphine/naloxone initiation. The patient began to fail initiation of buprenorphine/naloxone secondary to increased pain from abdominal spasms. The patient was offered ultrasound-guided abdominal muscle chemodenervation with botulinum toxin A, which resulted in the resolution of abdominal spasticity and facilitated successful buprenorphine/naloxone initiation. At 6 months post-initiation, the patient remained abstinent from non-prescribed opioids and compliant with buprenorphine/naloxone 8 mg/2 mg three times a day.. This case report demonstrates that inpatient buprenorphine/naloxone initiation by an Acute Pain Service can improve the success of treatment by addressing barriers to initiation. Acute Pain Service clinicians possess unique skills and knowledge, including ultrasound-guided interventions, that enable them to provide innovative and personalized approaches to care in the complex opioid use disorder population.

Topics: Analgesics, Opioid; Anesthesia, Conduction; Botulinum Toxins, Type A; Buprenorphine; Buprenorphine, Naloxone Drug Combination; Humans; Naloxone; Narcotic Antagonists; Opioid-Related Disorders; Pain; Pain Clinics

Patients with opioid use disorder (OUD) frequently leave the hospital as patient directed discharges (PDDs) because of untreated withdrawal and pain. Short-acting opioids can complement methadone, buprenorphine, and non-opioid adjuvants for withdrawal and pain, however little evidence exists for this approach. We described the safety and preliminary outcomes of short-acting opioid agonist treatment (sOAT) for hospitalized patients with OUD at an academic hospital in Philadelphia, PA.. From August 2021 to March 2022, a pharmacist guided implementation of a pilot sOAT protocol consisting of escalating doses of oxycodone or oral hydromorphone scheduled every four hours, intravenous hydromorphone as needed, and non-opioid adjuvants for withdrawal and pain. All patients were encouraged to start methadone or buprenorphine treatment for OUD. We abstracted data from the electronic health record into a secure platform. The primary outcome was safety: administration of naloxone, over-sedation, or a fall. Secondary outcomes were PDDs and respective length of stay (LOS), discharges on methadone or buprenorphine, and discharges with naloxone. We compared secondary outcomes to hospitalizations in the 12 months prior to the index hospitalization among the same cohort.. Of the 23 cases, 13 (56.5%) were female, 19 (82.6%) were 40 years or younger, and 22 (95.7%) identified as White. Twenty-one (91.3%) regularly injected opioids and four (17.3%) were enrolled in methadone or buprenorphine prior to hospitalization. sOAT was administered at median doses of 200-320 morphine milligram equivalents per 24-h period. Naloxone administration was documented once in the operating room, over-sedation was documented once after unsanctioned opioid use, and there were no falls. The PDD rate was 44% with median LOS 5 days (compared to PDD rate 69% with median LOS 3 days for prior admissions), 65% of sOAT cases were discharged on buprenorphine or methadone (compared to 33% for prior admissions), and 65% of sOAT cases were discharged with naloxone (compared to 19% for prior admissions).. Pilot implementation of sOAT was safe. Compared to prior admissions in the same cohort, the PDD rate was lower, LOS for PDDs was longer, and more patients were discharged on buprenorphine or methadone and with naloxone, however efficacy for these secondary outcomes remains to be established.

Topics: Analgesics, Opioid; Buprenorphine; Buprenorphine, Naloxone Drug Combination; Female; Humans; Hydromorphone; Male; Methadone; Naloxone; Opiate Substitution Treatment; Opioid-Related Disorders; Pain

Many structures of the central nervous system recruit different neurotransmitters in pain processing. This study focused on the contribution of histamine and its H 1 receptors in the ventral pallidum (VP) in mediating pain-triggered behaviors. Intra-VP microinjection of histamine and 2-pyridylethylamine (2-PEA, a histamine H 1 receptor agonist) at the same doses of 0.5 and 1 µg/200 nl reduced both the first and second phases of licking/biting duration as well as flinching number induced by intra-plantar (ipl) injection of formalin (2.5%, 50 µl). Premicroinjection of mepyramine (a histamine H 1 antagonist, 2 µg/200 nl) into the VP antagonized the suppressive effects of 1 µg/200 nl histamine and 2-PEA on licking/biting and flinching behaviors. The possible mechanisms of the above-mentioned pain-reducing effects were followed by intra-VP and intrathecal administration of naloxone (an opioid receptor antagonist). Naloxone (2 µg/200 nl) preadministration into the VP inhibited attenuating effects of histamine and 2-PEA on both the licking/biting and flinching behaviors, whereas intrathecal injection of naloxone only inhibited their suppressing effects on flinching behavior. None of the treatments used in this study altered the animal's motor activity. The obtained results may reveal the role of histamine and its activated H 1 receptor in the VP in suppressing the pain behaviors caused by formalin. Opioid receptors in the VP and spinal cord may contribute to these functions.

Topics: Animals; Basal Forebrain; Formaldehyde; Histamine; Histamine Agonists; Naloxone; Pain; Receptors, Opioid; Spinal Cord

While pain results from the activation of nociceptors following noxious stimuli, mounting evidence links pain- and stress-related responses in mammals. In zebrafish, the activation of hypothalamic-pituitary-interrenal (HPI) axis may also regulate body pigmentation (the camouflage response). Here, we aimed to investigate a putative relationship between pain-, stress-, and camouflage-related parameters in adult zebrafish. To answer this question, we assessed whether intraperitoneal acetic acid injection can activate the HPI axis, measuring whole-body cortisol and the camouflage response as physiological endpoints in the presence or absence of morphine or naloxone, an opioid antagonist. Acetic acid induced a stereotypic circling behavior in the top of the tank, accompanied by abdominal writhing-like response, a specific phenotype that reflects local nociceptive effect. Both whole-body cortisol levels and camouflage response increased in the acetic acid group, while morphine prevented these responses, and naloxone antagonized morphine-induced effects. Moreover, we observed positive correlations between representative behavioral, physiological and skin coloration endpoints, and a "pain index" was proposed to summarize phenotypic profile of zebrafish under different pharmacological manipulations. Collectively, these findings suggest a coordinated activation of pain, camouflage- and stress-related pathways following acetic acid injection in zebrafish. Our data also support that camouflage response represents a novel and relevant biomarker for future probing pain and stress neurobiology, with a robust sensitivity to opioidergic drugs.

Topics: Acetic Acid; Animals; Hydrocortisone; Mammals; Morphine; Naloxone; Pain; Phenotype; Zebrafish

Topics: Animals; Avoidance Learning; GABAergic Neurons; Male; Mice; Morphine; Naloxone; Pain; Periaqueductal Gray; TRPV Cation Channels

Morphine induces spinal 5-hydroxytryptamine (5-HT) release, but the role and mechanism of the spinal 5-HT release induced by morphine are not well understood. The purpose of this study was to define the role and mechanism of spinal 5-HT release induced by oral morphine. We also examined whether persistent pain affected the spinal 5-HT release induced by oral morphine. Spinal 5-HT release was measured using microdialysis of lumbar cerebrospinal fluid (CSF). Two opioids, morphine and oxycodone, were orally administered and 5-HT release was measured in awake rats. Naloxone and β-funaltrexamine (β-FNA) were used to determine whether the effect of morphine on 5-HT release was mediated by opioid receptor activation. To study persistent pain, a formalin test was used. At 45 min after oral morphine administration, the formalin test was started and spinal 5-HT release was measured. Oral morphine, but not oral oxycodone, increased 5-HT release at the spinal cord to approximately 4000% of the baseline value. This effect of morphine was not antagonized by either naloxone or β-FNA at a dose that antagonized the antinociceptive effect of morphine. Formalin-induced persistent pain itself had no effect on spinal 5-HT release but enhanced the oral morphine-induced spinal 5-HT release. Oral morphine-induced spinal 5-HT release was not mediated by opioid receptor activation. Spinal 5-HT induced by oral morphine did not play a major role in the antinociceptive effect of morphine in the hot plate test. Persistent pain increased oral morphine-induced spinal 5-HT release.

Topics: Analgesics, Opioid; Animals; Morphine; Naloxone; Oxycodone; Pain; Rats; Receptors, Opioid; Serotonin

To explore the mechanisms involved in the transformation of analgesia produced by low doses of CCL4 (pg/kg) to hyperalgesia when higher doses (ng/kg) are administered to mice.. The unilateral hot plate test was used to assess thermal nociception. CD3. IL-16 and CCR5 expression were demonstrated in CD4. CCL4-evoked hyperalgesia is related to the desensitization of CCR5 in CD4

Topics: Analgesia; Animals; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Chemokine CCL4; Flow Cytometry; Hot Temperature; Hyperalgesia; Male; Mice; Naloxone; Nociception; Pain; Receptors, CCR5

Pentazocine produces a wide variety of actions in the treatment of perioperative analgesia. Neostigmine is a cholinesterase inhibitor used to antagonize the residual effects of muscle relaxants and also produces an analgesic effect.. To investigate the analgesic effects of intrathecally injected pentazocine and neostigmine and their interaction.. Sprague-Dawley rats were used to test the analgesic effect of pentazocine and neostigmine using the paw formalin pain model and the incision mechanical allodynia model. Pentazocine (3, 10, 30, and 100 . Intrathecally administered pentazocine (3, 10, 30, and 100 . All of these results suggest that the combined application of pentazocine and neostigmine is an effective way to relieve pain from formalin and acute incision mechanical allodynia. The synergistic effect between pentazocine and neostigmine is mostly attributed to the kappa-opioid receptor and the cholinergic receptor in the spinal cord.

Topics: Analgesics; Animals; Atropine Derivatives; Clonidine; Formaldehyde; Humans; Hyperalgesia; Naloxone; Narcotic Antagonists; Neostigmine; Pain; Pentazocine; Rats; Rats, Sprague-Dawley

Eugenia uniflora (Myrtaceae) is a species native to Brazil and has a traditional use in the treatment of inflammation.. To evaluate the anti-inflammatory and antinociceptive effects, and the involvement of opioid receptors in the antinociceptive activity of extract and fractions from Eugenia uniflora leaves.. TLC and HPLC were used to characterize the spray-dried extract (SDE) and fractions. In the in vivo assays, Swiss (Mus musculus) mice were used. Carrageenan-induced hind-paw edema and carrageenan-induced peritonitis models were used to determine the anti-inflammatory effect of the extract (50, 100, or 200 mg/kg). Acetic acid-induced writhing, tail-flick, and formalin tests were used to determine the antinociceptive effect of the extract (50, 100, or 200 mg/kg). The aqueous (AqF) and ethyl acetate (EAF) fractions (6.25, 12.5, and 25 mg/kg) were then combined with naloxone to evaluate the involvement of opioid receptors in the antinociceptive activity.. In this work, the TLC and HPLC analysis evidenced the enrichment of EAF, which higher concentration of gallic acid (5.29 ± 0.0004 %w/w), and ellagic acid (1.28 ± 0.0002 %w/w) and mainly myricitrin (8.64 ± 0.0002 %w/w). The extract decreased the number of total leukocytes and neutrophils in the peritoneal cavity (p < 0.05), at doses of 100 and 200 mg/kg and showed significant inhibition in the increase of paw edema volume (p < 0.05). The treatment per oral route (doses of 50, 100, and 200 mg/kg) significantly reduced the nociceptive response in acetic acid-induced abdominal writhing (p < 0.05). The effect of the extract on the tail-flick test showed a significant increase in latency time of animals treated at doses of 200 and 100 mg/kg (p < 0.05). The extract and ethyl acetate fraction reduced the nociceptive effect in both phases of formalin at all tested doses. The naloxone reversed the antinociceptive effect of EAF, suggesting that opioid receptors are involved in mediating the antinociceptive activity of EAF of E. uniflora in the formalin test.. The current study demonstrates the anti-inflammatory and analgesic activities of water: ethanol: propylene glycol spray-dried extract from E. uniflora leaves using in vivo pharmacological models in mice. Our findings suggest that spray-dried extract and ethyl acetate fraction exhibit peripheral and central antinociceptive activity with the involvement of opioid receptors that may be related to the presence of flavonoids, mainly myricitrin.

Topics: Acetic Acid; Analgesics; Animals; Anti-Inflammatory Agents; Carrageenan; Edema; Ethanol; Eugenia; Mice; Naloxone; Pain; Plant Extracts; Propylene Glycols; Receptors, Opioid; Water

Intranasal fentanyl offers a means for safe and effective pain management in austere environments. Prehospital analgesia traditionally involves intravenous or intramuscular medication. However, for wilderness rescuers, these methods are often impractical.. We conducted a retrospective review of health records to evaluate the safety and efficacy of intranasal fentanyl administered by EMT-Basic certified ski patrollers. Our primary aim was to measure the reduction in initial pain scores to subsequent measurements at 5, 10, and 15 min using the pain numeric rating scale (0-10). Clinically significant reduction in severe pain has been established as ≥1.8 points. We used paired t-tests and multilevel modeling to measure statistical significance and potential interactions and reviewed patient charts for adverse events, including respiratory depression or the use of naloxone.. We compiled the results from the winter seasons for 2007 through 2012 and 2016 through 2020. A total of 247 patients were included. The initial pain score was 8.6±1.5 (mean±SD). The decrease in pain scores from 0 to 5, 10, and 15 min, respectively, was -1.8, -2.4, and -2.9 (P<0.0001), which demonstrated a clinically and statistically significant decrease in pain scores. There were no adverse events.. Traditional standard of care analgesics are invasive, elongate scene times, and increase the risk of environmental exposure and provider needlestick. Intranasal fentanyl offers a safe, noninvasive, and rapid analgesia that is well-suited for austere winter environments, such as those encountered at ski resorts. This study demonstrates the safety and efficacy of the administration of intranasal fentanyl by EMT-Basic certified providers.

Topics: Administration, Intranasal; Analgesia; Analgesics; Analgesics, Opioid; Fentanyl; Humans; Naloxone; Pain; Pain Management; Pain Measurement

Plenty information exists regarding the effects of chronic stress, although few data exist on the effects of short-lasting stressors, which would mimic daily challenges. Differences in craniofacial and spinal nociception have been observed, thus those observations obtained in spinally innervated areas cannot be directly applied to the orofacial region. Although, opioids are considered amongst the most effective analgesics, their use is sometimes hampered by the constipation they induce. Thus, our aims were to study if a short-lasting stressor, forced swim stress (FSS), modifies nociception, morphine antinociception and constipation in rats. Animals were submitted to 10-20 min of FSS for three days, nociception and gastrointestinal transit were studied 24 h after the last swimming session. Nociception and morphine (0.6-5 mg/kg) antinociception were evaluated in the formalin and hypertonic saline tests in the orofacial area and limbs. Morphine-induced modifications in the GI transit were studied through radiographic techniques. Naloxone was administered, before each swimming session, to analyse the involvement of the endogenous opioid system on the effect of stress. Overall, stress did not alter nociception, although interestingly it reduced the effect of morphine in the orofacial tests and in the inflammatory phase of the formalin tests. Naloxone antagonized the effect of stress and normalized the effect of morphine. Stress did not modify the constipation induced by morphine. Opioid treatment may be less effective under a stressful situation, whilst adverse effects, such as constipation, are maintained. The prevention of stress may improve the level of opioid analgesia.

Topics: Analgesia; Analgesics, Opioid; Animals; Constipation; Morphine; Naloxone; Pain; Rats

Eugenia pohliana DC.(Myrtaceae) is used in folk medicine by communities in Brazil. However, there are no reports on its biological activity. This is the first study to identify the components of E. pohliana essential oil (EpEO) and evaluate their antinociceptive and anti-inflammatory activities in an in vivo model at doses of 25, 50, and 100 mg/kg. The essential oil (EO) was obtained by hydrodistillation, and the analysis was performed by gas chromatography coupled with mass spectrometry. Antinociceptive activity was evaluated by writhing tests, tail movement, and formalin (neurogenic and inflammatory pain); naloxone was used to determine the nociception mechanism. Anti-inflammatory activity was assessed by oedema and peritonitis tests. We found that (E)-β-caryophyllene (BCP) (15.56%), δ-cadinene (11.24%) and α-cadinol (10.89%) were the major components. In the writhing test, there was a decrease in writing by 42.95-70.70%, in the tail movement, an increase in latency time by 69.12-86.63%, and in the formalin test, there was a reduction in pain neurogenic by 29.54-61.74%, and inflammatory pain by 37.42-64.87%. The antinociceptive effect of EpEO occurs through the activation of opioid receptors. In addition, a reduction in inflammation by 74.93‒81.41% was observed in the paw edema test and inhibition of the influx of leukocytes by 51.86‒70.38% and neutrophils by 37.74‒54.72% in the peritonitis test. It was concluded that EpEO has antinociceptive effect by the opioid pathway, as shown by the inhibitory effect of naloxone, and anti-inflammatory actions, and that its use does not cause hemolytic damage or behavioral change.

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Edema; Eugenia; Inflammation; Mice; Myrtaceae; Naloxone; Nociception; Oils, Volatile; Pain; Peritonitis; Plant Extracts

The involvement of the opioidergic system on anxiolytic and antinociceptive responses induced by cholestasis was investigated in cholestatic and addicted mice. Elevated plus-maze and tail-flick devices were used to assess anxiety and pain levels, respectively. The data indicated that induction of cholestasis and injection of opioid drugs including morphine and tramadol enhanced %OAT and %OAE but naloxone reduced %OAT and %OAE in the sham-operated and bile duct ligation (BDL) mice. Induction of cholestasis and addiction to morphine and tramadol prolonged tail-flick latency, which was reversed by naloxone. Coadministration of morphine and tramadol enhanced anxiolytic and analgesic effects in the sham-operated and BDL mice. It seems (a) cholestasis and addiction affect anxiety and pain behaviors, (b) μ-opioid receptors play a key role in anxiolytic and analgesic effects induced by cholestasis, and (c) cotreatment with morphine and tramadol augmented the effectiveness of them for induction of anxiolytic and analgesic effects both in cholestatic and addicted mice.

Topics: Analgesics, Opioid; Animals; Anti-Anxiety Agents; Cholestasis; Dose-Response Relationship, Drug; Mice; Morphine; Naloxone; Pain; Receptors, Opioid, mu; Tramadol

Rotigotine-loaded microspheres (RoMS), a sustained-release formulation with a continuous release of rotigotine for more than 7 days in vivo, have been conducted a clinical trial for the treatment of Parkinson's disease (PD). Previous work from our laboratory showed that RoMS exerted an antinociceptive effect in rat models of inflammatory pain. The purpose of this study was to investigate the mechanisms of action underlying the antinociceptive effect of RoMS. A rat model of inflammatory pain was prepared by an intraplantar injection of carrageenan. The hot plate test and the Randall-Selitto test were used to evaluate the effect of domperidone (selective D

Topics: Analgesics; Animals; Carrageenan; Corpus Striatum; Disease Models, Animal; Domperidone; Dopamine; Dopamine Agents; Dopamine D2 Receptor Antagonists; Inflammation; Injections; Male; Microspheres; Naloxone; Narcotic Antagonists; Pain; Periaqueductal Gray; Rats, Sprague-Dawley; Receptors, Dopamine D2; Receptors, Dopamine D3; Stress, Mechanical; Temperature; Tetrahydronaphthalenes; Thiophenes

Electroacupuncture is one of the most popular physical treatments for clinical pain, but the potential influence of a patient's age on the effectiveness of electroacupuncture treatment has not been clearly established. Objectives: The present study aimed to detect a potential difference in electroacupuncture- induced analgesia between juvenile and adult rats.. In this study, we investigated the effects of electroacupuncture treatment on the nociceptive jaw-opening reflex evoked by tooth-pulp stimulation in juvenile and adult rats.. Our results showed there were age differences in electroacupuncture-induced analgesic effects in rats, especially with naloxone antagonization. The ratio of naloxonereversibility against electroacupuncture analgesia was greater in adult rats than in juvenile rats.. These results suggest that electroacupuncture analgesia is produced mainly by the non-opioid system in juvenile rats and by the opioid system in adult rats.

Topics: Animals; Electroacupuncture; Jaw; Naloxone; Pain; Rats; Reflex

Opioid abuse has devastating effects on patients, their families, and society. Withdrawal symptoms are severely unpleasant, prolonged, and frequently hinder recovery or lead to relapse. The sharp increase in abuse and overdoses arising from the illicit use of potent and rapidly-acting synthetic opioids, such as fentanyl, highlights the urgency of understanding the withdrawal mechanisms related to these drugs. Progress is impeded by inconsistent reports on opioid withdrawal in different preclinical models. Here, using rats and mice of both sexes, we quantified withdrawal behaviors during spontaneous and naloxone-precipitated withdrawal, following two weeks of intermittent fentanyl exposure. We found that both mice and rats lost weight during exposure and showed increased signs of distress during spontaneous and naloxone precipitated withdrawal. However, these species differed in their expression of withdrawal associated pain, a key contributor to relapse in humans. Spontaneous or ongoing pain was preferentially expressed in rats in both withdrawal conditions, while no change was observed in mice. In contrast, withdrawal associated thermal hyperalgesia was found only in mice. These data suggest that rats and mice diverge in how they experience withdrawal and which aspects of the human condition they most accurately model. These differences highlight each species' strengths as model systems and can inform experimental design in studies of opioid withdrawal.

Topics: Analgesics, Opioid; Animals; Behavior, Animal; Female; Fentanyl; Humans; Hyperalgesia; Locomotion; Male; Mice; Mice, Inbred C57BL; Naloxone; Narcotic Antagonists; Narcotics; Pain; Rats; Rats, Wistar; Substance Withdrawal Syndrome

Opioid-induced constipation is the most prevalent adverse effect of opioid drugs. Peripherally acting mu opioid receptor antagonists (PAMORAs), including naloxegol, are indicated for the treatment of opioid-induced constipation. The aim of this study was the in vitro and in vivo pharmacological characterization of naloxegol in comparison with naloxone. In vitro experiments were performed to measure calcium mobilization in cells coexpressing opioid receptors and chimeric G proteins and mu receptor interaction with G protein and β-arrestin 2 using bioluminescence resonance energy transfer. In vivo experiments were performed in mice to measure pain threshold using the tail withdrawal assay and colonic transit using the bead expulsion assay. In vitro, naloxegol behaved as a selective and competitive mu receptor antagonist similarly to naloxone, being 3-10-fold less potent. In vivo, naloxone was effective in blocking fentanyl actions when given subcutaneously (sc), but not per os (po). In contrast, naloxegol elicited very similar effects with sc or po administration counteracting in a dose dependent manner the constipating effects of fentanyl without interfering with the fentanyl mediated analgesia. Thus, a useful PAMORA action could be obtained with naloxegol both after po and sc administration.

Topics: Administration, Oral; Analgesics, Opioid; Animals; Behavior, Animal; Calcium; CHO Cells; Constipation; Cricetulus; Fentanyl; Injections, Subcutaneous; Male; Mice; Morphinans; Morphine; Naloxone; Narcotic Antagonists; Pain; Polyethylene Glycols; Receptors, Opioid, mu

In order to find a new natural resource for pain-relief, the analgesic effects of Ilex dipyrena crude extract, fractions, and subfractions were evaluated in in-vivo mouse models with possible mechanism of action.. Analgesic effects of crude extract (100 and 200 mg/kg body weight), fractions and subfractions (75 mg/kg body weight) were screened using heat-induced (tail-immersion and hot plate test) and chemical-induced (formalin and acetic acid) nociception models in mice. The samples were also tested for the elucidation of a possible mechanism through opioidergic and GABAergic systems.. The administration of crude extract, fractions and subfractions produced analgesic responses in acetic acid, formalin, tail immersion, and hot plate model for pain similar to those obtained with the standard. Naloxone antagonized the antinociceptive effects of the tested samples, whereas bicuculline showed partial inhibition. Considering the analgesic response, crude extract, fractions, and subfractions demonstrated promising inhibitory activity against all test models for pain, which was further supported by the possible involvement of opioidergic and GABAergic systems.. The results suggest that this plant may be useful in the development of new analgesic drugs. Further research with regard to the isolation of bioactive compounds is required to verify these findings.

Topics: Analgesics; Animals; Bicuculline; GABA-A Receptor Antagonists; Ilex; Mice, Inbred BALB C; Models, Animal; Naloxone; Narcotic Antagonists; Pain; Plant Extracts; Toxicity Tests, Acute

Corticotropin-releasing factor (CRF) orchestrates our body's response to stressful stimuli. Pain is often stressful and counterbalanced by activation of CRF receptors along the nociceptive pathway, although the involvement of the CRF receptor subtypes 1 and/or 2 (CRF-R1 and CRF-R2, respectively) in CRF-induced analgesia remains controversial. Thus, the aim of the present study was to examine CRF-R1 and CRF-R2 expression within the spinal cord of rats with Freund's complete adjuvant-induced unilateral inflammation of the hind paw using reverse transcriptase polymerase chain reaction, Western blot, radioligand binding, and immunofluorescence confocal analysis. Moreover, the antinociceptive effects of intrathecal (i.t.) CRF were measured by paw pressure algesiometer and their possible antagonism by selective antagonists for CRF-R1 and/or CRF-R2 as well as for opioid receptors. Our results demonstrated a preference for the expression of CRF-R2 over CRF-R1 mRNA, protein, binding sites and immunoreactivity in the dorsal horn of the rat spinal cord. Consistently, CRF as well as CRF-R2 agonists elicited potent dose-dependent antinociceptive effects which were antagonized by the i.t. CRF-R2 selective antagonist K41498, but not by the CRF-R1 selective antagonist NBI35965. In addition, i.t. applied opioid antagonist naloxone dose-dependently abolished the i.t. CRF- as well as CRF-R2 agonist-elicited inhibition of somatic pain. Importantly, double immunofluorescence confocal microscopy of the spinal dorsal horn showed CRF-R2 on enkephalin (ENK)-containing inhibitory interneurons in close opposition of incoming mu-opioid receptor-immunoreactive nociceptive neurons. CRF-R2 was, however, not seen on pre- or on postsynaptic sensory neurons of the spinal cord. Taken together, these findings suggest that i.t. CRF or CRF-R2 agonists inhibit somatic inflammatory pain predominantly through CRF-R2 receptors located on spinal enkephalinergic inhibitory interneurons which finally results in endogenous opioid-mediated pain inhibition.

Topics: Acenaphthenes; Amphibian Proteins; Animals; Arthritis, Experimental; Corticotropin-Releasing Hormone; Enkephalins; Hyperalgesia; Interneurons; Male; Naloxone; Nociception; Pain; Peptide Hormones; Posterior Horn Cells; Rats; Rats, Wistar; Receptors, Corticotropin-Releasing Hormone; RNA, Messenger; Spinal Cord; Urocortins

Opioids such as morphine are the most effective treatment for pain, but termination of opioid use can produce severe withdrawal symptoms. The present study models this process by using home cage wheel running to assess well-being as a result of pain, morphine analgesia, and opioid withdrawal. Injection of CFA into the right hindpaw caused a dramatic decrease in wheel running and body weight. Implantation of two morphine pellets (75 mg each) resulted in an increase in body weight on Day 1 of administration and a more gradual restoration of wheel running that was only evident during the dark phase of the circadian cycle on Days 3 and 4 of morphine administration. Continuous morphine administration decreased wheel running during the relatively inactive light phase. These findings are consistent with the clinical goal of pain therapeutics to restore normal activity during the day and facilitate sleep at night. Administration of naloxone (1 mg/kg) on Day 5 of morphine administration depressed wheel running for approximately 4 h and caused an increase in wet dog shakes. Naloxone-precipitated changes were no longer evident 6 h after administration. These findings demonstrate that the use of morphine to treat pain does not protect against opioid withdrawal. Moreover, this study provides additional support for the use of home cage wheel running as a method to assess changes in well-being as a result of pain, analgesia, and opioid withdrawal.

Topics: Analgesics, Opioid; Animals; Behavior, Animal; Inflammation; Male; Morphine; Motor Activity; Naloxone; Narcotic Antagonists; Opioid-Related Disorders; Pain; Rats; Rats, Sprague-Dawley; Substance Withdrawal Syndrome

Four novel fluorinated cyclic analogues of biphalin with excellent to modest binding affinity for μ-, δ-, and κ-receptors were synthesized. The cyclic peptides have a combination of piperazine or hydrazine linker with or without a xylene bridge. Among the ligands,

Topics: Administration, Intravenous; Analgesics, Opioid; Animals; CHO Cells; Cricetulus; Female; Humans; Infusions, Subcutaneous; Male; Mice; Models, Molecular; Opioid Peptides; Pain; Peptides, Cyclic; Receptors, Opioid

The development of analgesic drugs is still a necessity due to the inefficiency of the current treatments for some pathological conditions and also due to the adverse effects produced by these drugs. The aim of this study was to deepen the pharmacological study of two new hybrids NSAIDs tetrahydropyran derivatives, regarding their antinociceptive effects on acute pain in mice. Male swiss mice were evaluated in the acetic acid-induced abdominal writhing, formalin, tail-flick, open-field, glutamate- and capsaicin-induced paw licking tests, and in vitro Cox inhibition assay, besides the acute toxicological evaluation. The compounds had an effect on the acetic acid-induced abdominal writhing, formalin (both phases), and tail-flick tests. In the study of the mechanism of action was observed reversion of the antinociceptive effect of the compounds from the previous administration of naloxone, L-NAME (L-nitro-arginine methyl ester), ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one), glibenclamide, and nor-binaltorphimine, by the intrathecal and intraperitoneal routes. The prior administration of MK-801 suggests that the modulation of NMDA receptor contributes to the antinociceptive effect of compounds. In summary, hybrid compounds presented central antinociceptive effect, demonstrating participation of the NO-cGMP-K

Topics: Adenosine Triphosphate; Analgesics; Analgesics, Opioid; Animals; Anti-Inflammatory Agents, Non-Steroidal; Cyclic GMP; Cyclooxygenase Inhibitors; Dizocilpine Maleate; Formaldehyde; Glyburide; Humans; Male; Mice; Naloxone; Naltrexone; NG-Nitroarginine Methyl Ester; Pain; Pain Measurement; Potassium Channels; Prostaglandin-Endoperoxide Synthases; Receptors, N-Methyl-D-Aspartate; Signal Transduction

Topics: Humans; Naloxone; Pain; Pleasure; Remifentanil

Topics: Analgesics, Opioid; Humans; Naloxone; Opioid Epidemic; Pain

Topics: Analgesics, Opioid; Animals; Binding, Competitive; Codeine; Freund's Adjuvant; Gastrointestinal Transit; Inflammation; Injections, Intraventricular; Male; Mice; Naloxone; Nociception; Pain; Rats, Wistar; Receptors, Opioid, mu

Drugs used to treat pain are associated with adverse effects, increasing the search for new drugs as an alternative treatment for pain. Therefore, we evaluated the antinociceptive behavior and possible neuromodulation mechanisms of triterpene 3β, 6β, 16β-trihydroxylup-20(29)-ene (CLF-1) isolated from Combretum leprosum leaves in zebrafish. Zebrafish (n = 6/group) were pretreated with CLF-1 (0.1 or 0.3 or 1.0 mg/mL; i.p.) and underwent nociception behavior tests. The antinociceptive effect of CFL-1 was tested for modulation by opioid (naloxone), nitrergic (L-NAME), nitric oxide and guanylate cyclase synthesis inhibitor (methylene blue), NMDA (Ketamine), TRPV1 (ruthenium red), TRPA1 (camphor), or ASIC (amiloride) antagonists. The corneal antinociceptive effect of CFL-1 was tested for modulation by TRPV1 (capsazepine). The effect of CFL-1 on zebrafish locomotor behavior was evaluated with the open field test. The acute toxicity study was conducted. CLF-1 reduced nociceptive behavior and corneal in zebrafish without mortalities and without altering the animals' locomotion. Thus, CFL-1 presenting pharmacological potential for the treatment of acute pain and corneal pain, and this effect is modulated by the opioids, nitrergic system, NMDA receptors and TRP and ASIC channels.

Topics: Acid Sensing Ion Channels; Amiloride; Analgesics; Animals; Camphor; Capsaicin; Combretum; Dose-Response Relationship, Drug; Female; Ketamine; Locomotion; Male; Methylene Blue; Naloxone; NG-Nitroarginine Methyl Ester; Nociception; Pain; Pain Measurement; Plant Extracts; Plant Leaves; Receptors, N-Methyl-D-Aspartate; Ruthenium Red; Triterpenes; TRPV Cation Channels; Zebrafish; Zebrafish Proteins

The primary goal of this work was to develop a computational tool to enable personalized prediction of pharmacological disposition and associated responses for opioids and antidotes. Here we present a computational framework for physiologically-based pharmacokinetic (PBPK) modeling of an opioid (morphine) and an antidote (naloxone). At present, the model is solely personalized according to an individual's mass. These PK models are integrated with a minimal pharmacodynamic model of respiratory depression induction (associated with opioid administration) and reversal (associated with antidote administration). The model was developed and validated on human data for IV administration of morphine and naloxone. The model can be further extended to consider different routes of administration, as well as to study different combinations of opioid receptor agonists and antagonists. This work provides the framework for a tool that could be used in model-based management of pain, pharmacological treatment of opioid addiction, appropriate use of antidotes for opioid overdose and evaluation of abuse deterrent formulations.

Topics: Analgesics, Opioid; Antidotes; Humans; Male; Morphine; Naloxone; Narcotic Antagonists; Opioid-Related Disorders; Pain; Receptors, Opioid

Fish are useful animal models in research and have been employed in developing new pharmacological approaches. This study aimed to establish the use of silver catfish (Rhamdia quelen) as an animal model to evaluate antinociceptive activity. Initially, different concentrations of acetic acid (2.5-20%), formalin 1% (1-10 μL), menthol 0.5% (1-10 μL) or vehicle were injected in the lips to establish which concentration of each sample promotes nociceptive-like behavior in various parameters. The effect of morphine (0.5-10 mg/kg) on locomotion parameters was also evaluated for antinociceptive concentration determination. Morphine was administered intramuscularly immediately prior to algogen administration. The inhibition was evaluated with the antagonist naloxone (5 mg/kg), which was administered in the same way. Recording time varied according to the algogen used in each test and locomotor activity was evaluated by ANY-maze® software. Acid acetic at 15%, 10 μL of 1% formalin, and 1 μL of 0.5% menthol were chosen since they promoted nociceptive-like behavior in several parameters. Morphine (5 mg/kg) reversed the algogen-induced nociceptive-like behavior and naloxone inhibited this effect. Therefore, the proposed experimental model demonstrated specificity for nociception, since the reversion of the nociceptive-like behavior for a compound with well-described analgesic activity was observed. This new pharmacological model contributes to evaluating compounds with analgesic potential and developing new analgesic drugs, in addition to being a promising alternative to use with rodents.

Topics: Acetic Acid; Analgesia; Analgesics, Opioid; Animals; Catfishes; Disease Models, Animal; Injections; Lip; Menthol; Morphine; Motor Activity; Naloxone; Narcotic Antagonists; Nociception; Pain; Pain Measurement

Uapaca togoensis is a medicinal plant used traditionally in Africa for the treatment of rheumatism, epilepsy, cough, pneumonia, vomitting and fever. Previously, the analgesic activity of its methanol stem bark extract has been scientifically demonstrated. However, the mechanism responsible for this activity remains to be investigated.. To elucidate the possible mechanism(s) through which the methanol stem bark extract of Uapaca togoensis (MEUT) exhibits analgesic activity in mice.. Analgesic activity of MEUT was evaluated using acetic acid-induced abdominal writhing test in mice at doses of 250, 500 and 1000 mg/kg orally. For the mechanistic studies, mice were pre-treated with Naloxone (2 mg/kg), Atropine (1 mg/kg), Yohimbine (1 mg/kg), Glibenclamide (10 mg/kg), Prazosin (1 mg/kg) and Yohimbine (1 mg/kg) 15 min prior to MEUT (1000 mg/kg) administration, then assessed using AAWT 1 h later. Data was analysed using One way Anova followed by Bonferroni post hoc test.. The extract (at the doses of 250, 500 and 1000 mg/kg) and morphine (10 mg/kg) significantly (p < 0.05) decreased the number of abdominal writhes. Naloxone (opioid receptor antagonist), Atropine (muscarinic receptor antagonist) and Glibenclamide (ATP-sensitive K+ channel blocker) significantly (p < 0.05) reversed the analgesic effect of MEUT. On the other hand, Prazosin and Yohimbine (α. The results obtained from this study suggests the possible involvement of opioidergic, cholinergic and sensitive potassium ATP channel pathways in the analgesic activity of the methanol stem bark extract of Uapaca togoensis.

Topics: Acetic Acid; Analgesics; Animals; Atropine; Coffea; Female; Glyburide; Lethal Dose 50; Male; Methanol; Mice; Muscarinic Antagonists; Naloxone; Narcotic Antagonists; Pain; Plant Bark; Plant Extracts; Potassium Channel Blockers; Solvents

Ketamine and magnesium sulphate showed synergic interaction in the tail-immersion test and additive interaction in the rat formalin test. Aim of study was to evaluate the influence of serotonergic and opioidergic system of this combination in the formalin test in rats.. Antinociceptive activity was assessed by the formalin test in male Wistar rats (200-250 g). Antagonists (naloxone and methysergide) were administrated 5 min before and magnesium sulphate 5 min after ketamine injection. Formalin (2.5%, 100 μL) was injected into the right hind paw surface (intraplantar) of rats 5 min after ketamine/magnesium combination. Data were recorded as the total time spent in pain related behavior after the injection of formalin or vehicle (0.9% NaCl).. In the intermediate phase of the formalin test, methysergide at a dose of 0.2 mg/kg did not have any effect, but at doses of 0.5 and 1 mg/kg it had a pronociceptive effect. Methysergide (0.2, 0.5 and 1 mg/kg) inhibited the antinociceptive effect of ketamine-magnesium sulphate combination. In the intermediate phase, naloxone at a dose of 0.2 mg/kg did not have any effect, but at a dose of 3 mg/kg it produced a pronociceptive effect. Naloxone (0.2 and 3 mg/kg) antagonized the antinociceptive effect of the ketamine (5 mg/kg)-magnesium sulphate (5 mg/kg) combination.. The results of the present study suggest that serotonergic and opioidergic systems are involved, at least in part, in the antinociceptive effect of the ketamine-magnesium sulphate combination in the model of inflammatory pain in rats.

Topics: Analgesics; Animals; Dose-Response Relationship, Drug; Drug Therapy, Combination; Formaldehyde; Ketamine; Magnesium Sulfate; Male; Methysergide; Naloxone; Pain; Pain Measurement; Rats; Rats, Wistar; Serotonergic Neurons

Ketamine is a drug largely used in clinical practice as an anesthetic and it can also be used as an analgesic to manage chronic pain symptoms. Despite its interactions with several other signaling systems such as cholinergic, serotoninergic and adrenergic, it is accepted that NMDA receptor antagonism is the main mechanism of action of this drug. In this study we investigated the actions of endogenous opioids in the mechanism of peripheral analgesia induced by ketamine. The nociceptive threshold for mechanical stimuli was measured in Swiss mice using the Randall and Selitto test. The drugs used in this study were administered via intraplantar injection. Our results demonstrated that non selective opioid receptor antagonism (naloxone), selective μ- and δ-opioid receptors antagonism (clocinamox and naltrindole, respectively) but not κ-opioid receptor antagonism (nor-binaltorphimine NORBNI) antagonized ketamine-induced peripheral antinociception in a dose-dependent manner. In addition, administration of aminopeptidase inhibitor bestatin significantly potentiated ketamine-induced peripheral antinociception. Ketamine injection in the right hind paw induced β-endorphine synthesis in the epithelial tissue of the hindpaw. Together these results indicate a role for μ- and δ-opioid receptors and for the endogenous opioid β-endorphine increased synthesis in ketamine-induced peripheral analgesia mechanism of action.

Topics: Analgesics; Animals; Cinnamates; Dinoprostone; Ketamine; Male; Mice; Morphine Derivatives; Naloxone; Naltrexone; Narcotic Antagonists; Pain; Receptors, Opioid, delta; Receptors, Opioid, mu

In the present study, we characterize the antinociceptive effects produced by the chemokine CCL4 in mice. The intraplantar administration of very low doses of CCL4 (0.1-3 pg) produced bilateral antinociception assessed by the unilateral hot-plate test (UHP) without evoking chemotactic responses at the injection site. Moreover, the subcutaneous administration of CCL4 (3-100 pg/kg) also yielded bilateral antinociception in the UHP and the paw pressure test and reduced the number of spinal neurons that express Fos protein in response to noxious stimulation. The implication of peripheral CCR5 but not CCR1 in CCL4-evoked antinociception was deduced from the inhibition produced by systemic but not intrathecal, administration of the CCR5 antagonist DAPTA, and the inefficacy of the CCR1 antagonist J113863. Besides, the inhibition observed after subcutaneous but not intrathecal administration of naloxone demonstrated the involvement of peripheral opioids and the efficacy of naltrindole but not cyprodime or nor-binaltorphimine supported the participation of δ-opioid receptors. In accordance, plasma levels of met-enkephalin, but not β-endorphin, were augmented in response to CCL4. Likewise, CCL4-evoked antinociception was blocked by the administration of an anti-met-enk antibody. Leukocyte depletion experiments performed with cyclophosphamide, anti-Ly6G, or anti-CD3 antibodies indicated that the antinociceptive effect evoked by CCL4 depends on circulating T lymphocytes. Double immunofluorescence experiments showed a four times more frequent expression of met-enk in CD4

Topics: Analgesics; Animals; CD4-Positive T-Lymphocytes; Chemokine CCL4; Enkephalin, Methionine; Mice; Naloxone; Naltrexone; Narcotic Antagonists; Nociception; Pain; Pain Measurement

This study attempted to evaluate the efficacy of ultra-low-dose intravenous (IV) naloxone combined with IV morphine, as compared to IV morphine alone, in terms of reducing pain and morphine-induced side effects in patients with renal colic.. In this double-blind clinical trial, 150 patients aged 34 to 60 years old who presented to the emergency department (ED) with renal colic were randomly allocated to either an intervention group that received ultra-low-dose IV naloxone combined with IV morphine or to a control group that received morphine plus a placebo. The severity of pain, sedation, and nausea were assessed and recorded for all patients at entrance to the ED (T1), then at 20 (T2), 40 (T3), 60 (T4), 120 (T5), and 180 (T6) minutes after starting treatment. The Numeric Rating Scale (NRS) was used for the assessment of pain and nausea intensities, and the Ramsay Sedation Scale (RSS) was used to assess sedation.. A GEE model revealed that patients in the naloxone group had non-significantly reduced pain scores compared to those in the morphine group (coefficient = -0.68; 95% CI: -1.24 to -0.11, Wald X2 (1) = 5.41, p = 0.02). The sedation outcome demonstrated no statistically significant differences at T1 to T4 among patients with renal colic compared to the ones who only received morphine. At T5 and T6, 1.5% vs. 20% and 1.5% vs. 16.9% of subjects from the naloxone group versus the morphine group obtained RSS scores equal to 3, respectively (p = 0.001 and p = 0.004, respectively).. Compared to patients who only received IV morphine, co-treatment of ultra-low-dose naloxone with morphine could not provide better analgesia and sedation/agitation states in renal colic patients.

Topics: Adult; Analgesia; Analysis of Variance; Double-Blind Method; Drug Therapy, Combination; Emergency Service, Hospital; Female; Humans; Iran; Male; Middle Aged; Morphine; Naloxone; Pain; Pain Management; Pain Measurement; Renal Colic; Statistics, Nonparametric

The processing of pain in the central nervous system is now known to have an important immune component, including T cells of the adaptive immune system. T cells have been shown to release endogenous opioids, and although it is well known that opioids have effects on T-cell populations, very little attention has been given to the converse: how T cells may affect opioid regulation. We find here that, in addition to displaying significantly increased baseline pain sensitivity across various pain modalities, T-cell-deficient mice (CD-1 nude, Rag1 null mutant, and Cd4 null mutant) exhibit pronounced deficiencies in morphine inhibition of thermal or inflammatory pain. Nude mice are also deficient in endogenous opioid-mediated analgesia, exhibiting no stress-induced analgesia from restraint. The relevant T-cell subpopulation seems to be CD4 T cells because adoptive transfer of them but not CD8 cells into nude mice rescues both the pain and morphine analgesia phenotypes. As previously reported, we also observe a sex difference in CD-1 mice, with females requiring 2- to 3-fold more morphine than males to produce equal analgesia. Nude mice display no sex differences in morphine analgesia, and the sex difference is restored in nude mice of either sex receiving CD4 T cells from CD-1 donor male or female mice. These results suggest that CD4 T cells play an as yet unappreciated role in opioid analgesia and may be a driver of sex differences therein.

Topics: Adoptive Transfer; Analgesics, Opioid; Animals; Antigens, CD1; CD4 Antigens; CD4-Positive T-Lymphocytes; Disease Models, Animal; Female; Homeodomain Proteins; Hyperalgesia; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Morphine; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Sex Factors; Transforming Growth Factor beta1

Ocular pain is a core symptom of inflammatory or traumatic disorders affecting the anterior segment. To date, the management of chronic ocular pain remains a therapeutic challenge in ophthalmology. The main endogenous opioids (enkephalins) play a key role in pain control but exhibit only transient analgesic effects due to their rapid degradation. The aim of this study was to explore the antinociceptive and anti-inflammatory effects of topical administration of PL265 (a dual enkephalinase inhibitor) on murine models of corneal pain. On healthy corneas, chronic PL265 topical administration did not alter corneal integrity nor modify corneal mechanical and chemical sensitivity. Then, on murine models of corneal pain, we showed that repeated instillations of PL265 (10 mM) significantly reduced corneal mechanical and chemical hypersensitivity. PL265-induced corneal analgesia was completely antagonized by naloxone methiodide, demonstrating that PL265 antinociceptive effects were mediated by peripheral corneal opioid receptors. Moreover, flow cytometry (quantification of CD11b+ cells) and in vivo confocal microscopy analysis revealed that instillations of PL265 significantly decreased corneal inflammation in a corneal inflammatory pain model. Chronic PL265 topical administration also decreased Iba1 and neuronal injury marker (ATF3) staining in the nucleus of primary sensory neurons of ipsilateral trigeminal ganglion. These results open a new avenue for ocular pain treatment based on the enhancement of endogenous opioid peptides' analgesic effects in tissues of the anterior segment of the eye. Dual enkephalinase inhibitor PL265 seems to be a promising topical treatment for safe and effective alleviation of ocular pain and inflammation.

Topics: Administration, Topical; Animals; Anti-Infective Agents, Local; Benzalkonium Compounds; Capsaicin; Cornea; Corneal Injuries; Disease Models, Animal; Enzyme Inhibitors; Hyperalgesia; Inflammation; Lipopolysaccharides; Male; Mice; Mice, Inbred C57BL; Naloxone; Narcotic Antagonists; Pain; Pain Threshold; Propionates; Sensory System Agents; Trigeminal Ganglion

Glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2) are gut derived hormones. GLP-1 and GLP-2 were shown to have pleiotropic effects in intestinal and pancreatic diseases.. We aimed to investigate the activities of GLP-1 and GLP-2 on nociception and inflammation in mice, involving their actions on serotonergic, nitrergic, and opioidergic systems.. Antinociceptive and anti-inflammatory activities of intraperitoneally injected GLPs were evaluated in hotplate latency test, formalin-induced behavioral, and paw edema tests. Ondansetron, a selective 5-HT. GLP-1 (0.2 mg/kg) and GLP-2 (0.05, 0.2 mg/kg) significantly increased pain threshold. GLP-1 (0.2 mg/kg) and GLP-2 (0.05, 0.1, 0.2 mg/kg) significantly decreased formalin-induced licking and shaking behaviors. GLP-1 or GLP-2 showed no significant inhibitory action on formalin-induced swelling in paws of mice. Antinociceptive actions of GLP-1 and GLP-2 were significantly decreased with ondansetron and naloxone, and paw shaking behavior significantly increased with naloxone. GLP-1 and GLP-2 did not impair rotarod performance, and did not cause a significant hypoglycemic effect in our normoglycemic mice after rotarod test.. These finding indicated that the antinociceptive and anti-inflammatory effect of GLP-1 was related to opioidergic system. Antinociceptive effect of GLP-2 was partially related to 5-HT3 serotonergic or opioidergic system in hotplate test. However, the anti-inflammatory effect of GLP-2 was not directly related to 5-HT3, NO or opioids.

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Edema; Female; Glucagon-Like Peptides; Male; Mice; Mice, Inbred BALB C; Naloxone; Narcotic Antagonists; Nitric Oxide; Nociception; Pain; Pain Measurement; Plant Extracts; Receptors, Serotonin, 5-HT3; Rotarod Performance Test; Serotonin 5-HT3 Receptor Antagonists

Fentanyl has a low molecular weight and is lipophilic making it suitable for transdermal administration. However, multiple factors appear to lead to interindividual variation in absorption via this route. Here we describe an unusual case where a patient was found to have twelve 100 μg/hour fentanyl patches in situ which she was using as background analgesia.

Topics: Analgesics, Opioid; Cachexia; Female; Fentanyl; Hospices; Humans; Middle Aged; Naloxone; Narcotic Antagonists; Pain; Pressure Ulcer; Skin Absorption; Transdermal Patch

Electrical stimulation of the anterior pretectal nucleus (APtN) activates two descending pain inhibitory pathways. One of these pathways relays in the ipsilateral lateral paragigantocellular nucleus (LPGi), whereas the other pathway relays in the contralateral pedunculopontine tegmental nucleus (PPTg). Antinociceptive effect of APtN stimulation has been seen in various pain models in the rodents. Similarly, LPGi or PPTg stimulation results in higher pain thresholds. Descending antinociceptive pathways activated by electrical APtN stimulation have been elucidated, but the underlying neurotransmitter mechanisms involved have not been clarified yet. This study investigates the role that endogenous signaling plays in the ipsilateral LPGi or contralateral PPTg after the APtN is stimulated in the tail-flick test. First, we submitted rats to excitotoxic injection of N-methyl-d-aspartate (NMDA) into the contralateral PPTg. Then, we examined whether blockage of NMDA (AP-7), serotonergic (methysergide), or opioid (naloxone) receptors in the ipsilateral LPGi is required for APtN stimulation-evoked analgesia (SEA). Likewise, we examined the effects of antagonists of NMDA, serotonergic, or cholinergic nicotinic (mecamylamine) receptors on the contralateral PPTg in ipsilateral LPGi-lesioned rats. Our results confirmed that APtN stimulation activates two pain inhibitory pathways and showed that endogenous opioid signaling in the ipsilateral LPGi appears to be necessary for APtN SEA and for endogenous NMDA, serotoninergic, and nicotinergic signaling in the contralateral PPTg.

Topics: Analgesia; Analgesics, Opioid; Animals; Electric Stimulation; Male; Methysergide; N-Methylaspartate; Naloxone; Narcotic Antagonists; Neurotransmitter Agents; Nociceptors; Pain; Pain Management; Pain Measurement; Pedunculopontine Tegmental Nucleus; Pretectal Region; Rats; Rats, Wistar

Opioid analgesics are powerful pain relievers; however, over time, pain control diminishes as analgesic tolerance develops. The molecular mechanisms initiating tolerance have remained unresolved to date. We have previously shown that desensitization of the μ-opioid receptor and interaction with β-arrestins is controlled by carboxyl-terminal phosphorylation. Here we created knockin mice with a series of serine- and threonine-to-alanine mutations that render the receptor increasingly unable to recruit β-arrestins. Desensitization is inhibited in locus coeruleus neurons of mutant mice. Opioid-induced analgesia is strongly enhanced and analgesic tolerance is greatly diminished. Surprisingly, respiratory depression, constipation, and opioid withdrawal signs are unchanged or exacerbated, indicating that β-arrestin recruitment does not contribute to the severity of opioid side effects and, hence, predicting that G-protein-biased µ-agonists are still likely to elicit severe adverse effects. In conclusion, our findings identify carboxyl-terminal multisite phosphorylation as key step that drives acute μ-opioid receptor desensitization and long-term tolerance.

Topics: Analgesia; Analgesics, Opioid; Animals; beta-Arrestins; Brain; Drug Tolerance; Female; Fentanyl; Gene Expression; Gene Knock-In Techniques; Infusion Pumps, Implantable; Male; Mice; Mice, Transgenic; Microtomy; Morphine; Naloxone; Pain; Pain Management; Phosphorylation; Protein Binding; Receptors, Opioid, mu; Tissue Culture Techniques

Pronounced analgesic activity of the innovative compound 4-(3,4-dibromthiophencarbonyl)-2,6,8,12-tetraacethyl-2,4,6,8,10,12hexaazatetracyclo[5,5,0,0

Topics: Analgesics; Animals; Disease Models, Animal; Gastric Mucosa; Male; Mice; Naloxone; Pain; Pain Measurement

Many patients on chronic opioid therapy suffer from constipation, one of the most common side effect of opioids. Movantik™ (naloxegol) is an opioid antagonist that is recently introduced in the market to treat opioid-induced constipation and contains naloxegol as the active ingredient. Naloxegol is a pegylated (polyethylene glycol-modified) derivative of α-naloxol. Detection of naloxone in the patients urine after consumption of naloxegol was not reported by the manufacturer and may mislead the prescribing clinicians. This study was conducted to investigate the presence of naloxone in the urine of patients that consume movnatik in pain management clinics.. The presence of naloxone and naloxol in the urine of 45 patients that consumed naloxegol and 25 patients that consumed suboxone™ were investigated using a liquid chromatography mass spectrometry (LCMS) method. The urinary concentration of naloxone, naloxol, and their glucuronide conjugates were evaluated in five volunteers that took one pill of naloxegol for one day and one volunteer who took the pill for three days.. Naloxone was detected in the urine of 45 individuals that were prescribed naloxegol. Urinary concentration of naloxone showed a distribution with a mean of 25 ± 18 ng/ml. Consumption of one pill of 25 mg naloxegol resulted in the detection of naloxol and naloxone in the urine of 5 volunteers 1 h after taking the pill. Evaluation of urine specimens from 25 patients that consumed suboxone™, resulted in the detection of naloxone (180 ± 187 ng/ml) and naloxol (6.3 ± 7.2 ng/ml).. This study demonstrated that consumption of naloxegol leads to appearance of naloxone in the urine of patients receiving opioid therapy in pain management clinics.

Topics: Adult; Female; Humans; Male; Middle Aged; Morphinans; Naloxone; Pain; Polyethylene Glycols; Retrospective Studies; Substance Abuse Detection

Nociceptive discharges caused by the unilateral tissue damage are processed in the spinal cord by both ipsi- and contralateral neuronal circuits. The mechanisms of the neurotransmitter control of this bilateral excitation spread is poorly understood. Spinally administered opiates are known to suppress nociceptive transmission and nociceptive withdrawal reflexes. Here we investigated whether three major types of opioid receptors are involved in the bilateral control of the spinal nociceptive sensorimotor processing. Effects of the µ-, δ- and κ-opioid receptor agonists on the ipsi- and contralateral nociceptive reflexes were studied by recording slow ventral root potentials in an isolated spinal cord preparation of the new-born rat. Absolute levels of expression of the opioid genes were analyzed by the droplet digital PCR. Ipsi- and contralateral slow ventral root potentials were most strongly suppressed by the µ-opioid receptor agonist DAMGO, by 63% and 85%, followed by the κ-opioid receptor agonist U-50488H, by 44% and 73%, and δ-opioid receptor agonist leucine-enkephalin, by 27% and 49%, respectively. All these agonists suppressed stronger contra- than ipsilateral responses. Naloxone prevented effects of the agonists indicating that they act through opioid receptors, which, as we show, are expressed in the neonatal spinal cord at the levels similar to those in adults. Thus, opioid receptor agonists suppress the segmental nociceptive reflexes. Stronger contralateral effects suggest that the endogenous opioid system regulates sensorimotor processing in the spinal commissural pathways. These effects of opioids may be relevant for treatment of symmetric clinical pain symptoms caused by unilateral tissue injury.

Topics: Analgesics, Opioid; Animals; Animals, Newborn; Female; Male; Morphine; Naloxone; Nociceptors; Pain; Rats; Rats, Wistar; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Reflex; Spinal Cord

Tagetes lucida Cav. is an ancient medicinal plant used to treat different ailments involving neurological diseases and pain. However, scientific studies to validate their medicinal properties as analgesic have not been described. The aim of this study was to evaluate the T. lucida antinociceptive response using pain models. Bioactive compounds and a possible mechanism of action were also explored. Dose-response effects of an ethanol crude extract were investigated in the writhing and formalin tests in mice and rats, respectively. The extract was fractionated to isolate active fractions and bioactive compounds (quercetagetin 7‑O‑β‑d‑glucoside and 6,7‑dimethoxycoumarin) using the formalin test. The antinociceptive effects were compared to the reference drugs (tramadol 10 mg/kg, diclofenac 50 mg/kg, and/or ketorolac 1 mg/kg, i.p.). The ethanol extract was explored in the presence of naloxone (3 mg/kg, i.p. a non-selective opioid receptor antagonist) and WAY100635 (0.5 mg/kg, s.c., a selective 5-HT

Topics: Analgesics; Animals; Curcumin; Female; Flavones; Male; Medicine, Chinese Traditional; Mice; Models, Animal; Naloxone; Narcotic Antagonists; Pain; Plant Extracts; Plant Leaves; Rats; Rats, Wistar; Receptor, Serotonin, 5-HT1A; Tagetes

The ability to detect noxious stimuli is essential to survival. However, pathological pain is maladaptive and severely debilitating. Endogenous and exogenous opioids modulate pain responses via opioid receptors, reducing pain sensibility. Due to the high genetic and physiological similarities to rodents and humans, the zebrafish is a valuable tool to assess pain responses and the underlying mechanisms involved in nociception. Although morphine attenuates pain-like responses of zebrafish, there are no data showing if the antagonism of opioid receptors prolongs pain duration in the absence of an exogenous opioid. Here, we investigated whether a common opioid antagonist naloxone affects the abdominal constriction writhing-like response, recently characterized as a zebrafish-based pain behavior. Animals were injected intraperitoneally with acetic acid (5.0%), naloxone (1.25 mg/kg; 2.5 mg/kg; 5.0 mg/kg) or acetic acid with naloxone to investigate the changes in their body curvature for 1 h. Acetic acid elicited a robust pain-like response in zebrafish, as assessed by aberrant abdominal body curvature, while no effects were observed following PBS injection. Although naloxone alone did not alter the frequency and duration of this behavior, it dose-dependently prolonged acetic acid-induced abdominal curvature response. Besides reinforcing the use of the abdominal writhing-like phenotype as a behavioral endpoint to measure acute pain responses in zebrafish models, our novel data suggest a putative role of endogenous opioids in modulating the recovery from pain stimulation in zebrafish.

Topics: Abdomen; Acetic Acid; Animals; Behavior, Animal; Constriction, Pathologic; Disease Models, Animal; Naloxone; Narcotic Antagonists; Pain; Visceral Pain; Zebrafish

Flavonoids are phenolic compounds that have always attracted pharmaceutical researchers and food manufacturers. Nature has indirectly provided us flavones in our daily diet i.e. tea, fruits, juices and vegetables. Flavones have got special position in research field of natural and synthetic organic chemistry due to their biological capabilities. Three substituted flavone derivatives have been synthesized from substituted O-hydroxy acetophenones and 4-trifluoromethyl benzaldehyde in good yield. The structures have been established by different spectroscopic techniques like

Topics: Analgesics; Animals; Crystallography, X-Ray; Drug Evaluation, Preclinical; Female; Flavonoids; Lipoxygenase Inhibitors; Magnetic Resonance Spectroscopy; Male; Mice; Molecular Structure; Morphine; Naloxone; Narcotic Antagonists; Pain; Spectrophotometry, Infrared; Toxicity Tests, Acute

The aim of this study was to investigate the antinociceptive potential of (-)-epicatechin and the possible mechanisms of action involved in its antinociceptive effect. The carrageenan and formalin tests were used as inflammatory pain models. A plethysmometer was used to measure inflammation and L5/L6 spinal nerve ligation as a neuropathic pain model. Oral (-)-epicatechin reduced carrageenan-induced inflammation and nociception by about 59 and 73%, respectively, and reduced formalin- induced and nerve injury-induced nociception by about 86 and 43%, respectively. (-)-Epicatechin-induced antinociception in the formalin test was prevented by the intraperitoneal administration of antagonists: methiothepin (5-HT1/5 receptor), WAY-100635 (5-HT1A receptor), SB-224289 (5-HT1B receptor), BRL-15572 (5-HT1D receptor), SB-699551 (5-HT5A receptor), naloxone (opioid receptor), CTAP (μ opioid receptor), nor-binaltorphimine (κ opioid receptor), and 7-benzylidenenaltrexone (δ1 opioid receptor). The effect of (-)-epicatechin was also prevented by the intraperitoneal administration of L-NAME [nitric oxide (NO) synthase inhibitor], 7-nitroindazole (neuronal NO synthase inhibitor), ODQ (guanylyl cyclase inhibitor), glibenclamide (ATP-sensitive K channel blocker), 4-aminopyridine (voltage-dependent K channel blocker), and iberiotoxin (large-conductance Ca-activated K channel blocker), but not by amiloride (acid sensing ion channel blocker). The data suggest that (-)-epicatechin exerts its antinociceptive effects by activation of the NO-cyclic GMP-K channels pathway, 5-HT1A/1B/1D/5A serotonergic receptors, and μ/κ/δ opioid receptors.

Topics: Analgesics; Animals; Carrageenan; Catechin; Cyclic GMP; Female; Hyperalgesia; Naloxone; Neuralgia; Nociception; Pain; Pain Management; Pain Measurement; Pain Perception; Rats; Rats, Wistar; Receptors, Opioid; Receptors, Serotonin; Spinal Nerves

As important as perceiving pain is the ability to modulate this perception in some contextual salient situations. The periaqueductal gray (PAG) is perhaps the most important site of endogenous pain modulation; however, little is known about dopaminergic mechanisms underlying PAG-mediated antinociception. In this study, we used a pharmacological approach to evaluate this subject. We found that µ-opioid receptor-induced antinociception (DAMGO, 0.3 μg) from PAG was blocked by the coadministration of either D1-like or D2-like dopaminergic antagonists (SCH23390, 2, 4, and 6 μg or raclopride, 2 and 4 μg, respectively) both in the tail-flick and in the mechanical paw-withdrawal test. A selective D2-like receptor agonist (piribedil, 6 and 12 μg into the PAG) induced antinociception in the mechanical paw-withdrawal test, but not in the tail-flick test. This effect was blocked by the coadministration of its selective antagonist (raclopride 4 μg), as well as by either a GABAA agonist (muscimol, 0.1 μg) or an opioid receptor antagonist (naloxone, 0.5 μg). A selective D1-like receptor agonist (SKF38393, 1, 5, and 10 μg into the PAG) induced a poor and transient antinociceptive effect, but when combined with piribedil, a potentiated antinociceptive effect emerged. None of these treatments affected locomotion in the open-field test. These findings suggest that µ-opioid antinociception from the PAG depends on dopamine acting on both D1-like and D2-like receptors. Selective activation of PAG D2-like receptors induces antinociception mediated by supraspinal mechanisms dependent on inhibition of GABAA and activation of opioid neurotransmission.

Topics: Analgesics; Analgesics, Opioid; Animals; Dopamine Agents; Dopaminergic Neurons; Male; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Periaqueductal Gray; Rats; Rats, Wistar; Receptors, Opioid; Receptors, Opioid, mu

In the past decade several studies have reported that in some brain areas, particularly, in the midbrain periaqueductal gray matter, rostral ventro-medial medulla, central nucleus of amygdala, nucleus raphe magnus, and dorsal hippocampus, microinjections of non-steroidal anti-inflammatory drugs (NSAIDs) induce antinociception with distinct development of tolerance. Given this evidence, in this study we investigated the development of tolerance to the analgesic effects of NSAIDs diclofenac, ketorolac and xefocam microinjected into the rostral part of anterior cingulate cortex (ACC) in rats.. Male Wistar experimental and control (saline) rats were implanted with a guide cannula in the ACC and tested for antinociception following microinjection of NSAIDs into the ACC in the tail-flick (TF) and hot plate (HP) tests. Repeated measures of analysis of variance with post-hoc Tukey-Kramer multiple comparison tests were used for statistical evaluations.. Treatment with each NSAID significantly enhanced the TF and HP latencies on the first day, followed by a progressive decrease in the analgesic effect over a 4-day period, i.e., developed tolerance. Pretreatment with an opioid antagonist naloxone completely prevented the analgesic effects of the three NSAIDs in both behavioral assays.. These findings support the concept that the development of tolerance to the antinociceptive effects of NSAIDs is mediated via an endogenous opioid system possibly involving descending pain modulatory systems.

Topics: Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Diclofenac; Drug Tolerance; Gyrus Cinguli; Ketorolac; Male; Microinjections; Naloxone; Narcotic Antagonists; Opioid Peptides; Pain; Piroxicam; Rats, Wistar

Topics: Analgesics, Opioid; Delayed-Action Preparations; Drug Combinations; Humans; Liver Cirrhosis; Naloxone; Oxycodone; Pain

Opioid-related overdose has increased 137% in the past decade. Training nonmedical bystanders to administer naloxone (Narcan™) is a widely-researched intervention that has been associated with decreases in overdose rates in the communities in which it has been implemented. A recent review advocated for noninjectable formulations of naloxone, however patient preference for naloxone formulations has not yet been examined (Strang et al., 2016).. Two cohorts of respondents (N. Results were remarkably similar across both cohorts. Specifically, respondents preferred noninjectable formulations (intranasal, sublingual, buccal) over injectable (intravenous, intramuscular) formulations. A small percent (8.9%-9.8%) said they would never be willing to administer naloxone. An identical percent of respondents in both cohorts (44.9%) rated intranasal as their most preferred formulation.. Two independent cohorts of respondents who were receiving opioid medications for pain management reported a preference for noninjectable over injectable formulations of naloxone to reverse an opioid overdose. Though initial preference is only one of many factors that impacts ultimate public acceptance and uptake of a new product, these results support the additional research and development of noninjectable naloxone formulations.

Topics: Administration, Buccal; Administration, Intranasal; Administration, Intravenous; Administration, Sublingual; Adolescent; Adult; Analgesics, Opioid; Drug Overdose; Female; Humans; Injections, Intramuscular; Male; Middle Aged; Naloxone; Narcotic Antagonists; Pain; Patient Preference; Young Adult

Acute pain secondary to trauma is commonly encountered on the battlefield. The use of morphine to manage pain during combat has been well established since the 19th century. Despite this, there is relatively little research on analgesia use in this environment. This study aims to review the use and complications of morphine and other opioids during Operation HERRICK.. A database search of the Joint Theatre Trauma Registry was completed looking for all incidences of morphine, fentanyl or naloxone use from February 2007 to September 2014. Microsoft Excel was used to analyse the results.. Opioid analgesia was administered to 5801 casualties. Morphine was administered 6742 times to 3808 patients. Fentanyl was administered 9672 times to 4318 patients. Naloxone was used 18 times on 14 patients, giving a complication rate of 0.24%. Opioid doses prior to naloxone administration range from 0 to 72 mg of morphine and from 0 to 100 mcg of fentanyl. Four casualties (two local civilians and two coalition forces) received naloxone despite no recorded opioids being administered. Opium abuse was prevalent among the local population in Afghanistan, and this could explain the rationale behind two local national casualties receiving naloxone without any documented opioids being given.. The use of opioids in a battlefield environment is extremely safe. Complication rates are similar to previously published data which is reassuring. The efficacy of different opioids was not covered by this study, and further analysis is required, particularly following the introduction of oral transmucosal fentanyl citrate and the availability of novel non-opioid analgesics.

Topics: Adolescent; Adult; Afghan Campaign 2001-; Afghanistan; Analgesics, Opioid; Child; Child, Preschool; Dose-Response Relationship, Drug; Drug Administration Routes; Drug Utilization; Fentanyl; Humans; Middle Aged; Morphine; Naloxone; Pain; Registries; Retrospective Studies; United Kingdom; Wounds and Injuries; Young Adult

The purpose of this study was to determine if employing a home healthcare model for education and treatment of opioid overdose using the Evzio (Naloxone) auto-injector in a private practice pain clinic.. A prospective survey was used to determine the feasibility of integrating a naloxone auto-injector within the patient's home with a home care training model. Twenty moderate or high-risk patients were enrolled from the chronic pain clinic. Patients who were moderate or high risk completed an evaluation survey. The naloxone auto-injector was dispensed to all patients meeting criteria. The treating provider after prescribing the naloxone auto-injector then consulted home health per standard clinical practice. All patients had home health consulted to perform overdose identification and rescue training. A Cochran's Q test was conducted to examine differences in patient knowledge pre- and post-training. The post training test was done 2-4 weeks later.. Forty subjects enrolled after meeting inclusion/exclusion criteria. Twenty withdrew because their insurance declined coverage for the naloxone auto-injector. Those completing home health showed a statistically significant difference in their ability to correctly identify the steps needed to effectively respond to an overdose (p = .03).. Preliminary evidence would suggest training on overdose symptom recognition and proper use of prescription naloxone for treatment in the home setting by home health staff would prove more beneficial than the clinic setting, but feasibility was hindered by unaffordable costs related to insurance coverage limitations.

Topics: Adult; Aged; Ambulatory Care Facilities; Analgesics, Opioid; Drug Overdose; Feasibility Studies; Female; Home Care Services; Humans; Male; Middle Aged; Naloxone; Narcotic Antagonists; Pain; Pain Clinics; Private Practice; Prospective Studies

To examine the roles of opioid receptors in the inhibition of nociceptive and nonnociceptive bladder reflexes by sacral dorsal root ganglion (DRG) stimulation in cats.. Hook electrodes were placed in the right S1 and S2 DRG of cats. The bladders were infused with physiologic saline or 0.25% acetic acid (AA). Naloxone (0.1, 0.3, and 1 mg/kg), an opioid receptor antagonist, was administered intravenously. S1 or S2 DRG stimulation was applied before and after administering the drug. Multiple cystometrograms were performed to determine the effects of DRG stimulation and opioid receptors on the micturition reflex under nociceptive and non-nociceptive conditions.. AA significantly (P < 0.01) reduced bladder capacity (BC). DRG stimulation at threshold (T) and 1.5 T significantly increased BC of the saline control under nociceptive and non-nociceptive conditions. When saline was infused, naloxone (0.1-1 mg/kg) significantly (P < 0.01) reduced BC; however, naloxone did not change BC during AA irritation. During saline infusion, naloxone (0.3 and 1 mg/kg) partly blocked S1 DRG stimulation-induced inhibition but had only a slight effect on S2 DRG stimulation. During AA infusion, naloxone (0.3 and 1 mg/kg) only partially blocked S1 DRG stimulation at T intensity but not during 1.5 T stimulation. However, no doses of naloxone significantly affected S2 DRG stimulation.. Opioid receptors play a role in sacral DRG stimulation on non-nociceptive condition but are not involved in the inhibitory effect of stimulation in nociceptive conditions.

Topics: Animals; Cats; Electric Stimulation; Electrodes, Implanted; Female; Ganglia, Spinal; Male; Naloxone; Narcotic Antagonists; Nociceptors; Pain; Receptors, Opioid; Reflex; Urination

Topics: Analgesics; Animals; Behavior, Animal; Capsaicin; Coffee; Disease Models, Animal; Female; Formaldehyde; Glutamic Acid; Hot Temperature; Hyperalgesia; Male; Mice; Naloxone; Narcotic Antagonists; Ondansetron; Pain; Pain Measurement; Piperidines; Pyrazoles; Serotonin

Cognition and pain share common neural substrates and interact reciprocally: chronic pain compromises cognitive performance, whereas cognitive processes modulate pain perception. In the present study, we established a non-drug-dependent rat model of context-based analgesia, where two different contexts (dark and bright) were matched with a high (52°C) or low (48°C) temperature in the hot-plate test during training. Before and after training, we set the temperature to the high level in both contexts. Rats showed longer paw licking latencies in trials with the context originally matched to a low temperature than those to a high temperature, indicating successful establishment of a context-based analgesic effect in rats. This effect was blocked by intraperitoneal injection of naloxone (an opioid receptor antagonist) before the probe. The context-based analgesic effect also disappeared after optogenetic activation or inhibition of the bilateral infralimbic or prelimbic sub-region of the prefrontal cortex. In brief, we established a context-based, non-drug dependent, placebo-like analgesia model in the rat. This model provides a new and useful tool for investigating the cognitive modulation of pain.

Topics: Action Potentials; Analgesics; Animals; Disease Models, Animal; Electric Stimulation; Female; In Vitro Techniques; Naloxone; Narcotic Antagonists; Optogenetics; Pain; Pain Measurement; Pain Threshold; Patch-Clamp Techniques; Physical Stimulation; Prefrontal Cortex; Pyramidal Cells; Rats; Rats, Sprague-Dawley; Time Factors

Discaria americana (Rhamnaceae) root bark infusion have been used in traditional medicine as antipyretic, tonic, ameliorative of stomach and skin diseases and diabetes. This study was designed to investigate whether the methanolic extract of the root bark of Discaria americana (MEDa) exhibits antinociceptive effects in mice. Furthermore, it was investigated the involvement of the opioidergic system in MEDa mechanism of action as well the interactions with TRP/ASIC channels in its effect.. The antinociceptive effect of intra-gastric gavage (i.g.) of MEDa (0.3-300 mg/kg) was evaluated in mice subjected to acute chemical (acetic-acid, formalin, glutamate, capsaicin, cinnamaldehyde, and acidified saline) or thermal (hot plate) tests of pain. The involvement of opioid system was evaluated in the formalin test. A nonspecific effect of MEDa was observed by measuring locomotor activity and exploratory behavior in open field test.. MEDa significantly reduced the number of writhing induced by acetic acid and inhibited the nociception in the two phases of formalin. These effects were inhibited by pretreatment with naloxone. The nociception induced by hot plate and intraplantar injection of glutamate, capsaicin, cinnamaldehyde and acidified saline were significantly inhibited by MEDa. Only the dose of 300 mg/kg altered the locomotor activity.. Our results demonstrated, for the first time, that the methanolic extract of the root bark of Discaria americana presents antinociceptive effect in chemical and thermal stimuli and its analgesic properties can be due activation of the opioidergic system. These results support the use of Discaria americana in traditional medicine and demonstrate that this plant presents a therapeutic potential for the development of phytomedicines with antinociceptive profile.

Topics: Acid Sensing Ion Channel Blockers; Analgesics, Opioid; Animals; Behavior, Animal; Male; Mice; Naloxone; Narcotic Antagonists; Pain; Phytotherapy; Plant Bark; Plant Extracts; Plant Roots; Rhamnaceae; Transient Receptor Potential Channels

Topics: Adult; Analgesia; Conditioning, Psychological; Cross-Over Studies; Double-Blind Method; Female; Hot Temperature; Humans; Imagination; Male; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Pain Perception; Visual Perception; Young Adult

Bilateral electrical pudendal nerve stimulation (bPNS) reduces bladder hypersensitivity in rat models of bladder pain and anecdotally reduces pain in humans with pelvic pain of urologic origin. The spinal neurochemical mechanisms of this antinociception are unknown. In the present study, bladder hypersensitivity was produced by neonatal bladder inflammation in rat pups coupled with a second inflammatory insult as an adult. Visceromotor responses (VMRs; abdominal muscle contractions) to urinary bladder distension (UBD) were used as a nociceptive endpoint under urethane-isoflurane anesthesia. bPNS consisted of bilateral biphasic electrical stimulation of the mixed motor/sensory component of the pudendal nerves. Following determination of the inhibitory effect of bPNS on VMRs, pharmacological antagonists were administered via an intrathecal catheter onto the lumbosacral spinal cord and bPNS effects on VMRs redetermined. bPNS resulted in statistically significant inhibition of VMRs to UBD in hypersensitive rats that was statistically reduced by the intrathecal administration of methysergide, WAY100636, CGP35348 and strychnine but was unaffected by naloxone, bicuculline, phentolamine, ondansetron and normal saline. This study suggests that inhibitory effects of bPNS may include serotonergic, GABA-B-ergic and glycinergic mechanisms suggesting the potential for interaction of the neuromodulatory effect with concommitant drug therapies.

Topics: Animals; Cyclohexanes; Electric Stimulation; Female; Muscle Contraction; Naloxone; Pain; Piperazines; Pudendal Nerve; Rats, Sprague-Dawley; Reflex; Spinal Cord; Urinary Bladder

Background Tetracera alnifolia Willd. (Dilleniaceae) is used in traditional African Medicine for the treatment of headache, abdominal pain, and rheumatism. Hence, this study sought to investigate the antinociceptive and anti-inflammatory effects of the hydroethanolic leaf extract of T. alnifolia (HeTA) in rodents. Methods Antinociceptive activity was evaluated using the acetic acid-induced writhing, formalin-/capsaicin-induced paw licking and hot plate tests in mice. The contribution of opioidergic, l-arginine-nitric oxide, and ATP-sensitive potassium channel pathways in HeTA-induced antinociception was also evaluated. The anti-inflammatory effect was assessed using the carrageenan-induced paw edema, xylene ear edema, cotton pellet granuloma, and complete Freund's adjuvant (CFA)-induced arthritis in rats. Results HeTA (100, 200, and 400 mg/kg, p.o.) produced significant (p<0.05) decrease in mean number of acetic acid-induced writhing, time spent licking paw in formalin, and capsaicin tests as well as time course increase in nociceptive reaction latency in hot plate test. HeTA-induced antinociception was prevented by pretreatment of mice with naloxone (non-selective opioid receptor antagonist), l-arginine (nitric oxide precursor), or glibenclamide (ATP-sensitive potassium channel blocker). HeTA (100 mg/kg, p.o.) produced a significant anti-inflammatory effect against carrageenan-induced rat paw edema (1-5 h), xylene-induced ear edema, cotton pellet-induced granuloma formation, and CFA-induced arthritis in rats. The effects of HeTA in various models were similar to the effect of the standard reference drugs. Conclusions Findings from this study showed that HeTA possesses antinociceptive effect possibly mediated through peripheral opioid receptors with activation of l-arginine-nitric oxide and ATP-sensitive potassium channel pathway as well as anti-inflammatory activity.

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Arginine; Arthritis; Carrageenan; Dilleniaceae; Edema; Glyburide; Male; Medicine, African Traditional; Mice; Naloxone; Pain; Pain Measurement; Phytotherapy; Plant Extracts; Plant Leaves; Rats

Eslicarbazepine acetate (ESL) is a novel dibenzazepine antiepileptic, that has demonstrated efficacy against trigeminal pain, both in preclinical and clinical studies. However, ESL's mechanism of antinociceptive action remains uncertain. Here, we aimed to examine the contribution of adrenergic/cholinergic/opioid receptors to the antinociceptive effects of ESL in a trigeminal pain model, as these neurotransmitter systems are known to have an important role in the modulation of trigeminal nociception.. ESL's effects in the orofacial formalin test were examined following peroral and local peripheral administration (subcutaneous, into the perinasal region). The involvement of adrenergic/cholinergic/opioid receptors was evaluated by intraperitoneally pretreating mice with an appropriate antagonist immediately after peroral application of ESL. We used antagonists of α. ESL dose-dependently reduced formalin-induced nociceptive behavior after systemic and local peripheral application. Systemic administration of yohimbine, propranolol, metoprolol, atropine and naloxone inhibited ESL's antinociceptive effects in a dose-related manner. Prazosin and mecamylamine did not produce inhibitory effects. Local application of yohimbine, atropine and naloxone into the perinasal area also produced a dose-related inhibition of ESL's efficacy, whereas metoprolol failed to inhibit the local antinociceptive effects of ESL.. This study suggests that ESL's efficacy against trigeminal nociception is mediated by peripheral (and possibly central) α

Topics: Adrenergic Antagonists; Analgesics; Animals; Atropine; Cholinergic Antagonists; Dibenzazepines; Formaldehyde; Male; Mice; Naloxone; Narcotic Antagonists; Pain; Receptors, Adrenergic; Receptors, Cholinergic; Receptors, Opioid; Trigeminal Neuralgia; Yohimbine

Based on structure activity analysis of morphine related opiates, we have synthesized some novel benzopyran fused isoxazolidines (2a-e) and derived conformationally constrained β

Topics: Amino Alcohols; Analgesics; Animals; Benzopyrans; Cell Line; Chemistry Techniques, Synthetic; Drug Design; Female; Humans; Isoxazoles; Male; Mice; Molecular Docking Simulation; Pain; Prostaglandin-Endoperoxide Synthases; Protein Conformation; Receptors, Opioid

Topics: Analgesia; Analgesics, Opioid; Animals; Antigens, Ly; Carrageenan; Female; Inflammation; Macrophages; Mice; Morpholines; Naloxone; Narcotic Antagonists; Neutrophils; Oligopeptides; Pain; Piperazines; Pro-Opiomelanocortin; Pyrazoles; Quaternary Ammonium Compounds; Receptors, sigma; Sigma-1 Receptor

The anterior cingulate cortex (ACC) is crucial in the modulation of the sensory, affective and cognitive aspects of nociceptive processing. Also, it participates in the planning and execution of behavioral responses evoked by nociceptive stimuli via descending projections to the brainstem. In laboratory animals nociceptive experimental tests evaluate behavioral responses that preferentially express the sensory-discriminative or affective-motivational component of pain. The objective of this study was to investigate the participation of opioid and cholinergic neurotransmission in the ACC on different nociceptive responses in guinea pigs. We used nociceptive tests of formalin and vocalization evoked by peripheral noxious stimuli (electric shock) to evaluate the behavioral expression of the sensory-discriminative and affective motivational components, respectively. We verified that the microinjection of morphine (4.4nmol) in the ACC of guinea pigs promotes antinociception in the two experimental tests investigated. This effect is blocked by prior microinjection of naloxone (2.7nmol). On the other hand, the microinjection of carbachol (2.7nmol) in the ACC induces antinociception only in the vocalization test. This effect was prevented by prior microinjection of atropine (0.7nmol) and naloxone (2.7nmol). In fact, the blockade of µ-opioids receptors with naloxone in ACC prevented the antinociceptive effect of carbachol in the vocalization test. Accordingly, we suggest that the antinociception promoted by carbachol was mediated by the activation of muscarinic receptors on local ACC opioid interneurons. The release of endogenous opioids seems to inhibited the expression of the behavioral response of vocalization. Therefore, we verified that the antinociceptive effect of morphine microinjection in ACC is broader and more robust than that promoted by carbachol.

Topics: Acetylcholine; Analgesics, Opioid; Animals; Atropine; Carbachol; Cholinergic Agents; Guinea Pigs; Gyrus Cinguli; Male; Microinjections; Morphine; Muscimol; Naloxone; Narcotic Antagonists; Nociceptors; Opioid Peptides; Pain; Receptors, Opioid; Synaptic Transmission; Vocalization, Animal

Stigmasterol is a common sterol found in plants, but the anti-nociceptive effect of this compound and its mechanism of action are not fully explored. Thus, in the present study, the anti-nociceptive effect of stigmasterol was investigated in acute and chronic models of pain and its mechanism of action. We used adult male albino Swiss mice (25-35 g) to observe the anti-nociceptive effect of stigmasterol in acetic-acid writhing test or in complete Freund's adjuvant injection, surgical incision in hind paw, or partial sciatic nerve ligation. Moreover, we investigate the involvement of opioid receptors (naloxone, 2 mg/kg, intraperitoneally) in stigmasterol anti-nociceptive effect and stigmasterol action on acetylcholinesterase activity. Some possible adverse effects caused by stigmasterol were also investigated. Stigmasterol (0.3-3 mg/kg, orally) exhibited an anti-nociceptive effect on acetic-acid-induced writhing test. Furthermore, it markedly attenuated the mechanical allodynia caused by surgical incision (after acute treatment with stigmasterol, preventive and curative effects were observed) and partial sciatic nerve ligation (after acute treatment with stigmasterol) and complete Freund's adjuvant (after acute or repeated treatment with stigmasterol). The anti-nociceptive effect of stigmasterol was not reversed by naloxone. Moreover, stigmasterol did not alter in vitro acetylcholinesterase activity in spinal cord or brain samples. Also, stigmasterol did not cause gastric ulcers or alter the gastrointestinal transit of mice. Taken together, these results support the potential anti-nociceptive effect of stigmasterol in different models of pain.

Topics: Acetic Acid; Acetylcholinesterase; Acute Disease; Analgesics; Animals; Brain; Chronic Disease; Freund's Adjuvant; Gastrointestinal Transit; Hyperalgesia; Male; Mice; Naloxone; Narcotic Antagonists; Pain; Sciatic Nerve; Spinal Cord; Stigmasterol; Stomach

The GABAergic tail of the ventral tegmental area (tVTA), also named rostromedial tegmental nucleus (RMTg), exerts an inhibitory control on dopamine neurons of the VTA and substantia nigra. The tVTA has been implicated in avoidance behaviors, response to drugs of abuse, reward prediction error, and motor functions. Stimulation of the lateral habenula (LHb) inputs to the tVTA, or of the tVTA itself, induces avoidance behaviors, which suggests a role of the tVTA in processing aversive information. Our aim was to test the impact of aversive stimuli on the molecular recruitment of the tVTA, and the behavioral consequences of tVTA lesions. In rats, we assessed Fos response to lithium chloride (LiCl), β-carboline, naloxone, lipopolysaccharide (LPS), inflammatory pain, neuropathic pain, foot-shock, restraint stress, forced swimming, predator odor, and opiate withdrawal. We also determined the effect of tVTA bilateral ablation on physical signs of opiate withdrawal, and on LPS- and LiCl-induced conditioned taste aversion (CTA). Naloxone-precipitated opiate withdrawal induced Fos in μ-opioid receptor-positive (15%) and -negative (85%) tVTA cells, suggesting the presence of both direct and indirect mechanisms in tVTA recruitment during withdrawal. However, tVTA lesion did not impact physical signs of opiate withdrawal. Fos induction was also present with repeated, but not single, foot-shock delivery. However, such induction was mostly absent with other aversive stimuli. Moreover, tVTA ablation had no impact on CTA. Although stimulation of the tVTA favors avoidance behaviors, present findings suggest that this structure may be important to the response to some, but not all, aversive stimuli.

Topics: Animals; Antimanic Agents; Behavior, Animal; Carbolines; Conditioning, Classical; Disease Models, Animal; Lipopolysaccharides; Lithium Chloride; Male; Morphine Dependence; Naloxone; Narcotic Antagonists; Neuralgia; Neurotoxins; Olfactory Perception; Pain; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Receptors, Opioid, mu; Substance Withdrawal Syndrome; Ventral Tegmental Area

Naloxone is indicated for reversal of opioid-induced respiratory depression. The objective of this study is to evaluate patterns of naloxone use in hospitalized patients.. Retrospective chart review at the University of California, San Diego Health. Subjects included adults ≥18 years old who were admitted to and received naloxone in the medical-surgical, telemetry, intermediate care, or obstetrics/gynecology units from May 1. 124 episodes of naloxone were identified during the study period. 62% of naloxone administrations resulted in an improved level of consciousness. In contrast to this, only 30 (24.2%) episodes of naloxone administration met the criteria for respiratory depression. Of these 30 episodes, naloxone reversed respiratory depression in 25 (83.3%) of them. The most frequent opioid routes of administration were short-acting oral (53.2%) and IV opioids (44.4%). Of the concomitant medications, gabapentin (28.2%) was the most frequently associated sedating medication.. In our study, naloxone was more often used for reversal of sedation than for respiratory depression. Gabapentin may pose a risk factor for oversedation when combined with opioids, leading to increased naloxone use. Further studies are needed to explore these patterns.

Topics: Adult; Aged; Aged, 80 and over; Analgesics, Opioid; California; Conscious Sedation; Consciousness; Female; Humans; Hypnotics and Sedatives; Inpatients; Lung; Male; Middle Aged; Naloxone; Narcotic Antagonists; Pain; Respiratory Insufficiency; Retrospective Studies; Risk Factors

The implementation of interventions to mitigate the causes of opioid-induced oversedation and respiratory depression (OSRD) is reported.. A single-site retrospective review of eligible rescue naloxone cases was conducted to identify the causes of opioid-induced OSRD in a hospital as well as to identify risk factors. A survey was used to assess potential opioid knowledge deficits among hospitalist prescribers. Based on the findings of the case reviews and results of the opioid knowledge assessments, a series of interventions to address noted deficiencies was implemented over the ensuing months, including enhanced monitoring for sedation, improved clinical decision support in the electronic medical record (EMR), and various adjustments to dosing for high-risk patients. The primary endpoint of our analysis was naloxone use for documented cases of opioid-induced OSRD to determine the effectiveness of the interventions. A mean of 16 OSRD events occurred per quarter before intervention implementation. An average of five risk factors (range, two to six) was found among OSRD cases, most commonly age of >60, obesity, and comorbidities of the kidneys and lungs. Deficiencies of clinical care were found in four inter-related domains: knowledge deficits, inadequate monitoring, failure to leverage the EMR, and cultural issues regarding pain assessments and sedation management.. Implementation of solution bundles that utilized an EMR to create meaningful clinical decision support and cultural changes related to pain goals and communication about sedation level at an acute care hospital resulted in a fivefold reduction in OSRD events that has been sustained for two years.

Topics: Analgesics, Opioid; Decision Support Systems, Clinical; Dose-Response Relationship, Drug; Electronic Health Records; Health Knowledge, Attitudes, Practice; Hospitalists; Humans; Middle Aged; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Respiratory Insufficiency; Retrospective Studies; Risk Factors

Topics: Analgesics, Opioid; Humans; Naloxone; Narcotic Antagonists; Pain; Primary Health Care

There is growing appreciation for the importance of gastrointestinal microbiota in many physiological and pathophysiological processes. While morphine and other narcotics are the most widely prescribed therapy for moderate to severe pain clinically, they have been noted to alter microbial composition and promote bacterial translocation to other tissues. Here we examined the pharmacodynamic properties of chronic morphine in mice following bacterial depletion with oral gavage of an antibiotic cocktail (ABX). ABX significantly reduced gut bacteria and prevented chronic morphine induced increases in gut permeability, colonic mucosal destruction, and colonic IL-1β expression. In addition, ABX prevented the development of antinociceptive tolerance to chronic morphine in both the tail-immersion and acetic acid stretch assays. Morphine tolerance was also reduced by oral vancomycin that has 0% bioavailability. These findings were recapitulated in primary afferent neurons isolated from dorsal root ganglia (DRG) innervating the lower gastrointestinal tract, wherein in-vivo administration of ABX prevented tolerance to morphine-induced hypoexcitability. Finally, though ABX repeatedly demonstrated an ability to prevent tolerance, we show that it did not alter susceptibility to precipitation of withdrawal by naloxone. Collectively, these finding indicate that the gastrointestinal microbiome is an important modulator of physiological responses induced by chronic morphine administration.

Topics: Analgesics, Opioid; Animals; Anti-Bacterial Agents; Cecum; Drug Tolerance; Dysbiosis; Ganglia, Spinal; Gastrointestinal Microbiome; Male; Mice; Morphine; Morphine Dependence; Naloxone; Narcotic Antagonists; Pain; Spleen; Stomach; Substance Withdrawal Syndrome

Visceral pain has a greater emotional component than somatic pain. To determine if the stress-induced analgesic response is differentially expressed in visceral versus somatic pain states, we studied the effects of a mild social stressor in either acute visceral or somatic pain states in mice. We show that the presence of an unfamiliar conspecific mouse (stranger) in an adjacent cubicle of a standard transparent observation box produced elevated plasma corticosterone levels compared with mice tested alone, suggesting that the mere presence of a stranger is stressful. We then observed noxious visceral or somatic stimulation-induced nociceptive behavior in mice tested alone or in mildly stressful conditions (ie, beside an unfamiliar stranger). Compared with mice tested alone, the presence of a stranger produced a dramatic opioid-dependent reduction in pain behavior associated with visceral but not somatic pain. This social stress-induced reduction of visceral pain behavior relied on visual but not auditory/olfactory cues. These findings suggest that visceral pain states may provoke heightened responsiveness to mild stressors, an effect that could interfere with testing outcomes during simultaneous behavioral testing of multiple rodents.. In mice, mild social stress due to the presence of an unfamiliar conspecific mouse reduces pain behavior associated with noxious visceral but not somatic stimulation, suggesting that stress responsiveness may be enhanced in visceral pain versus somatic pain states.

Topics: Acetic Acid; Animals; Capsaicin; Corticosterone; Cues; Disease Models, Animal; Formaldehyde; Male; Mice; Naloxone; Narcotic Antagonists; Nociception; Pain; Receptors, Opioid; Recognition, Psychology; Social Behavior; Stress, Psychological; Visual Perception

Chronic pain affects the lives of millions yearly, but few new treatments are available. Due to decreasing budgets and increasing costs of preclinical research, alternatives are sought with high translatability and low cost. Here we demonstrate the utility of a zebrafish-based model of nociception to serve as a novel screening tool for analgesic drugs. Zebrafish swimming behavior was measured following administration of various algogens including histamine, cinnamaldehyde, mustard oil, acetic acid and complete Freund's adjuvant. All compounds reduce distance traveled, thought to be an expression of nociception. Additionally, the suppression of swimming was attenuated by administration of the common analgesic, morphine. Together these data provide support for the use of zebrafish as a cost-effective and translatable model of nociception.

Topics: Acetic Acid; Acrolein; Analgesics, Opioid; Animals; Antineoplastic Agents, Phytogenic; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Freund's Adjuvant; Histamine; Histamine Agonists; Male; Morphine; Mustard Plant; Naloxone; Narcotic Antagonists; Nociception; Pain; Plant Oils; Swimming; Zebrafish

Dynorphin A (Dyn A) is an endogenous ligand for the opioid receptors with preference for the κ opioid receptor (KOR), and its structure-activity relationship (SAR) has been extensively studied at the KOR to develop selective potent agonists and antagonists. Numerous SAR studies have revealed that the Arg

Topics: Animals; Cell Line; CHO Cells; Cricetulus; Dose-Response Relationship, Drug; Dynorphins; Guinea Pigs; Male; Mice; Mice, Inbred ICR; Narcotic Antagonists; Pain; Rats; Receptors, Opioid, kappa; Structure-Activity Relationship

The amygdala has an important role in pain and pain modulation. We showed previously in animal studies that α2 -adrenoreceptor activation in the central nucleus of the amygdala (CeA) mediates hypoalgesia produced by restraint stress, and that direct application of an α2 -agonist in this region produces analgesia.. In the present animal experiments, we investigated the pathways through which α2 -sensitive systems in the CeA produce behavioural analgesia. The CeA has dense connections to a descending pain modulatory network, centred in the midbrain periaqueductal grey (PAG) and the rostral ventromedial medulla (RVM), which is implicated in various forms of stress-related hypoalgesia and which mediates the antinociceptive effect of morphine applied in the basolateral amygdala. We investigated whether this circuit mediates the hypoalgesic effects of α2 -adrenergic agonist administration into the CeA as well as the contribution of endogenous opioids and cannabinoids. We also tested the possibility that activation of α2 -receptors in the CeA produces antinociception by recruitment of noradrenergic pathways projecting to the spinal cord.. Hypoalgesia resulting from bilateral application of the α2 -adrenergic agonist clonidine in the CeA was not reversed by chemical inactivation of the RVM or by systemic injections of naloxone (μ-opioid antagonist) or rimonabant (CB1 antagonist). By contrast, spinal α2 -receptor blockade (intrathecal idazoxan) completely prevented the hypoalgesic effect of clonidine in the CeA, and unmasked a small but significant hyperalgesia.. In rats, adrenergic actions in the CeA mediating hypoalgesia require spinal adrenergic neurotransmission but not the PAG-RVM pain modulatory network, or opiate or cannabinoid systems.

Topics: Amygdala; Analgesics, Opioid; Animals; Hyperalgesia; Male; Morphine; Naloxone; Narcotic Antagonists; Norepinephrine; Pain; Pain Measurement; Periaqueductal Gray; Rats; Rats, Sprague-Dawley

The present study was designed to investigate the anti-nociceptive activity of a few structurally related trimethoxy flavones (7,2',3'-TMF, 7,2',4'-TMF, 7,3',4'-TMF and 7,5,4'-TMF) and the possible mechanisms involved.. Anti-nociceptive activity was evaluated in mice by employing acetic acid-induced writhing, formalin-induced nociception and hot water tail immersion methods. The involvement of opioid, GABAergic, tryptaminergic, adrenergic and dopaminergic mechanisms and K+ATP channels in the anti-nociceptive activity of trimethoxy flavones was investigated using suitable interacting chemicals.. Trimethoxy flavones exhibited a significant and dose-dependent inhibition of acetic acid writhing. The paw-licking response time was reduced both in the early and late phases of formalin nociception in a dose-dependent manner by trimethoxy flavones. A significant increase in tail withdrawal latency time was also observed after trimethoxy flavones treatment. These observations revealed the potential anti-nociceptive action of the investigated trimethoxy flavones. Pretreatment with naloxone and bicuculline significantly attenuated the reduction of abdominal constrictions produced by all the tested trimethoxy flavones indicating a definite role of opioid and GABAergic mechanisms in the anti-nociceptive effect of trimethoxy flavones. The anti-nociceptive action elicited by various trimethoxy flavones was differently modulated by glibenclamide, ondansetron, yohimbine and sulpiride.. The investigated trimethoxy flavones exhibited promising anti-nociceptive activity in various nociceptive models, and multiple mechanisms are involved in the anti-nociceptive activity of these compounds.

Topics: Acetic Acid; Analgesics; Analgesics, Opioid; Animals; Behavior, Animal; Flavones; Formaldehyde; Male; Mice; Naloxone; Pain; Pain Measurement; Plant Extracts

Amylin (AMY) is a member of calcitonin family of peptides. In this study, the effects of intrathecal (i.t) injection of AMY on the inflammatory pain and on the cAMP accumulation in the rat spinal cells were investigated. By using AMY receptor antagonists, we also studied the pharmacology of AMY receptors in the spinal cells. Formalin model of inflammatory pain was induced by intraplantar injection of formalin. AMY (0.06250-2500pmol/rat) was administrated i.t 15min before the injection of formalin. Antagonists were injected i.t 10min before the injection of AMY and/or morphine. AMY reduced formalin-induced pain in a dose dependent mode. This effect was inhibited by the potent AMY antagonist, AC187 but not CGRP8-37. rAMY8-37, most commonly reported as a weak AMY antagonist, showed to be equally or more potent than AC187 in antagonizing the above effects. The opioid antagonist, naloxone, had no significant effects on AMY antinociceptive effects. Primary dissociated cell culture was used to investigate the effect of AMY on cAMP production and to characterize AMY receptors in the spinal cells. AMY moderately increases cAMP accumulation in the spinal cells with an EC50 value of 74.62nM. This effect was not affected by CGRP8-37 but was inhibited by AC187 and rAMY8-37 with pA2 values of 7.94 and 7.87 respectively. In conclusion, effects of AMY in reducing formalin induced pain and on the cAMP accumulation by spinal cells are mediated through undefined receptors.

Topics: Amylin Receptor Agonists; Analgesics; Analgesics, Opioid; Animals; Calcitonin Gene-Related Peptide; Cyclic AMP; Formaldehyde; Inflammation; Injections, Spinal; Islet Amyloid Polypeptide; Male; Morphine; Naloxone; Narcotic Antagonists; Nociception; Pain; Pain Threshold; Peptide Fragments; Primary Cell Culture; Rats; Rats, Sprague-Dawley; Receptors, Islet Amyloid Polypeptide; Spinal Cord

Major attention has been on dietary and medicinal phytochemicals that inhibit or reverse abnormal conditions caused by nociceptive and inflammatory stimuli. Garcinia kola (Guttiferae) seed, known as "bitter kola", plays an important role in African ethno-medicine and traditional hospitality like in the treatment of inflammation, colds, bronchitis, bacterial, and viral infections. A number of useful phytochemicals have been isolated from the seed, and the most prominent of them is kolaviron (Garcinia bioflavonoid), which has been suggested to have antinociceptive and anti-inflammatory potentials. The aim of this experiment is to explore the mechanisms of action of the antinociceptive and anti-inflammatory potentials of kolaviron.. The probable mechanisms of action of kolaviron were assessed by using naloxone, prazosin, and atropine to investigate the involvement of adrenergic, opioidergic, and cholinergic systems, respectively, using tail flick, the acetic acid-induced writhing, formalin-induced paw licking, and carrageenan-induced paw edema models. Also, hematoxylin and eosin (H&E) staining was used to analyze the level of inflammation.. In the acetic acid-induced writhing test in mice, pretreatment with naloxone, prazosin, and atropine significantly reversed the antinociception effects of kolaviron (200 mg/kg) when compared with control and kolaviron groups. In the formalin-induced paw licking test in mice, there was a significant decrease on the antinociceptive effects of kolaviron in the late phase when compared with the control, while the pretreatment with naloxone and prazosin significantly reversed the antinociception of kolaviron but atropine did not have any significant decrease when compared with the kolaviron group. In the tail flick latency assay in rats, pretreatment with naloxone and prazosin significantly reversed the antinociception of kolaviron but atropine; however, did not have any significant increase when compared with the control and kolaviron groups. The result of the study also shows a highly significant inhibition of paw edema in the carrageenan-induced receiving kolaviron when compared with the vehicle carrageenan-induced groups. Histological staining also showed that kolaviron significantly reduced the infiltration of inflammatory cells in the paw tissues.. Kolaviron possesses antinociceptive and anti-inflammatory activity, both centrally and peripherally, which justifies its folkloric use to relieve pain and inflammation. It may be exerting its effects through mechanisms that involve opioidergic and adrenergic systems, and may not involve the cholinergic system.

Topics: Acetic Acid; Analgesics; Animals; Anti-Inflammatory Agents; Atropine; Carrageenan; Edema; Female; Flavonoids; Inflammation; Male; Mice; Naloxone; Pain; Phytotherapy; Plant Extracts; Prazosin; Rats; Rats, Wistar

Topics: Analgesics, Opioid; Drug Overdose; Education, Medical; Humans; Naloxone; Opioid-Related Disorders; Pain; Risk Reduction Behavior; United States

The most dangerous adverse effect of opioids is respiratory depression. Naloxone is used to reverse this, although in patients receiving long-term opioid therapy it can cause acute opioid withdrawal and opioid-refractory pain.. To determine if naloxone is appropriately administered to patients receiving long-term opioid therapy.. This retrospective case series based on chart reviews systematically identified patients over one year in a district general hospital. All patients aged 18 years or older receiving long-term opioid therapy admitted to medicine, surgery or the high dependency unit who were administered naloxone during their admission were included.. A total of 1206 patient drug administration records were reviewed. Sixteen patients receiving long-term opioid therapy were administered naloxone. Twelve of these did not have opioid-induced respiratory depression and four did not have respiratory rate and oxygen saturations documented in the medical notes. All naloxone doses administered were higher than those recommended by national guidelines for this patient group.. No patient receiving long-term opioid therapy who was administered naloxone had evidence of respiratory depression. More thorough assessment and documentation are needed. Verbal and physical stimulation as well as oxygenation should be considered prior to naloxone administration; this should be followed by close observation, hydration, renal function tests and opioid dose review.

Topics: Adult; Aged; Analgesics, Opioid; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Naloxone; Narcotic Antagonists; Pain; Respiratory Insufficiency; Retrospective Studies; Substance Withdrawal Syndrome; Time Factors; Young Adult

There has been growing interest in the synthesis of new derivatives from isatin, found in Isatis genus. Our objectives were to characterize the antinociceptive mechanism of action of isatin, N-methyl-isatin (MI) and N-methyl-3-(2-oxopropyl)-3-hydroxy-2-oxindole (MOI).. Substances (0.1-10mg/kg, p.o.) were studied in chemical (paw licking induced by formalin, capsaicin or glutamate) or thermal (hot plate) models of nociception. The involvement of several systems was evaluated using different receptor antagonists.. All three substances inhibit both phases of formalin-induced licking, increase the area under the curve and MI and MOI have a higher effect than that of morphine (in hot plate). Capsaicin and glutamate-induced licking were also reduced by all three substances. In the hot plate model, the antinociceptive effect of isatin was reduced by naloxone and atropine; naloxone, atropine and L-NAME reduced MI effect while naloxone, atropine, L-NAME, mecamylamine and ondansetron reduced MOI effect.. Our results suggest that isatin, MI and MOI: 1) present activity in models of nociception; 2) capsaicin and glutamate receptors seems to participate in the mechanism of action; 3) opioid, cholinergic, serotoninergic, nitrergic and adrenergic systems may be involved, at least in part, in the mechanism of action of some of these substances.

Topics: Analgesics; Animals; Atropine; Dose-Response Relationship, Drug; Isatin; Mecamylamine; Mice; Morphine; Naloxone; NG-Nitroarginine Methyl Ester; Ondansetron; Pain; Pain Measurement

This study aimed to investigate the involvement of opioid receptors in the systemic and peripheral antinociceptive activities of montelukast in different animal models of pain. Rats and mice were injected with montelukast to produce analgesia. The formalin and acetic acid-induced writhing tests were used to assess the nociceptive activity. The results showed that i.p. administration of montelukast (0.3-10mg/kg) dose-dependently reduced flinching behavior in both the first and second phases of formalin test with mean ED50 of 0.55 and 5.31mg/kg, respectively. Also, intraplantar administration of montelukast (3-30μg/paw) produced antinociception against the two phases of formalin assay in a dose-dependent way with mean ED30 of 2.92 and 8.11μg/paw, respectively. Furthermore, pre-treatment with naloxone (a non-selective opioid receptor antagonist) significantly inhibited both the systemic and also peripheral antinociceptive actions of montelukast in formalin test. In writhing test, the results showed that intraperitoneal administration of montelukast (3-10mg/kg) significantly reduced the writhe number induced by acetic acid in mice. Moreover, co-administration of non-effective doses of montelukast (0.3 and 1mg/kg; i.p.) and morphine (0.25mg/kg; i.p.) significantly decreased the writhes number induced by acetic acid. Also, this effect was naloxone-reversible. These findings suggest that the systemic and peripheral antinociception produced by montelukast were mediated through the opioid receptors in central and peripheral nervous systems. Moreover, combination of montelukast and morphine could be noted as a new strategy for pain relief.

Topics: Acetates; Acetic Acid; Analgesics; Animals; Behavior, Animal; Cyclopropanes; Disease Models, Animal; Drug Synergism; Formaldehyde; Male; Mice; Naloxone; Pain; Quinolines; Rats; Receptors, Opioid; Sulfides; Visceral Pain

Since bone marrow receives innervation from A-delta and C-fibers and since an increase in intramedullary pressure in bone marrow may induce acute pain in orthopedic patients during surgery and chronic pain in patients with bone marrow edema, skeletal pain may partly originate from bone marrow. Intraosseous lesions, such as osteomyelitis and bone cancer, are also known to produce cutaneous hypersensitivity, which might be referred pain from bone. However, little is known about pain perception in bone marrow and referred pain induced by bone disease. Thus, we carried out an in vivo electrophysiological study and behavioral study to determine whether increased intraosseous pressure of the femur induces acute pain and whether increased intraosseous pressure induces referred pain in the corresponding receptive fields of the skin.. Intraosseous balloon inflation caused spontaneous pain-related behavior and mechanical hyperalgesia and allodynia in the lumbosacral region. Single neuronal activities of spinal dorsal horn neurons were extracellularly isolated, and then evoked responses to non-noxious and noxious cutaneous stimuli and intraosseous balloon inflation were recorded. Ninety-four spinal dorsal horn neurons, which had somatic receptive fields at the lower back and thigh, were obtained. Sixty-two percent of the wide-dynamic-range neurons (24/39) and 86% of the high-threshold neurons (12/14) responded to intraosseous balloon inflation, while none of the low-threshold neurons (0/41) responded to intraosseous balloon inflation. Spinally administered morphine (1 µg) abolished balloon inflation-induced spontaneous pain-related behavior and mechanical hyperalgesia in awake rats and also suppressed evoked activities of wide-dynamic-range neurons to noxious cutaneous stimulation and intraosseous balloon inflation.. The results suggest that mechanical stimulation to bone marrow produces nociception, concomitantly producing its referred pain in the corresponding skin fields. These mechanisms might contribute to pain caused by skeletal diseases.

Topics: Animals; Bone Marrow; Catheterization; Evoked Potentials; Femur; Ganglia, Spinal; Hyperalgesia; Injections, Spinal; Male; Morphine; Naloxone; Nociception; Pain; Posterior Horn Cells; Rats, Sprague-Dawley; Sensation; Spinal Cord; Stress, Mechanical

Stephania japonica is a common plant, widely distributed in all over Bangladesh. Traditionally, this plant is considered as one of the important ingredients in treatment of a variety of ailments including inflammation, pain, rheumatism, cancer, bone fracture, fever etc. However, the scientific reports regarding the antinociceptive effect of this plant are very limited. This study evaluated the antinociceptive effect of methanolic extract of S. japonica (MESJ) leaves.. The antinociceptive effect of MESJ was investigated using both heat- and chemical-induced nociceptive models such as hot plate, tail immersion, acetic acid-induced writhing, formalin and glutamate tests at the doses of 50, 100 and 200mg/kg. Morphine (5mg/kg) and diclofenac sodium (10mg/kg) were used as reference drugs in thermal and chemical models, respectively. Moreover, naloxone (2mg/kg) was used in the thermal models to justify the possible role of the opioid receptors.. MESJ produced a significant and dose-dependent increase in the hot plate and tail immersion latencies which were reversed by the treatment with naloxone, suggests the possible involvement of opioid receptors in this activity. Moreover, MESJ inhibited acetic acid-induced writhing, formalin and glutamate-induced lickings in a dose-dependent manner. In parallel, the reference drugs also produced desired antinociceptive effects in this study.. These results strongly support the antinociceptive activity of the leaves of Stephania japonica and rationalize the traditional use of the leaves in treatment of different painful conditions.

Topics: Acetic Acid; Analgesics; Animals; Formaldehyde; Glutamic Acid; Hot Temperature; Male; Mice; Naloxone; Narcotic Antagonists; Pain; Phytotherapy; Plant Extracts; Plant Leaves; Receptors, Opioid; Stephania

Dehydrocorydaline (DHC) is an alkaloidal component isolated from Rhizoma corydalis. Previous studies have shown that DHC has anti-inflammatory and anti-tumor effects and that it can protect the cardiovascular system. However, there are few studies of the antinociceptive effects of DHC in vivo. This study explored the antinociceptive effects and possible mechanisms of DHC in mice using two inflammatory pain models: the acetic acid-induced writhing test and the formalin paw test. The intraperitoneal administration of DHC (3.6, 6 or 10 mg/kg) showed a dose-dependent antinociceptive effect in the acetic acid-induced writhing test and significantly attenuated the formalin-induced pain responses in mice. The antinociceptive effects of DHC were not associated with changes in the locomotor activity or motor responses of animals, and no obvious acute or chronic toxic effects were observed in the mice. Furthermore, the use of naloxone confirmed the involvement of the opioid receptor in the central antinociceptive effects of DHC. DHC reduced formalin-induced paw edema, which indicated that DHC may produce an anti-inflammatory effect in the periphery. In the formalin test, DHC decreased the expression of caspase 6 (CASP6), TNF-α, IL-1β and IL-6 proteins in the spinal cord. These findings confirm that DHC has antinociceptive effects in mice.

Topics: Acetates; Alkaloids; Analgesics; Animals; Anti-Inflammatory Agents; Cytokines; Disease Models, Animal; Dose-Response Relationship, Drug; Formaldehyde; Gene Expression Regulation; Humans; Injections, Intraperitoneal; Mice; Naloxone; Pain; Receptors, Opioid

Individuals with Alzheimer's disease (AD) are in susceptible patient groups in which pain is an important clinical issue that is often underdiagnosed. However, it is unclear whether decreased pain complaints in patients with AD result from elevated pain tolerance or an impaired ability to communicate sensations. Here, we explored if AD-related pathology is present in key regions of the pain pathway and assessed whether nociceptive thresholds to acute noxious stimulation are altered in the double-mutant APPswe × PS1.M146V (TASTPM) transgenic mouse model of AD. TASTPM mice exhibited an age-dependant cognitive deficit at the age of 6 months, but not at 4 months, a deficit that was accompanied by amyloid plaques in the cortex, hippocampus, and thalamus. In the spinal cord, β-amyloid (APP/Aβ) immunoreactivity was observed in dorsal and ventral horn neurons, and the expression of vesicular glutamate transporter 2 (VGLUT2) was significantly reduced, while the expression of the inhibitory peptides enkephalins was increased in TASTPM dorsal horn, consistent with an increased inhibitory tone. TASTPM mice displayed reduced sensitivity to acute noxious heat, which was reversed by naloxone, an opioid antagonist. This study suggests that increased inhibition and decreased excitation in the spinal cord may be responsible for the reduced thermal sensitivity associated with AD-related pathology.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Analgesics, Opioid; Animals; Brain; Carrageenan; Cognition Disorders; Disease Models, Animal; Locomotion; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Naloxone; Narcotic Antagonists; Nerve Tissue Proteins; Pain; Pain Measurement; Presenilin-1; Recognition, Psychology; Sensory Thresholds

This study was designed to investigate the contribution of prostaglandins to the maintenance of inflammatory pain. Inflammation was induced by intraplantar (i.pl.) injection of carrageenan in right hindpaw in rats. Indomethacin (non-selective COX inhibitor) was administered i.pl. 1 h after the carrageenan injection, and paw withdrawal latency (PWL) responding to noxious heat was measured. β-endorphin (β-END) and μ-opioid receptor (MOR) expressed in the inflamed site were examined by using immunocytochemistry, ELISA and RT-PCR techniques. The results showed that indomethacin dose-dependently increased PWL to the levels that were above the baseline on the day 2 and 3, referred to as hypoalgesia. The hypoalgesia was abolished by a local injection of the non-selective opioid receptor inhibitor naloxone methiodide. The number of β-END-positive cells, the content of β-END and the expression of MOR mRNA in the inflammatory site of inflammation model rats were all significantly increased by indomethacin. These results reveal a novel mechanism of prostaglandins for the inhibition of inflammation-induced endogenous opioid activity. This study provides further evidence that inhibition of prostaglandins in inflamed site could be a promising therapy for inflammatory pain.

Topics: Analgesics, Opioid; Animals; beta-Endorphin; Carrageenan; Indomethacin; Inflammation; Naloxone; Pain; Prostaglandins; Rats; Receptors, Opioid

Topics: Analgesics, Opioid; Chronic Pain; Humans; Mainstreaming, Education; Naloxone; Narcotic Antagonists; Pain

Insulin resistance is a metabolic disorder which affects the diabetes mellitus pathophysiology and alters the cell excitability. This study has been designed to evaluate the anti-nociceptive and anti-inflammatory effects of chronic administration of Withania somnifera root (WSR) in fructose drinking water rats.. An experiment was carried out on 48 Wistar-Albino male rats, weighting 200±30 g, which were divided into six groups (n=8): control group (C), control morphine (CM), W. somnifera group (WS) which received WSR (62.5 mg/g diet), W. somnifera naloxone group (WSN) which received WSR and naloxone, fructose (F) group which received fructose drinking water and FWS group which received fructose-enriched drinking water and WSR during the trial period. A biphasic pain response was induced after intraplantar injection of formalin (50 μL, 1%). Pain behavior was measured using Dubuisson methods. The obtained data were analyzed by SPSS software V. 18, using ANOVA and Tukey test. Results were expressed as mean±SD. Statistical differences were considered significant at p<0.05.. The results showed that the insulin resistance index, blood sugar, insulin, IL-6, TNF-α, and acute and chronic pain score in the F group were significantly increased in comparison with the control group, but these parameters in the FWS group were significantly decreased compared with the F group (p<0.001).. Our findings indicated that chronic oral administration of WSR has analgesic and anti-inflammatory effects in fructose drinking water rats and causes improved insulin resistance index.

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Blood Glucose; Body Weight; Diet; Fructose; Glucose Tolerance Test; Insulin; Insulin Resistance; Interleukin-6; Male; Naloxone; Pain; Plant Extracts; Plant Roots; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha; Withania

Topics: Analgesics; Animals; Bicuculline; Botulinum Toxins, Type A; Calcitonin Gene-Related Peptide; Capsaicin; Carrageenan; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Routes; Functional Laterality; Hyperalgesia; Male; Naloxone; Pain; Pain Measurement; Rats; Rats, Wistar; Spinal Cord; Synaptosomal-Associated Protein 25

Pain represents a major contributing factor to the individual's quality of life. Although pain killers as opioids, endogenous or exogenous peptides can decrease pain perception, the chronic use of them leads to antinociceptive tolerance. It has been demonstrated that neuropeptide apelin has potent antinoceptive effect. However, the possibility of the induction of its antinociceptive tolerance has not yet been clarified. The tail-flick test was used to assess the nociceptive threshold. All experiments were carried out on male Wistar rats which received intrathecal apelin for 7days. To determine the role of apelin and opioid receptors on the development of apelin analgesic tolerance, their receptor antagonists (F-13 A and naloxone, respectively) were injected simultaneously with apelin. The lumbar spinal cord was assayed to determine apelin receptor levels by the western blotting method. Plasma corticosterone levels were assayed using ELISA. Results showed that apelin (3μg/rat) induced strong thermal antinociception. In addition, chronic apelin produced tolerance to its antinociceptive effect and down regulated spinal apelin receptor. F-13 A and naloxone could inhibit apelin tolerance development. The corticosterone levels did not change following drug administration. Taken together, the data indicated that apelin like other analgesic drugs leads to the induction of side effects such as analgesic tolerance which is mediated partly via the apelin and opioid receptors activation.

Topics: Animals; Apelin Receptors; Dose-Response Relationship, Drug; Drug Tolerance; Injections, Spinal; Intercellular Signaling Peptides and Proteins; Male; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Rats; Rats, Wistar; Receptors, G-Protein-Coupled; Receptors, Opioid; Spinal Cord

This study was planned to examine the antinociceptive efficacy of agomelatine against acute mechanical, thermal, and chemical nociceptive stimuli, as well as to determine the opioid receptor subtypes mediating these effects.. Tail-clip, hot-plate, and acetic acid-induced writhing tests were performed to evaluate anti-nociceptive effect. Besides, possible effect of agomelatine on the motor coordination of animals was assessed with a Rota-rod test.. Agomelatine (40mg/kg and 60mg/kg) significantly prolonged the reaction time of mice in both the tail-clip and hot-plate tests, suggesting the antinociceptive activity is related to both spinal and supraspinal mechanisms. This drug also reduced the number of writhing behaviors indicating the presence of a peripherally mediated antinociceptive effect. Rota-rod testing displayed no notable effect on the motor activity of the animal supporting the conclusion that the observed antinociceptive effect is specific. The agomelatine-induced antinociceptive activity abrogated following pretreatment with naloxone (a non-selective opioid receptor antagonist, 5.48mg/kg, i.p.), which suggested the participation of opioid mechanisms to the antinociception. The possible contribution of μ, δ and ҡ subtypes of opioid receptors to the anti-nociceptive effect were evaluated using naloxonazine (7mg/kg, s.c.), naltrindole (0.99mg/kg, i.p.), and nor-binaltorphimine (1.03mg/kg, i.p.), respectively. Pretreatments using these antagonists abolished the antinociceptive activity of agomelatine in all of the nociceptive test paradigms used, which pointed out that μ, δ, and ҡ opioid receptors participated to the action of agomelatine on pain.. These results demonstrated the therapeutic potential of agomelatine in the treatment of pain disorders.

Topics: Acetamides; Analgesics; Animals; Dose-Response Relationship, Drug; Injections, Intraventricular; Male; Mice; Motor Activity; Naloxone; Naltrexone; Pain; Pain Measurement; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Rotarod Performance Test

Cissus quadrangularis L. (Vitaceae) is used as a bonesetter and as an analgesic. However, the bioactive fractions and the pharmacological mechanism of analgesic activity are not clearly known. Hence, this study aimed to characterize the analgesic activity profile of successively extracted fractions of C. quadrangularis and the pharmacological mechanism of analgesic activity in mice.. Dried C. quadrangularis stem was extracted successively with chloroform and methanol. The dried extracts were separately administered to mice intraperitoneally at the doses of 75, 150 and 300 mg/kg. The mice were tested separately in hot plate and tail flick tests. The mechanism of analgesic activity of chloroform extract was explored in the hot plate test at the dose of 300 mg/kg after pretreatment with naloxone, p-chlorophenylalanine methyl ester (pCPA) and phentolamine. The data were analyzed by one-way analysis of variance followed by Dunnett's test.. Chloroform extract showed significant (p<0.05) analgesic effect at the doses of 75, 150 and 300 mg/kg in hot plate and tail flick tests. Methanol extract showed significant (p<0.05) analgesic effect at the dose of 300 mg/kg in hot plate and tail flick tests. Analgesic activity was not blocked (p<0.05) in the group pretreated with phentolamine but blocked in the groups pretreated with naloxone and pCPA.. The chloroform extract was found to be more potent than methanol extract in inducing analgesic effect in mice, and the analgesic activity may be mediated through opioidergic and serotonergic pathways.

Topics: Analgesics; Animals; Cissus; Dose-Response Relationship, Drug; Fenclonine; Mice; Naloxone; Pain; Phentolamine; Plant Extracts; Plant Stems; Solvents

Most opioid receptor agonists have abuse potential, and the rewarding effects of opioids can be reduced in the presence of pain. While each of the enantiomers of pentazocine has a differential pharmacologic profile, (±)-pentazocine has been used clinically for the treatment of pain. However, little information is available regarding which components of pentazocine are associated with its rewarding effects, and whether the (±)-pentazocine-induced rewarding effects can be suppressed under pain. Therefore, the present study was performed to investigate the effects of pain on the acquisition of the rewarding effects of (±)-pentazocine, and to examine the mechanism of the rewarding effects of (±)-pentazocine using the conditioned place preference paradigm. (±)-Pentazocine and (-)-pentazocine, but not (+)-pentazocine, produced significant rewarding effects. Even though the rewarding effects induced by (±)-pentazocine were significantly suppressed under pain induced by formalin, accompanied by increase of preprodynorphin mRNA levels in the nucleus accumbens, a high dose of (±)-pentazocine produced significant rewarding effects under pain. In the normal condition, (±)-pentazocine-induced rewarding effects were blocked by a low dose of naloxone, whereas the rewarding effects induced by high doses of pentazocine under pain were suppressed by naltrindole (a δ-opioid receptor antagonist). Interestingly, (±)-pentazocine did not significantly affect dopamine levels in the nucleus accumbens. These findings suggest that the rewarding effects of (-)-pentazocine may contribute to the abuse potential of (±)-pentazocine through μ- as well as δ-opioid receptors, without robust activation of the mesolimbic dopaminergic system. We also found that neural adaptations can reduce the abuse potential of (±)-pentazocine under pain.

Topics: Analgesics, Opioid; Analysis of Variance; Animals; Conditioning, Psychological; Dose-Response Relationship, Drug; Isomerism; Male; Naloxone; Naltrexone; Narcotic Antagonists; Nucleus Accumbens; Pain; Pentazocine; Rats; Receptors, Opioid, delta; Receptors, Opioid, mu; Reward

We have recently shown that several classes of glucuronide metabolites, including the morphine metabolite morphine-3-glucuronide and the ethanol metabolite ethyl glucuronide, cause toll like receptor 4 (TLR4)-dependent signaling in vitro and enhanced pain in vivo. Steroid hormones, including estrogens and corticosterone, are also metabolized through glucuronidation. Here we demonstrate that in silico docking predicts that corticosterone, corticosterone-21-glucuronide, estradiol, estradiol-3-glucuronide and estradiol-17-glucuronide all dock with the MD-2 component of the TLR4 receptor complex. In addition to each docking with MD-2, the docking of each was altered by pre-docking with (+)-naloxone, a TLR4 signaling inhibitor. As agonist versus antagonist activity cannot be determined from these in silico interactions, an in vitro study was undertaken to clarify which of these compounds can act in an agonist fashion. Studies using a cell line transfected with TLR4, necessary co-signaling molecules, and a reporter gene revealed that only estradiol-3-glucuronide and estradiol-17-glucuronide increased reporter gene product, indicative of TLR4 agonism. Finally, in in vivo studies, each of the 5 drugs was injected intrathecally at equimolar doses. In keeping with the in vitro results, only estradiol-3-glucuronide and estradiol-17-glucuronide caused enhanced pain. For both compounds, pain enhancement was blocked by the TLR4 antagonist lipopolysaccharide from Rhodobacter sphaeroides, evidence for the involvement in TLR4 in the resultant pain enhancement. These findings have implications for several chronic pain conditions, including migraine and temporomandibular joint disorder, in which pain episodes are more likely in cycling females when estradiol is decreasing and estradiol metabolites are at their highest.

Topics: Alkaline Phosphatase; Animals; Corticosterone; Estradiol; Glucuronides; Gonadal Steroid Hormones; HEK293 Cells; Humans; Hyperalgesia; Male; Molecular Docking Simulation; Naloxone; Pain; Physical Stimulation; Rats, Sprague-Dawley; Toll-Like Receptor 4

We examined antinociception and gene expression of mu-opioid receptor 1 (MOR1) in some brain areas of cholestatic rats, 21 days after common bile duct ligation (BDL). Cholestasis was induced in male Wistar rats during laparotomy and common BDL. Pain behavior was assessed on days 7, 14 or 21 of BDL using a hotplate test in control, sham and cholestatic groups. On day 21 of BDL, other groups of rats were sacrificed, whole brains were extracted, and the hypothalamus, prefrontal cortex (PFC), hippocampus and striatum in control, sham and cholestatic rats were dissected. We used a semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) method for evaluating MOR1 gene expression. The results revealed that cholestatic rats showed significant antinociception on days 14 and 21 of ligation with the most significant effect on day 21, which was prevented by naloxone (1 mg/kg). On the other hand, the expression of MOR1 gene compared to the sham group was decreased by 42% in the hypothalamus, 41% in the PFC, and 67% in the hippocampus after 21 days of BDL, while no significant change in its expression in the striatum was observed. It can be concluded that a change in endogenous opioid levels and its subsequent influence on the gene expression of MOR in some areas of the rat brain may underlie the altered nociception and other possible pathological changes such as pruritus after induction of cholestasis.

Topics: Analysis of Variance; Animals; Bile Duct Diseases; Brain; Disease Models, Animal; Gene Expression Regulation; Laparotomy; Male; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Rats; Rats, Wistar; Receptors, Opioid, mu; RNA, Messenger; Time Factors

Opioid use disorder and pain often co-occur, complicating the treatment of each condition. Owing to its partial agonist properties, buprenorphine/naloxone (BUP/NX) may confer advantages over full agonist opioids for treatment of both conditions. The optimal dose of BUP/NX for comorbid pain is not known. We examined dose and other factors associated with pain intensity among patients initiating BUP/NX for opioid use disorder.. We studied 1106 patients initiating BUP/NX treatment for opioid use disorder from 2003 to 2010. Information on pain level, diagnoses, and treatment were extracted from medical records. Eligible patients had at least one self-reported pain intensity numerical rating score (NRS) within 30 days before BUP/NX initiation (baseline) and at least one between 15 and 90 days after BUP/NX initiation (during treatment). The primary outcome was NRS decrease (2 or greater) from baseline to during treatment. We used generalized estimating equations to model odds of the primary outcome with BUP/NX dose as the independent variable of interest in the subset of patients with a baseline NRS ≥ 2.. The sample was 94% male and 73% White. Mean age was 50. Psychiatric and non-opioid substance use comorbidities were common. The following demographic and clinical correlates were associated with a decrease in pain intensity: age 18-29 (compared to 30-39 and 40-49); absence of PTSD diagnosis and absence of a chronic pain diagnosis. BUP/NX dose was not associated with decreased pain intensity in bivariate or multivariable analysis.. BUP/NX maintenance treatment was generally consistent with improvements in pain intensity; however, factors other than BUP/NX dose contribute to improved pain intensity among those initiating the medication.

Topics: Adolescent; Adult; Analgesics, Opioid; Buprenorphine; Comorbidity; Female; Humans; Male; Middle Aged; Naloxone; Opiate Substitution Treatment; Opioid-Related Disorders; Pain; Pain Measurement; Retrospective Studies; Treatment Outcome; Young Adult

In recent years, studies have substantiated the view that P2X3 receptors play a part in the generation and transmission of purinergic signals in inflammatory and chronic neuropathic pain. Data have also been presented to suggest that the process of P2X3 receptor antagonism inhibits inflammatory hyperalgesia, involving the spinal opioid system. The aim of this study was to investigate the effect of the selective P2X3 receptor antagonist A-317491 on the development of antinociceptive tolerance to chronic morphine administration in mice. Daily systemic injection of A-317491 attenuated the morphine-induced antinociceptive tolerance to von Frey and thermal stimuli. Repeated morphine injections alone led to a significant rightward shift in the morphine dose-response curve compared with that with A-317491. A single dose of A-317491 also showed a reversal effect in morphine-tolerant mice. In a withdrawal test, co-administration of A-317491 and morphine also reduced the naloxone-induced withdrawal symptoms compared with the morphine-alone group. Thus, we propose that the P2X3 receptor is involved in the process of morphine antinociceptive tolerance and may be a new therapeutic target in the prevention of tolerance to morphine-induced antinociception.

Topics: Analgesics, Opioid; Animals; Dose-Response Relationship, Drug; Drug Tolerance; Male; Mice; Mice, Inbred BALB C; Morphine; Naloxone; Narcotic Antagonists; Pain; Phenols; Polycyclic Compounds; Purinergic P2X Receptor Antagonists; Receptors, Purinergic P2X3; Spinal Cord; Substance Withdrawal Syndrome

Hedyotis corymbosa (Linn.) Lam. is a small herb commonly called as khetpapra, traditionally used to treat a wide range of diseases including abdominal pain, arthritis and inflammation. This study was conducted to evaluate the antinociceptive effect of ethanol extract of Hedyotis corymbosa (EEHC) whole plant.. The antinociceptive activity of EEHC was evaluated in mice using both chemical- and heat-induced pain models such as acetic acid-induced writhing, hot plate, tail immersion, formalin, and glutamate tests at 50, 100, and 200mg/kg doses. In order to verify the possible involvement of opioid receptors in the central antinociceptive effect of EEHC, the effects found in hot plate and tail immersion tests were antagonized with naloxone.. EEHC produced a dose-dependent antinociceptive effect against the chemical- and heat-induced pain in mice, significantly at 100 and 200mg/kg doses. These findings suggest that the action of EEHC involves both peripheral and central antinociceptive mechanisms. The antinociceptive activity of EEHC was significantly attenuated by pretreatment with naloxone, indicating the influence of opioid receptors on the exertion of EEHC action centrally.. This study reports the antinociceptive activity of Hedyotis corymbosa and possible underlying mechanism(s) that supports the traditional use of this plant in the treatment of different painful conditions.

Topics: Acetic Acid; Analgesics; Animals; Ethanol; Female; Formaldehyde; Glutamic Acid; Hedyotis; Hot Temperature; Male; Mice; Naloxone; Narcotic Antagonists; Pain; Phytotherapy; Plant Extracts; Receptors, Opioid; Solvents

The aim of the present study was to investigate the role of the amygdala in the potentiative effect of minocycline, a semisynthetic tetracycline antibiotic, on morphine analgesia in male Wistar rats. We also examined the involvement of the amygdala μ-opioid and N-methyl-D-aspartate (NMDA) receptors in the minocycline-induced potentiation of morphine analgesia. Intraperitoneal administration of morphine (3-9 mg/kg) induced analgesia in a tail-flick test. Bilateral intra-amygdala injection of minocycline (10-20 μg/rat) enhanced the analgesic response of an ineffective dose of morphine (3 mg/kg). Injection of a higher dose of minocycline into the amygdala also induced analgesia. Moreover, bilateral intra-amygdala injection of naloxone (0.5-1.5 µg/rat) reversed minocycline-induced potentiation of morphine analgesia. Pretreatment of animals with NMDA (0.01-0.1 μg/rat, intra-amygdala) also inhibited the potentiative effect of minocycline on morphine response. Bilateral intra-amygdala injection of the same doses of naloxone or NMDA plus morphine had no effect on the tail-flick latency in the absence of minocycline. It can be concluded that the amygdala has a key role in the potentiative effect of minocycline on morphine analgesia. In addition, amygdala opioidergic and glutamatergic mechanisms may be involved, probably through μ-opioid and NMDA receptors, in the modulation of the minocycline-induced potentiation of morphine analgesia in the tail-flick test.

Topics: Amygdala; Analgesics; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Therapy, Combination; Excitatory Amino Acid Agonists; Hot Temperature; Injections, Intraperitoneal; Male; Minocycline; Morphine; N-Methylaspartate; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Random Allocation; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Receptors, Opioid, mu

Prolonged-release oxycodone/naloxone (OXN PR) showed improved gastrointestinal tolerability and equivalent analgesic efficacy compared to oxycodone alone in patients with non-cancer pain or cancer pain. This is the first dataset to demonstrate its effectiveness and safety compared to other strong opioids in opioid-naïve patients.. This is a subgroup analysis of a 4- to 6-week multicenter, observational study. A total of 162 opioid-naïve patients with moderate-to-severe pain of varying etiologies received either OXN PR or other strong opioids (control group). Documented parameters include pain relief (numeric rating scale), bowel function (Bowel Function Index [BFI]), pain-related functional impairment (Brief Pain Inventory Short Form), quality of life (QoL; EuroQol EQ-5D-3L) and a global therapy assessment.. OXN group patients experienced a substantial clinically important reduction in mean pain intensity of 51.4%, compared to a 28.6% reduction in control patients. Although the BFI remained in the reference range in both groups, there was a difference between BFI changes during treatment in favor of OXN PR. The superior effectiveness of OXN PR was paralleled by greater improvements of pain interference and QoL and fewer adverse drug reactions compared to other strong opioids.. The favorable outcomes under real-life conditions suggest that OXN PR provides a valuable option for treatment of moderate-to-severe pain without using weak opioids first.

Topics: Aged; Constipation; Defecation; Delayed-Action Preparations; Drug Combinations; Female; Humans; Male; Middle Aged; Naloxone; Narcotics; Neoplasms; Oxycodone; Pain; Pain Management; Prospective Studies; Quality of Life

Opioid-induced bowel dysfunction, of which constipation is the most common aspect, is a major limiting factor in the use of opioids for pain management. The availability of an oral, long-acting formulation of oxycodone and naloxone represents a highly significant development in pain management. The combination of an opioid analgesic with an opioid antagonist offers reliable pain control with a significant reduction in the burden of opioid-induced constipation.

Topics: Administration, Oral; Analgesics, Opioid; Constipation; Delayed-Action Preparations; Drug Combinations; Humans; Naloxone; Narcotic Antagonists; Oxycodone; Pain

In traditional medicine, Bauhinia glauca subsp. hupehana has long been used as an analgesic agent in China. The aim of this study was to evaluate the antinociceptive activity of the ethanol extract of the aerial parts of B. glauca subsp. hupehana (BHE) in rats and its chemical fingerprint. The antinociceptive activity of BHE was assessed in mice using chemically and heat-induced pain models, such as the acetic acid-induced writhing, hot plate, tail-flick and glutamate tests. Naltrexone hydrochloride, a non-selective opioid receptor antagonist, was utilized to determine the involvement of the opioid system. In addition to this, the involvements of the cGMP and ATP-sensitive K+ channel pathways were also detected using methylene blue and glibenclamide. The oral administration of BHE (at doses of 50, 100 and 200 mg/kg) produced significant and dose-related inhibitions in both the chemically and heat-induced pain models. Interestingly, in the abdominal constriction test, when the dose of BHE was increased to 800 mg/kg (p.o., n = 10), the inhibition rate was 100%. The antinociceptive mechanism may involve the cGMP pathway and ATP sensitive K+ channel pathway. The central antinociceptive effect was not antagonized by naltrexone. One phenolic acid, one lignin and five flavonoids were isolated from BHE. The antinociceptive activity of BHE was most likely due to the presence of the flavonoids. The acute toxicity results showed that BHE was safe at a high dose (2 g/kg, p.o.). The current investigation demonstrates that B. glauca subsp. hupehana is a potential candidate for the development of novel, non-opioid, analgesic phytomedicines.

Topics: Acetic Acid; Analgesics; Animals; Bauhinia; Cyclic GMP; Dose-Response Relationship, Drug; Ethanol; Female; Hot Temperature; KATP Channels; Male; Mice, Inbred ICR; Naloxone; Narcotic Antagonists; Pain; Phytochemicals; Phytotherapy; Plant Components, Aerial; Plant Extracts; Rats; Signal Transduction

Pain is characterized as a complex experience, dependent not only on the regulation of nociceptive sensory systems, but also on the activation of mechanisms that control emotional processes in limbic brain areas such as the amygdala and the hippocampus. We have recently found that repeated microinjection of non-steroidal anti-inflammatory drugs (NSAIDs) into the dorsal hippocampus of rats for four consecutive days induces antinociceptive tolerance as revealed by a progressive decrease of the latency in the tail-flick and hot plate tests compared to controls treated with saline into the dorsal hippocampus. Here we found that on the first day microinjection of NSAIDs, ketorolac, clodifen and xefocam into the DH produced antinociception as revealed by a latency increase in the TF and HP compared to the baseline control of intact rats and a control group with saline microinjected into the same site as well. Subsequent NSAIDs microinjections, without testing on the second and third days, caused progressively less antinociception, i.e. developed tolerance. After two days resting, by day 7 antinociception was almost completely restored for all the three drugs. Thus we demonstrated that this antinociceptive tolerance is due to pharmacological tolerance to these drugs and not to conditioning by repeating testing or hyperalgesia or other nonspecific mechanisms.

Topics: Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Drug Tolerance; Humans; Morphine; Naloxone; Pain; Pain Measurement; Rats

In anesthetized rats and conscious humans, a gentle touch using a soft disc covered with microcones (with a texture similar to that of a finger), but not with a flat disc, inhibits nociceptive somatocardiac reflexes. Such an inhibitory effect is most reliably evoked when touch is applied to the skin ipsilateral and closest to nociceptive inputs. However, the mechanism of this inhibition is not completely elucidated. We aimed to clarify the types of cutaneous afferent fibers and spinal opioid receptors that contribute to antinociceptive effects of microcone touch.. The present study comprised two experiments with urethane-anesthetized rats. In the first experiment, unitary activity of skin afferent fibers was recorded from the saphenous nerve, and responses to a 10-min touch using a microcone disc and a flat disc (control) were compared. Greater discharge rate during microcone touch was observed in low-threshold mechanoreceptive Aδ and C afferent units, whereas many Aβ afferents responded similarly to the two types of touch. In the second experiment, the effect of an intrathecal injection of opioid receptor antagonists on the inhibitory effects of microcone touch on heart rate responses to noxious heat stimulation was examined. The magnitude of the heart rate response was significantly reduced by microcone touch in rats that received saline or naltrindole (δ-opioid receptor antagonist) injections. However, such an inhibition was not observed in rats that received naloxone (non-selective opioid receptor antagonist) or Phe-Cys-Tyr-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP; μ-opioid receptor antagonist) injections.. Microcone touch induced greater responses of low-threshold mechanoreceptive Aδ and C afferent units than control touch. The antinociceptive effect of microcone touch was abolished by intrathecal injection of μ-opioid receptor antagonist. These results suggest that excitation of low-threshold mechanoreceptive Aδ and C afferents produces the release of endogenous μ-opioid ligands in the spinal cord, resulting in the inhibition of nociceptive transmission that contributes to somatocardiac reflexes.

Topics: Analgesics, Opioid; Animals; Heart Rate; Hot Temperature; Male; Naloxone; Naltrexone; Narcotic Antagonists; Pain; Pain Management; Rats, Wistar; Receptors, Opioid; Reflex; Skin; Spinal Cord; Touch

Persicaria hydropiper (Linn.) Delarbre is a common plant of Polygonaceae family commonly called Bishkatali in Bangladesh. Leaves of the plant are traditionally used in the treatment of rheumatic pain, gout, and skin diseases such as ringworms, scabies, boils, abscesses, carbuncles, bites of snakes, dogs or insects. This study evaluated the antinociceptive effect of the methanol extract of P. hydropiper leaves (MEPH).. The antinociceptive activity of MEPH was investigated using heat-induced (hot-plate and tail-immersion test) and chemical-induced (acetic acid, formalin, glutamic acid, cinnamaldehyde) nociception models in mice at 25, 50, and 75 mg/kg doses. Involvement of opioid system, cyclic guanosine monophosphate (cGMP) pathway, and ATP-sensitive K(+) channel pathway were also tested using naloxone, methylene blue and glibenclamide respectively.. MEPH showed antinociceptive activity in both heat- and chemical induced pain models. In both hot plate and tail immersion tests MEPH significantly increases the latency to the thermal stimuli. In acetic acid-induced writhing test the extract inhibited the number of abdominal writhing. Likewise, MEPH produced significant dose-dependent inhibition of paw licking in both neurogenic and inflammatory pain induced by intraplantar injection of formalin. Besides, MEPH also significantly inhibited the glutamate-induced pain and cinnamaldehyde-induced pain in mice. It was also clear that pretreatment with naloxone significantly reversed the antinociception produced by MEPH in hot plate and tail immersion test suggesting the involvement of opioid system in its effect. In addition, administration of methylene blue, a non specific inhibitor of NO/guanylyl cyclase, enhanced MEPH induced antinociception while glibenclamide, an ATP-sensitive K(+) channel antagonist, could not reverse antinociceptive activity induced by MEPH.. Based on the results of the current study it can be said that MEPH possesses significant antinociceptive activity which acts in both peripheral and central mechanisms.

Topics: Acetic Acid; Acrolein; Analgesics; Analgesics, Opioid; Animals; Anti-Inflammatory Agents; Bangladesh; Behavior, Animal; Formaldehyde; Glutamic Acid; Male; Medicine, Traditional; Mice; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Phytotherapy; Plant Extracts; Plant Leaves; Polygonum

Seed oil (Pp-oil) of Plukenetia polyadenia is used by native people of the Brazilian Amazon against arthritis and rheumatism, spreading it on the arms and legs to reduce the pain and inflammation. Pp-oil was obtained by pressing dried seeds at room temperature to give a 47.0% yield of oil. It was then subjected to fatty acid composition analysis. The principal fatty acids were linoleic acid (46.5%), α-linolenic acid (34.4%) and oleic acid (13.9%). Then, it was evaluated for its antinociceptive activity in mice, using the acetic acid-induced abdominal writhing, hot plate and formalin test models. Additionally, its toxicity was determined. The Pp-oil proved to have no toxicological effects, showing dose-dependent antinociceptive effect under chemical stimulation. At oral doses of 25-100 mg/kg, Pp-oil significantly reduced the abdominal writhes in the writhing test. A higher oral dose of 200 mg/kg did not induce alterations in the latency time of the hot plate test when compared to the control, suggesting an analgesic activity of peripheral origin. At oral doses of 50 and 100 mg/kg, the Pp-oil significantly reduced the second phase of the algic stimulus in the formalin test. In addition, the antinociception of Pp-oil was reversed by naloxone in the evaluation of its mechanism of action. Therefore, the Pp-oil proved to be safe at very high doses and to show significant analgesic properties. The role of Pp-oil is still being investigated with respect the mechanism of action, but the results suggest that opiod receptors could be involved in the antinociception action observed for the oil of P. polyadenia.

Topics: Analgesics; Animals; Euphorbiaceae; Fatty Acids; Male; Mice; Naloxone; Oils, Volatile; Pain; Pain Measurement

Our aim was to investigate the influence of thymic polypeptides on pain sensitivity and to analyze a possible role of the opioid system in the implementation of the analgesia caused by immobilization stress.. The study was performed on male Wistar rats at the Moscow state University named after M. V. Lomonosov. We studied effects of thymus peptides: thymuline (0.15 mg/kg), fraction 5 thymosin (0.25 microgram/kg) and cattle thymus extracted product (CTEP) (0.5 mg/kg) on pain sensitivity in rats using test "tail flick" without stress, with acute (3 h) and sub acute (12 h) immobilization stress. The comparison groups were animals treated with saline and spleen polypeptides.. It is shown that preparations of thymus increase the threshold of pain sensitivity in the intact animals. Immobilization stress duration 3 and 12 h in thymus peptides treated rats caused a less pronounced increase in pain threshold than in the control groups (immobilization stress 3 h: CTEP--p = 0.025, thymuline--p = 0.022, fraction 5 thymosin--p = 0.033; immobilization stress 12 h: CTEP--p = 0.034, thymuline--p = 0.027, fraction 5 thymosin--p = 0.036). The opioid receptor blocker naloxone (1 mg/kg) did not completely block the stress-induced analgesia, indicating the presence of both opioid and non -opioid components in this state. In thymus peptides treated rats, opioid component was less pronounced than in the control groups (CTEP--p = 0.031, thymuline--p = 0.026, fraction 5 thymosin--p = 0.029).. Pre-activation of the opioid system by the thymus polypeptides leads to an increase in the share of non-opioid component of the stress-induced analgesia and prevents the depletion of the opioid system in immobilization stress.

Topics: Analgesia; Animals; Cattle; Male; Models, Animal; Naloxone; Narcotic Antagonists; Pain; Pain Management; Rats; Rats, Wistar; Receptors, Opioid; Restraint, Physical; Thymic Factor, Circulating; Thymosin; Thymus Extracts; Thymus Gland

Different analgesic combinations with caffeine have shown this drug to be capable of increasing the analgesic effect. Many combinations with nonsteroidal anti-inflammatory drugs (NSAIDs) have been carried out, but, in regard to opioids, only combinations with morphine and tramadol have been reported. The antinociceptive synergism mechanism of these combinations is not well understood. The purpose of the present study was to determine the participation of spinal and supraspinal opioidergic and serotonergic systems in the synergic effect of the tramadol+caffeine combination in the rat formalin test. At the supraspinal level, the opioid antagonist, naloxone, completely reversed the effect of the drug combination, whereas ketanserin, a 5-HT2 receptor antagonist, inhibited the effect by 60%; however, ondansetron, a 5-HT3 receptor antagonist, did not alter the combination effect. When the antagonists were intrathecally administered, there was a significant reduction in all tramadol-caffeine combination effects. With respect to tramadol alone, there was significant participation of the opioid system at the supraspinal level, whereas it was the serotonergic system that participated at the spinal level by means of the two receptors studied. In conclusion, the tramadol+caffeine combination synergically activated the opioid and serotonergic systems at the supraspinal level, as well as at the spinal level, to produce the antinociception.

Topics: Analgesics, Opioid; Animals; Caffeine; Dose-Response Relationship, Drug; Drug Synergism; Ketanserin; Naloxone; Ondansetron; Pain; Pain Measurement; Rats; Tramadol

Polyalthia longifolia var. pendula is a very popular herb in Bangladesh due to its traditional uses in treatment of rheumatism, bone fracture and gastric ulcer. The present study was conducted to investigate the antinociceptive activity of ethanol extract of P. longifolia (EEPL) bark.. Hot plate and tail immersion tests, acetic acid-induced writhing test, glutamate and formalin-induced paw licking tests in mice were employed in this study. In all the experiments EEPL was administered orally at the doses of 50, 100 and 200mg/kg body weight. To investigate the possible participation of opioid system in EEPL-mediated effects, naloxone was used to antagonize the action.. EEPL showed a significant antinociceptive activity against both heat and chemical-induced nociception. The effects were dose-dependent and significant at the doses of 100 and 200mg/kg of EEPL. Besides, pretreatment with naloxone caused significant inhibition of the antinociceptive activity induced by EEPL, revealing the possible involvement of the opioid receptors.. These results indicate the antinociceptive activity of the bark of P. longifolia and support the ethnomedical use of this plant in treatment of different painful conditions.

Topics: Analgesics; Animals; Bangladesh; Disease Models, Animal; Dose-Response Relationship, Drug; Ethanol; Medicine, Traditional; Mice; Naloxone; Pain; Plant Bark; Plant Extracts; Polyalthia; Receptors, Opioid

Selective activation of peripheral κ opioid receptors (KORs) may overcome the dose-limiting adverse effects of conventional opioid analgesics. We recently developed a vicinal disulfide-stabilized class of peptides with subnanomolar potency at the KOR. The aim of this study was to assess the analgesic effects of one of these peptides, named conorphin-1, in comparison with the prototypical KOR-selective small molecule agonist U-50488, in several rodent pain models. Surprisingly, neither conorphin-1 nor U-50488 were analgesic when delivered peripherally by intraplantar injection at local concentrations expected to fully activate the KOR at cutaneous nerve endings. While U-50488 was analgesic when delivered at high local concentrations, this effect could not be reversed by coadministration with the selective KOR antagonist ML190 or the nonselective opioid antagonist naloxone. Instead, U-50488 likely mediated its peripheral analgesic effect through nonselective inhibition of voltage-gated sodium channels, including peripheral sensory neuron isoforms NaV1.8 and NaV1.7. Our study suggests that targeting the KOR in peripheral sensory nerve endings innervating the skin is not an alternative analgesic approach.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Analgesics, Non-Narcotic; Animals; Carrageenan; Cisplatin; Disease Models, Animal; Freund's Adjuvant; Gene Expression Regulation; HEK293 Cells; Humans; Inflammation; Male; Mice; Mice, Inbred C57BL; Naloxone; Nerve Endings; Oligopeptides; Pain; Pain Measurement; Peptides; Peripheral Nervous System Diseases; Rats; Rats, Wistar; Receptors, Opioid, kappa; Skin

Cancer pain directly affects the patient's quality of life. We have previously demonstrated that the subcutaneous administration of the mammary adenocarcinoma known as Ehrlich tumor induces pain in mice. Several studies have shown that the flavonoid quercetin presents important biological effects, including anti-inflammatory, antioxidant, analgesic, and antitumor activity. Therefore, the analgesic effect and mechanisms of quercetin were evaluated in Ehrlich tumor-induced cancer pain in mice. Intraperitoneal (i.p.) treatments with quercetin reduced Ehrlich tumor-induced mechanical and thermal hyperalgesia, but not paw thickness or histological alterations, indicating an analgesic effect without affecting tumor growth. Regarding the analgesic mechanisms of quercetin, it inhibited the production of hyperalgesic cytokines IL-1β and TNFα and decreased neutrophil recruitment (myeloperoxidase activity) and oxidative stress. Naloxone (opioid receptor antagonist) inhibited quercetin analgesia without interfering with neutrophil recruitment, cytokine production, and oxidative stress. Importantly, cotreatment with morphine and quercetin at doses that were ineffective as single treatment reduced the nociceptive responses. Concluding, quercetin reduces the Ehrlich tumor-induced cancer pain by reducing the production of hyperalgesic cytokines, neutrophil recruitment, and oxidative stress as well as by activating an opioid-dependent analgesic pathway and potentiation of morphine analgesia. Thus, quercetin treatment seems a suitable therapeutic approach for cancer pain that merits further investigation.

Topics: Analgesics; Analgesics, Opioid; Animals; Anti-Inflammatory Agents; Behavior, Animal; Carcinoma, Ehrlich Tumor; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Interleukin-1beta; Male; Mice; Morphine; Naloxone; Neutrophil Infiltration; Oxidative Stress; Pain; Quercetin; Skin; Spinal Cord; Tumor Necrosis Factor-alpha

Topics: Analgesics, Opioid; Drug Combinations; Humans; Naloxone; Narcotic Antagonists; Oxycodone; Pain

Kahweol is a diterpene present in the oil derived from coffee beans. Although several pharmacological activities of kahweol are already well described in the literature, no study was done in order to assess the analgesic activity of this substance. Thus, the aim of this study was to investigate the possible peripheral antinociceptive effect of kahweol. Considering that the opioid peptides have been implicated in peripheral antinociception induced by non-opioidergic compounds, the present study also evaluated the endogenous opioids involvement in this effect.. The rat paw pressure test was used, and hyperalgesia was induced by intraplantar injection of prostaglandin E2 (2μg/paw). All drugs were administered subcutaneously in the hindpaws of male Wistar rats. The expression of β-endorphin was examined by immunohistochemistry in the skin tissue samples of the plantar surface of rat right hindpaws.. Intraplantar injection of kahweol (40 and 80μg) induced significant peripheral antinociception. The antinociceptive effect of kahweol was due to a local peripheral action because the higher dose (80μg/paw) did not produce any effect in the contralateral paw. The opioid receptor antagonist naloxone (50 and 100μg/paw) prevented action of kahweol (80μg/paw) and the aminopeptidases inhibitor bestatin (400μg/paw) potentiated the antinociceptive effect of kahweol (40μg/paw). Furthermore, kahweol treatment increased the intensity of β-endorphin immunoreactivity in the epithelium of rat paws.. The results discussed here provide evidence that kahweol treatment has peripheral antinociceptive effect and suggest that this effect is mediated by the release of endogenous opioids.

Topics: Analgesics; Animals; beta-Endorphin; Coffee; Dinoprostone; Diterpenes; Hyperalgesia; Leucine; Male; Naloxone; Narcotic Antagonists; Opioid Peptides; Pain; Pain Measurement; Peptides; Pressure; Rats; Rats, Wistar; Skin

The Condalia buxifolia root bark infusion is used in traditional medicine in Brazil as antipyretic, anti-inflammatory and against dysentery. This study was designed to investigate whether the methanolic extract of the root bark of Condalia buxifolia (MECb) exhibits antinociceptive and anti-inflammatory effects in mice. Furthermore, also was investigated the involvement of glutamatergic and opioidergic system in the antinociceptive effect induced by MECb.. The antinociceptive and anti-inflammatory effects of intra-gastric gavage (i.g.) administered MECb (10-300 mg/kg) were evaluated in mice subjected to chemical (formalin, acetic-acid, glutamate) or thermal (hot plate) models of pain. The involvement of opioid system in the antinociceptive effect of the MECb was investigated in formalin test. Furthermore, a nonspecific effect of MECb was evaluated by measuring locomotor activity and exploratory behavior in open field test. Finally, was performed a phytochemical analysis of MECb.. The phytochemical analysis of MECb was performed through HPLC analysis showing that the alkaloid Condaline-A is the main constituent. The intragastric administration of MECb (100-300 mg/kg) significantly inhibited the nociception caused by acetic acid (48 ± 2%), inflammatory phase (49 ± 3%) and paw edema (32 ± 6) caused by formalin, and MECb (100mg/kg, i.g.) also inhibited nociception caused by glutamate (41 ± 7%). In addition, MECb (100-300 mg/kg, i.g.) increased the paw withdrawal latency in hot-plate test, without affecting the locomotor activity and exploratory behavior in open field test. Finally, the antinociceptive effects of MECb (100mg/kg, i.g.) were significantly reversed by naloxone (1mg/kg, i.p.) in the formalin test.. These data show, for the first time, that MECb has significant antinociceptive and anti-inflammatory effects, which appear to be related to the inhibition of the glutamatergic system and the activation of opioid mechanism, besides present central effects. These results support the use of Condalia buxifolia in traditional medicine and demonstrate that this plant has therapeutic potential for the development of phytomedicines with antinociceptive and anti-inflammatory properties.

Topics: Acetic Acid; Analgesics; Animals; Anti-Inflammatory Agents; Behavior, Animal; Edema; Female; Formaldehyde; Glutamic Acid; Hot Temperature; Medicine, Traditional; Mice; Motor Activity; Naloxone; Narcotic Antagonists; Pain; Phytotherapy; Plant Extracts; Plant Roots; Rhamnaceae

Topics: Analgesics, Opioid; Female; Humans; Male; Naloxone; Oxycodone; Pain; Parkinson Disease

Homomeric P2X3 receptors expressed in primary nociceptive neurons are crucial elements in the pain signal generation. In turn, opioid system regulates the intensity of this signal in both CNS and PNS. Here we describe the effects of opioids on P2X3 receptors in DRG neurons studied by using patch clamp technique. Activation of G-protein coupled opioid receptors by endogenous opioid Leu-enkephalin (Leu), resulted in the two opposite effects on P2X3 receptor-mediated currents (P2X3 currents). In particular, application of 1 µM Leu lead to the complete inhibition of P2X3 currents. However, after pretreatment of the neurons with a Gi/o-protein inhibitor pertussis toxin (PT), the same concentration of Leu caused facilitation of P2X3 currents. PLC inhibitor U-73122 at concentration of 1 µM completely eliminated both facilitating and inhibitory effects of Leu on P2X3 currents. Thus, opioid receptor agonists cause two oppositely directed effects on P2X3 receptors in DRG neurons of rats and both of them are mediated through PLC signaling pathway. Our results point to a possible molecular basis of the mechanism for the well-known transition inhibitory action of opioids (analgesia) to facilitating (hyperalgesia).

Topics: Action Potentials; Adenosine Triphosphate; Animals; Enkephalins; Enzyme Inhibitors; Estrenes; Ganglia, Spinal; Gene Expression; Naloxone; Nociception; Nociceptors; Pain; Patch-Clamp Techniques; Pertussis Toxin; Phosphatidylinositols; Primary Cell Culture; Protein Kinase C; Pyrrolidinones; Rats; Rats, Wistar; Receptors, Purinergic P2X3; Signal Transduction; Staurosporine; Type C Phospholipases

We suggest a new placebo analgesia animal model and investigated the role of the dopamine and opioid systems in placebo analgesia. Before and after the conditioning, we conducted a conditioned place preference (CPP) test to measure preferences for the cues (Rooms 1 and 2), and a hot plate test (HPT) to measure the pain responses to high level-pain after the cues. In addition, we quantified the expression of tyrosine hydroxylase (TH) in the ventral tegmental area (VTA) and c-Fos in the anterior cingulate cortex (ACC) as a response to reward learning and pain response. We found an enhanced preference for the low level-pain paired cue and enhanced TH expression in the VTA of the Placebo and Placebo + Naloxone groups. Haloperidol, a dopamine antagonist, blocked these effects in the Placebo + Haloperidol group. An increased pain threshold to high-heat pain and reduced c-Fos expression in the ACC were observed in the Placebo group only. Haloperidol blocked the place preference effect, and naloxone and haloperidol blocked the placebo analgesia. Cue preference is mediated by reward learning via the dopamine system, whereas the expression of placebo analgesia is mediated by the dopamine and opioid systems.

Topics: Analgesia; Animals; Dopamine Antagonists; Gyrus Cinguli; Haloperidol; Immunohistochemistry; Male; Models, Animal; Naloxone; Narcotic Antagonists; Pain; Pain Threshold; Placebo Effect; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Tyrosine 3-Monooxygenase; Ventral Tegmental Area

The μ-opioid receptor (MOR) is the major opioid receptor targeted by most analgesics in clinical use. However, the use of all known MOR agonists is associated with severe adverse effects. We reported that the 1-phenyl-3,6,6-trimethyl-1,5,6,7-tetrahydro-4H-indazol-4-ones are novel opioid receptor agonists. Subsequent structural modification resulted in the potent MOR/KOR (κ-opioid receptor) agonists 19, 20, and 21. Testing the analgesic effect of these in WT B6 mice (tail-flick test) gave ED50 values of 8.4, 10.9, and 26.6mg/kg, respectively. The 1-phenyl-3,6,6-trimethyl-1,5,6,7-tetrahydro-4H-indazol-4-one core could be addressed in 1 or 2 synthetic steps with moderate to high percent of yield. In the adenylyl cyclase assay, compound 19 displayed a MOR/KOR agonist profile, with IC50 values of 0.73 and 0.41μM, respectively. Current results suggest that compound 19 is a promising lead to go further development and in vitro/in vivo adverse effects studies.

Topics: Analgesics; Animals; Dose-Response Relationship, Drug; Drug Discovery; HEK293 Cells; Humans; Indazoles; Mice; Mice, Congenic; Molecular Structure; Pain; Pain Measurement; Receptors, Opioid, kappa; Receptors, Opioid, mu; Structure-Activity Relationship; Tail

Tarragon [Artemisia dracunculus L. (Asteraceae)] is used as a commercial flavoring and in perfumery. In traditional folk medicine, tarragon has been used for treatment of pain and gastrointestinal disturbances.. This study investigated the antinociceptive effect of the essential oil of A. dracunculus (EOAD) in various experimental models.. The median lethal dose (LD50) of EOAD was estimated using the method of Lorke. The antinociceptive effect was assessed using chemical (formalin and acetic acid) and thermal (hot-plate) nociceptive tests in rats and mice. In all experiments, EOAD was administered intraperitoneally at the doses of 10, 30, 100 and 300 mg/kg.. In the acute toxicity test, the value of estimated LD50 for EOAD was 1250 mg/kg. EOAD (100 and 300 mg/kg) significantly reduced (p < 0.001) the pain response in the first (59.5 and 91.4%) and second (52.5 and 86.3%) phases of the formalin test, respectively. Central involvement in analgesic profile was confirmed by the hot-plate test, in which the EOAD showed a significant analgesic activity by increasing latency time. EOAD (10, 30, 100 and 300 mg/kg) significantly (p < 0.001) inhibited (89, 95, 97 and 97%) the nociception produced by acetic acid. Naloxone failed to antagonize the antinociceptive effect of the essential oil in the acetic acid-induced writhing test. It seems that mechanism(s) other than opioid receptors is (are) involved in the analgesic effect of EOAD.. This study reported the peripheral and central antinociceptive activity of the EOAD and rationalized the traditional use of the plant in the treatment of different painful conditions.

Topics: Analgesics; Animals; Artemisia; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Injections, Intraperitoneal; Lethal Dose 50; Male; Medicine, Traditional; Mice; Naloxone; Oils, Volatile; Pain; Pain Measurement; Rats; Rats, Wistar; Toxicity Tests, Acute

The antinociceptive effect of cyanocobalamin (Vit B12) has been reported in animal models and human studies. Our previous study showed the effect of Vit B12 on morphine tolerance. The dependence and tolerance were induced in male mice using subcutaneous morphine injections, 3 times a day (50, 50 and 75 mg/kg/day) for 3 days. Mice also received Vit B12 (100, 250 and 500 µg/kg), clonidine, memantine and saline intraperitoneally before morphine administration. On fourth day mice received only 7 mg /kg morphine just before tail-flick test. To determine the expression of morphine dependence and tolerance, all compounds were injected once intraperitoneally on the day of experiment. The tolerance was evaluated by the tail-flick test. The effect of Vit B12 and other agents on dependence were evaluated by counting the number of jumps (induced by naloxone 5 mg/kg). Co-administration of Vit B12 (100-500 µg/kg) and morphine in 3 days reduced the development of tolerance to morphine analgesic effect (8.2±0.5 and 7.83±0.5 s. vs. normal saline, 3.57±0.3 s). Repeated administration of Vit B12, also, diminished the reduced naloxane withdrawal signs of naloxone withdrawal test (100-500 µg/kg: 5±1.9 and 1.2±0.8 jumps vs. normal saline 72.6±12.2). However, Vit B12 had no effect on the expression of morphine tolerance and physical dependence. It is concluded that co-administration of Vit B12 and morphine could reduce tolerance to analgesic effect of morphine chronic administration and also reduce its withdrawal symptoms.

Topics: Analgesics, Opioid; Animals; Clonidine; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Tolerance; Male; Memantine; Mice; Morphine; Morphine Dependence; Naloxone; Pain; Vitamin B 12

Endogenous opioid activity plays an important role in ethanol consumption and reinforcement in infant rats. Opioid systems are also involved in mediation and regulation of stress responses. Social isolation is a stressful experience for preweanling rats and changes the effects of ethanol through opioid-dependent mechanisms. The present study assessed effects of intracisternal (i.c.) administration of a selective mu-opioid antagonist (CTOP) and i.p. administration of a nonspecific opioid antagonist (naloxone) on voluntary intake and behavior in socially isolated 12-day-old (P12) pups treated with 0.5 g/kg ethanol. Voluntary intake of 0.1% saccharin or water, locomotion, rearing activity, paw licking and grooming were assessed during short-term isolation from littermates (STSI; 8-min duration). Thermal nociceptive reactivity was measured before and after this intake test, with normalized differences between pre- and post-test latencies of paw withdrawal from a hot plate (49°C) used as an index of isolation-induced analgesia (IIA). Results indicated several effects of social isolation and ethanol mediated through the mu-opioid system. Effects of low dose ethanol (0.5 g/kg) and voluntary consumption of saccharin interacted with endogenous mu-opioid activity associated with STSI. Blockade of mu-opioid receptors on saccharin consumption and paw licking-grooming affected intoxicated animals. Low dose ethanol and ingestion of saccharin blunted effects of CTOP on rearing behavior and nociceptive reactivity. Central injections of CTOP stimulated paw licking and grooming dependent on ethanol dose and type of fluid ingested. Ethanol selectively increased saccharin intake during STSI in females, naloxone and CTOP blocked ethanol-mediated enhancement of saccharin intake. We suggest that enhancement of saccharin intake by ethanol during STSI is the product of synergism between isolation-induced mu-opioid activity that increases the pup's sensitivity to appetitive taste stimulation and the anxiolytic effects of 0.5 g/kg ethanol that decreases behaviors otherwise competing with independent ingestive activity.

Topics: Animals; Central Nervous System Depressants; Drinking Behavior; Drinking Water; Ethanol; Female; Grooming; Male; Maternal Deprivation; Motor Activity; Naloxone; Narcotic Antagonists; Pain; Rats; Rats, Sprague-Dawley; Receptors, Opioid, mu; Saccharin; Social Isolation; Somatostatin; Stress, Psychological

μ-opioid receptors (MORs) are necessary for the analgesic and addictive effects of opioids such as morphine, but the MOR-expressing neuronal populations that mediate the distinct opiate effects remain elusive. Here we devised a new conditional bacterial artificial chromosome rescue strategy to show, in mice, that targeted MOR expression in a subpopulation of striatal direct-pathway neurons enriched in the striosome and nucleus accumbens, in an otherwise MOR-null background, restores opiate reward and opiate-induced striatal dopamine release and partially restores motivation to self administer an opiate. However, these mice lack opiate analgesia or withdrawal. We used Cre-mediated deletion of the rescued MOR transgene to establish that expression of the MOR transgene in the striatum, rather than in extrastriatal sites, is needed for the restoration of opiate reward. Our study demonstrates that a subpopulation of striatal direct-pathway neurons is sufficient to support opiate reward-driven behaviors and provides a new intersectional genetic approach to dissecting neurocircuit-specific gene function in vivo.

Topics: Analysis of Variance; Animals; Conditioning, Operant; Corpus Striatum; Disease Models, Animal; Dopamine; Enkephalins; Exploratory Behavior; Flow Cytometry; Green Fluorescent Proteins; Mice; Mice, Transgenic; Microdialysis; Morphine; Naloxone; Narcotic Antagonists; Narcotics; Neural Pathways; Neurons; Pain; Pain Measurement; Protein Precursors; Receptors, Opioid, mu; Reward; Substance Withdrawal Syndrome

Topics: Aged; Analgesics, Opioid; Breast Neoplasms; Female; Humans; Liver Neoplasms; Naloxone; Narcotic Antagonists; Oxycodone; Pain

The present work reports the anti-inflammatory and antinociceptive activities of the ethanol extract obtained from the stem bark of Sterculia striata A. St.-Hil. & Naudin (Ss-EtOH) in the experimental models of edema induced by carrageenan, dextran, or histamin and nociception induced by chemical stimuli, such as acetic acid, formalin, capsaicin, or glutamate. The Ss-EtOH (50 mg/kg) promoted a marked inhibition on the hind paw edema induced by carrageenan or dextran (30% and 73%, respectively). Besides, Ss-EtOH (25 mg/kg) exhibited a slight activity (30%) on the hind paw edema induced by histamin. The Ss-EtOH (12.5 and 25 mg/kg) showed the antinociceptive activity on chemical stimuli induced by acetic acid (65.59% and 38.37%, respectively), formalin, in the initial (35.08% and 31.5%, respectively) and late phases (44.09% and 83.57%, respectively), capsaicin (43.77% and 51.31%, respectively), or glutamate (36.6% and 52.12%, respectively). Regarding the possible mechanism involved in the antinociceptive effect, Ss-EtOH (12.5 mg/kg) showed a decrease in the antinociceptive effect (65.8%) in the acetic acid model after pretreatment with naloxone. Thus, opioid mechanisms might be underlying this response.

Topics: Acetic Acid; Analgesics; Animals; Anti-Inflammatory Agents; Capsaicin; Carrageenan; Dextrans; Edema; Formaldehyde; Glutamic Acid; Histamine; Inflammation; Male; Mice; Naloxone; Pain; Phytotherapy; Plant Bark; Plant Extracts; Plant Stems; Rats, Wistar; Sterculia

Extracellular acidosis is a common feature in pain-generating pathological conditions. Acid-sensing ion channels (ASICs), pH sensors, are distributed in peripheral sensory neurons and participate in nociception. Morphine exerts potent analgesic effects through the activation of opioid receptors for various pain conditions. A cross-talk between ASICs and opioid receptors in peripheral sensory neurons has not been shown so far. Here, we have found that morphine inhibits the activity of native ASICs in rat dorsal root ganglion (DRG) neurons. Morphine dose-dependently inhibited proton-gated currents mediated by ASICs in the presence of the TRPV1 inhibitor capsazepine. Morphine shifted the proton concentration-response curve downwards, with a decrease of 51.4±3.8% in the maximum current response but with no significant change in the pH0.5 value. Another μ-opioid receptor agonist DAMGO induced a similar decrease in ASIC currents compared with morphine. The morphine inhibition of ASIC currents was blocked by naloxone, a specific opioid receptor antagonist. Pretreatment of forskolin, an adenylyl cyclase activator, or the addition of cAMP reversed the inhibitory effect of morphine. Moreover, morphine altered acid-evoked excitability of rat DRG neurons and decreased the number of action potentials induced by acid stimuli. Finally, peripheral applied morphine relieved pain evoked by intraplantar of acetic acid in rats. Our results indicate that morphine can inhibit the activity of ASICs via μ-opioid receptor and cAMP dependent signal pathway. These observations demonstrate a cross-talk between ASICs and opioid receptors in peripheral sensory neurons, which was a novel analgesic mechanism of morphine.

Topics: Acetic Acid; Acid Sensing Ion Channel Blockers; Acid Sensing Ion Channels; Action Potentials; Analgesics, Opioid; Animals; Capsaicin; Dose-Response Relationship, Drug; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Ganglia, Spinal; In Vitro Techniques; Male; Morphine; Naloxone; Narcotic Antagonists; Neurons; Nociception; Pain; Protons; Rats; Rats, Sprague-Dawley; Receptors, Opioid, mu; TRPV Cation Channels

Pain is characterized as a complex experience, dependent not only on the regulation of nociceptive sensory systems, but also on the activation of mechanisms that control emotional processes in limbic brain areas such as the amygdala and the hippocampus. Several lines of investigations have shown that in some brain areas, particularly the midbrain periaqueductal gray matter, rostral ventro-medial medulla, central nucleus of amygdala and nucleus raphe magnus, microinjections of non-steroidal anti-inflammatory drugs (NSAIDs) induce antinociception with distinct development of tolerance. The present study was designed to examine whether microinjection of NSAIDs, clodifen, ketorolac and xefocam into the dorsal hippocampus (DH) leads to the development of antinociceptive tolerance in male rats.. The experiments were carried out on experimental and control (with saline) white male rats. Animals were implanted with a guide cannula in the DH and tested for antinociception following microinjection of NSAIDs into the DH in the tail-flick (TF) and hot plate (HP) tests. Repeated measures of analysis of variance with post-hoc Tukey-Kramer multiple comparison tests were used for statistical evaluations.. We found that microinjection of these NSAIDs into the DH induces antinociception as revealed by a latency increase in the TF and HP tests compared to controls treated with saline into the DH. Subsequent tests on days 2 and 3, however, showed that the antinociceptive effect of NSAIDs progressively decreased, suggesting tolerance developed to this effect of NSAIDs. Both pretreatment and post-treatment with the opioid antagonist naloxone into the DH significantly reduced the antinociceptive effect of NSAIDs in both pain models.. Our results indicate that microinjection of NSAIDs into the DH induces antinociception which is mediated via the opioid system and exhibits tolerance.

Topics: Analgesics, Opioid; Animals; Anti-Inflammatory Agents, Non-Steroidal; Behavior, Animal; Diclofenac; Drug Resistance; Hippocampus; Ketorolac; Male; Microinjections; Naloxone; Narcotic Antagonists; Pain; Piroxicam; Rats; Rats, Wistar

The analgesic activity of Porcellio laevis Latreille, Rhizoma Corydalis, and Radix Cynanchi Paniculati have been reported in recent years. A new formula named Jia-Yuan-Qing pill (JYQP) is therefore created by combining the three herbs at 9:7:7 ratio according to traditional Chinese theories. The present study aims to evaluate the effect of JYQP as a novel painkiller in various models. Acute toxicity test was applied to evaluate the safety of JYQP. Acetic-acid-induced writhing, hot plate test, formalin test, and naloxone-pretreated writhing test were employed to elaborate the analgesic activity of JYQP and its possible mechanism. A bone cancer pain mouse model was performed to further assess the effect of JYQP in relieving cancer pain. Test on naloxone-precipitated withdrawal symptoms was conduct to examine the physical dependence of mice on JYQP. Data revealed that JYQP reduced writhing and stretching induced by acetic acid; however, this effect could not be blocked by naloxone. JYQP specifically suppressed the phase II reaction time in formalin-treated mice; meanwhile, no analgesic effect of JYQP in hot plate test was observed, indicating that JYQP exerts analgesic activity against inflammatory pain rather than neurogenic pain. Furthermore, JYQP could successfully relieve bone cancer pain in mice. No physical dependence could be observed upon long-term administration in mice. Collectively, our present results provide experimental evidence in supporting clinical use of JYQP as an effective and safe agent for pain treatment.

Topics: Analgesics; Animals; Bone Neoplasms; Corydalis; Cynanchum; Female; Inflammation; Isopoda; Male; Medicine, Chinese Traditional; Mice; Mice, Inbred C57BL; Naloxone; Narcotic Antagonists; Pain; Phytotherapy; Plant Extracts

Patients with sickle cell disease (SCD) suffer from intermittent vaso-occlusive pain crises (VOCs). These crises lead to frequent hospitalizations, significant morbidity, and increased mortality risk. Care pathways can enhance efficiency and quality of care. Our study sought to evaluate the development and implementation of a care pathway for patients with SCD experiencing VOCs.. The University of North Carolina (UNC) Comprehensive Sickle Cell Program provides all levels of care for a large population of patients with sickle cell anemia. All patients admitted to UNC Hospitals with SCD VOCs from January 2009 through June 2011 were evaluated. During this time period, we also assessed sequential prospective cohorts during progressive phases of developing and implementing a quality improvement and pathway of care program for this patient population in our study. The developed pathway entailed geographic localization for VOC patients, a single group of faculty physicians caring for these patients, and early use of patient-controlled analgesia (PCA) to achieve pain control. Physicians from the UNC Hospital Medicine Program were responsible for the initiatives. Cohorts were compared to a baseline historical control. Outcomes of interest included patient length of stay (LOS) in the hospital, 30-day readmission rate, need for transfusion, incidence of acute chest syndrome, use of naloxone, and use of PCA.. Compared with an historical baseline cohort, the development and implementation of a VOC care pathway for patients with SCD led to reduction in average hospital LOS by 1.44 days (P < 0.05) and an increase in use of PCAs (P < 0.05). Patient readmission rates, number of transfusions, incidence of acute chest syndrome, and use of naloxone did not significantly change.. Hospitalist-led management of patients with SCD VOCs using a care pathway that emphasizes early, aggressive PCA-based pain control is associated with reduced hospital LOS. The LOS reduction seen in our study is clinically meaningful. Notably, other measures of patient outcomes and quality of care metrics did not change significantly, and some trended towards improvement.

Topics: Acute Chest Syndrome; Adult; Analgesia, Patient-Controlled; Anemia, Sickle Cell; Blood Transfusion; Critical Pathways; Female; Hospitalists; Humans; Length of Stay; Male; Naloxone; Narcotic Antagonists; Pain; Pain Management; Patient Readmission; Prospective Studies; Quality of Health Care; Severity of Illness Index; Socioeconomic Factors; Vascular Diseases

Modafinil [2-((diphenylmethyl) sulfinyl) acetamide] is a central nervous system stimulant. It has received considerable attention as a potential psychotropic agent in several psychiatric disorders. The current study was carried out to investigate the effect of modafinil after acute administration on animal models of pain in mice. Also, this study evaluated the effect of L-NG-nitroarginine methyl ester (L-NAME), 7-nitroindazole (7-NI) and naloxone following chronic administration of modafinil. Modafinil was administered in the doses of 50, 100 or 200 mg/kg once in acute study and it showed significantly increased tail-flick latency (tfl) and paw-licking latency. In formalin test modafinil (100 mg/kg) significantly reduced licking/biting time in both early and late phases in comparison to control. In chronic study, modafinil 100 mg/kg administered for 10 days, produced a progressive decrease in the reaction time (i.e., tfl/paw-licking latency) in comparison to day 1 values which started building up from day 4 and fully established at day 6, indicating hyperalgesic response. Prior administration of 7-NI (on day 7) and L-NAME (on day 10) prevented the hyperalgesic response while naloxone on day 10 did not have a significant effect on modafinil-induced hyperalgesia. These results demonstrate that modafinil has a potential role in pain as it exhibited antinociceptive effect after acute administration in a dose-dependent manner and on chronic administration it caused hyperalgesia. This hyperalgesia is reversed by nitric oxide synthase inhibitors, suggesting the possibility of involvement of nitric oxide pathway. Further studies are required to evaluate the role of modafinil in clinical pain.

Topics: Analgesics; Animals; Behavior, Animal; Benzhydryl Compounds; Central Nervous System Stimulants; Formaldehyde; Hot Temperature; Hyperalgesia; Indazoles; Male; Mice; Modafinil; Naloxone; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Pain

Mu opioid receptor (MOR) selective antagonists and partial agonists have been used for the treatment of opioid abuse and addiction. Our recent efforts on the identification of MOR antagonists have provided several novel leads displaying interesting pharmacological profiles. Among them, 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-[(3'-isoquinolyl)acetamido]morphinan (NAQ) showed sub-nanomolar binding affinity to the MOR with significant selectivity over the delta opioid receptor (DOR) and the kappa opioid receptor (KOR). Its central nervous system penetration capacity together with marginal agonism in the MOR-GTPγS binding assay made it a very interesting molecule for developing novel opioid abuse and addiction therapeutic agents. Therefore, further pharmacological characterization was conducted to fully understand its biological profile. At the molecular and cellular level, NAQ not only induced no translocation of β-arrestin2 to the MOR, but also efficaciously antagonized the effect of DAMGO in MOR-βarr2eGFP-U2OS cells in the β-arrestin2 recruitment assay. At the in vivo level, NAQ displayed a potent inhibition of the analgesic effect of morphine in the tail-flick assay (ID50=1.19 mg/kg). NAQ (10 mg/kg) also significantly decreased the hyper-locomotion induced by acute morphine without inducing any vertical jumps. Meanwhile NAQ precipitated lesser withdrawal symptoms in morphine dependent mice than naloxone. In conclusion, NAQ may represent a new chemical entity for opioid abuse and addiction treatment.

Topics: Analgesics; Animals; Arrestins; Behavior, Animal; beta-Arrestins; Cell Line, Tumor; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Humans; Isoquinolines; Ligands; Male; Mice, Inbred ICR; Morphinans; Morphine; Motor Activity; Naloxone; Narcotic Antagonists; Opioid-Related Disorders; Pain; Receptors, Opioid, mu

Long-term exposure to opiates induces tolerance to the analgesic effect and dependence. The purpose of the present study is to investigate the effects of pioglitazone, a peroxisome proliferator-activated receptors gamma (PPAR-γ) agonist, on the morphine-induced tolerance and dependence. Groups of rats received morphine in combination with a vehicle or pioglitazone (5, 10, 20, and 40 mg/kg) daily. Thirty minutes before pioglitazone (40 mg/kg), GW-9662, a selective PPAR-γ antagonist, (2 mg/kg) was administrated in order to evaluate the possible role of the PPAR-γ. Nociception was assessed by a tail flick apparatus, and the percentage of the maximal possible effect was calculated as well. For 9 days, rats received additive doses of morphine to induce dependence. Naloxone was administrated 2 h after the morphine last dose, and withdrawal symptoms were recorded for 45 min. Morphine administration to rats over a duration of 17 days resulted in the development of tolerance, whereas pioglitazone (40 mg/kg) delayed the day of the established tolerance for 15 days. Administration of pioglitazone also prevented morphine-induced 50 % effective dose (ED50) shift to the right in the dose-response curve and increased the global analgesic effect of morphine. In addition, pioglitazone decreased the total withdrawal score significantly, whereas GW-9662 significantly reversed the pioglitazone effects on the morphine tolerance and dependence. The prevention of the morphine-induced glia activation and the proinflammatory responses were the possible mechanisms for pioglitazone effect on delaying the morphine tolerance and attenuating the dependence.

Topics: Analgesics, Opioid; Anilides; Animals; Behavior, Animal; Drug Tolerance; Male; Morphine; Motor Activity; Naloxone; Narcotic Antagonists; Pain; Pioglitazone; PPAR gamma; Rats, Wistar; Substance Withdrawal Syndrome; Thiazolidinediones

Crataeva nurvala Buch.-Ham. (Family: Capparidaceae) is widely used as anti-inflammatory, contraceptive, laxative, lithotropic, febrifuge and as tonic in traditional medicine. This study evaluated the antinociceptive effect of the methanolic extract of the leaves of Crataeva nurvala (MECN).. The antinociceptive activity was investigated using heat-induced (hot-plate and tail-immersion test) and chemical-induced (acetic acid, formalin and glutamic acid) nociception models in mice at different doses (50, 100, and 200 mg/kg, p.o.) of MECN. Morphine sulphate (5 mg/kg, i.p.) and diclofenac sodium (10 mg/kg, i. p.) were used as reference analgesic drugs.. MECN produced significant dose-dependent antinociception when assessed using hot plate test, tail immersion test and acetic acid-induced abdominal writhing test (65.55%). Likewise, MECN at similar doses produced significant dose-dependent inhibition in both neurogenic (50.82%) and inflammatory pain (73.53%) induced by intraplantar injection of formalin (2.5% formalin, 20 μl/paw). Besides, MECN also significantly inhibited the glutamate-induced (10 μM/paw) pain in mice (74.68%). It was demonstrated that pretreatment with naloxone (2 mg/kg, i.p.) significantly reversed antinociception produced by MECN in hot plate and tail immersion test suggesting the involvement of opioid receptor. In addition, administration of glibenclamide (10 mg/kg, i.p.), an ATP-sensitive K+ channel antagonist could not reverse antinociceptive activity induced by MECN.. The results suggest that MECN possesses antinociceptive activity involving inhibition of opioid system as well as the glutamatergic system supporting its traditional uses.

Topics: Analgesics; Animals; Behavior, Animal; Capparaceae; Methanol; Mice; Naloxone; Pain; Pain Management; Plant Extracts; Plant Leaves; Plants, Medicinal

Antinociception induced by the adenosine A1 receptor agonist N6-cyclopentyladenosine (CPA) is linked to opioid receptors. We studied the subtype of receptors to which CPA action is related, as well as a possible enhancement of antinociception when CPA is coadministered with opioid receptor agonists. Spinal cord neuronal nociceptive responses of male Wistar rats with inflammation were recorded using the single motor unit technique. CPA antinociception was challenged with naloxone or norbinaltorphimine. The antinociceptive activity of fentanyl and U-50488H was studied alone and combined with CPA. Reversal of CPA antinociception was observed with norbinaltorphimine (82.9±13% of control) but not with low doses of naloxone (27±8% of control), indicating an involvement of κ-opioid but not µ-opioid receptors. Low doses of CPA did not modify fentanyl antinociception. However, a significant enhancement of the duration of antinociception was seen when U-50488H was coadministered with CPA. We conclude that antinociception mediated by CPA in the spinal cord is associated with activation of κ-opioid but not µ-opioid receptors in inflammation. In addition, coadministration of CPA and κ-opioid receptor agonists is followed by significantly longer antinociception, opening new perspectives in the treatment of chronic inflammatory pain.

Topics: Adenosine; Animals; Carrageenan; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Electric Stimulation; Fentanyl; Inflammation; Male; Naloxone; Naltrexone; Narcotic Antagonists; Pain; Pain Measurement; Rats; Rats, Wistar; Receptors, Opioid, kappa; Reflex; Spinal Cord

The current study was designed to explore the antinociceptive, antiinflammatory and antipyretic activity of pistagremic acid (PA), isolated from Pistacia integerima bark in various animal paradigms. The results illustrated significant inhibition of noxious stimulation in acetic acid induced writhing test with maximum effect of 68% at 10mg/kg i.p. In tail immersion test, pretreatment with PA demonstrated marked activity during various assessment times in a dose dependent manner. The maximum pain inhibition was 59.46% at 10mg/kg i.p. after 90 min of PA treatment. However, the injection of naloxone did not antagonize this induced effect. PA significantly ameliorated post carrageenan induced edema dose dependently during various stages of inflammation. The effect was most dominant (60.02%) after 3(rd) h of drug administration when examined for 5h. Similarly, it provoked dose dependent antipyretic effect in febrile mice with maximum of 60.04% activity at 10mg/kg i.p. after 3rd hour of PA post treatment. Furthermore, molecular docking was carried out to understand the binding mode of PA. From the docking study it was observed that PA fits well in the active site of COX-2 enzyme due to hydrogen and hydrophobic moiety interactions to the important active site of molecule. In conclusion, PA possesses strong peripheral and central antinociceptive activity independent of opioidergic effect which was augmented by its anti-inflammatory and antipyretic activities.

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Antipyretics; Female; Fever; Inflammation; Male; Mice; Mice, Inbred BALB C; Molecular Docking Simulation; Molecular Structure; Naloxone; Pain; Pistacia; Triterpenes

Restraint stress modulates pain and inflammation. The present study was designed to evaluate the effect of acute restraint stress on inflammatory pain induced by subcutaneous injection of bee venom (BV). First, we investigated the effect of 1 h restraint on the spontaneous paw-flinching reflex (SPFR), decrease in paw withdrawal mechanical threshold (PWMT) and increase in paw volume (PV) of the injected paw induced by BV. SPFR was measured immediately after BV injection, and PWMT and PV were measured 2 h before BV and 2-8 h after BV. The results showed that acute restraint inhibited significantly the SPFR but failed to affect mechanical hyperalgesia. In contrast, stress enhanced significantly inflammatory swelling of the injected paw. In a second series of experiments, the effects of pretreatment with capsaicin locally applied to the sciatic nerve, systemic 6-hydroxydopamine (6-OHDA), and systemic naloxone were examined on the antinociception and proinflammation produced by acute restraint stress. Local capsaicin pretreatment inhibited BV-induced nociception and inflammatory edema, and had additive effects with stress on nociception but reduced stress enhancement of edema. Systemic 6-OHDA treatment attenuated the proinflammatory effect of stress, but did not affect the antinociceptive effect. Systemic naloxone pretreatment eliminated the antinociceptive effect of stress, but did not affect proinflammation. Taken together, our data indicate that acute restraint stress contributes to antinociception via activating an endogenous opioid system, while sympathetic postganglionic fibers may contribute to enhanced inflammation in the BV pain model.

Topics: Animals; Bee Venoms; Capsaicin; Disease Models, Animal; Edema; Hindlimb; Hyperalgesia; Inflammation; Male; Naloxone; Nociception; Oxidopamine; Pain; Rats; Rats, Sprague-Dawley; Restraint, Physical; Sciatic Nerve; Stress, Psychological; Sympathetic Nervous System

Stephanolepis hispidus is one of the most common filefish species in Brazil. Its skin is traditionally used as a complementary treatment for inflammatory disorders. However, there are very few studies on chemical and pharmacological properties using the skin of this fish. This study was undertaken in order to investigate the effect of aqueous crude extract of S. hispidus skin (SAE) in different nociception models. Here, we report that intraperitoneal administration of SAE inhibited the abdominal constrictions induced by acetic acid in mice. In addition to the effect seen in the abdominal constriction model, SAE was also able to inhibit the hyperalgesia induced by carrageenan and prostaglandin E2 (PGE2) in mice. This potent antinociceptive effect was observed in the hot plate model too, but not in tail-flick test. Naloxone, an opioid receptor antagonist, was able to block the antinociceptive effect of SAE in the abdominal constriction and hot plate models. In addition, SAE did not present cytotoxic or genotoxic effect in human peripheral blood cells. Our results suggest that aqueous crude extract from S. hispidus skin has antinociceptive activity in close relationship with the partial activation of opioid receptors in the nervous system. Moreover, aqueous crude extract from S. hispidus skin does not present toxicity and is therefore endowed with the potential for pharmacological control of pain.

Topics: Analgesics; Animals; Brazil; Disease Models, Animal; Fishes; Humans; Injections, Intraperitoneal; Male; Mice; Naloxone; Narcotic Antagonists; Pain; Rats; Rats, Wistar; Receptors, Opioid; Skin; Tissue Extracts

Opioids can induce respiratory depression by invoking a centrally mediated decrease in involuntary respiratory rate, which in severe cases can cause a decrease in oxygen saturation. If respiratory depression is opioid induced, both low respiratory rate and low oxygen saturation will be present. If this is the case, oxygenation, rousing by verbal and physical stimulation and decreasing the opioid dose should be tried first. Naloxone, an opioid antagonist, should be avoided if at all possible but, if essential, titrate slowly to respiratory function administering 20-100 µg intravenously every two minutes. If used as a bolus for a patient on long-term opioids for chronic cancer pain, then refractory pain and symptomatic opioid withdrawal can result.

Topics: Analgesics, Opioid; Bone Neoplasms; Female; Humans; Lung Neoplasms; Male; Naloxone; Narcotic Antagonists; Oxygen Inhalation Therapy; Pain; Prostatic Neoplasms; Respiratory Insufficiency; Substance Withdrawal Syndrome

In the present study, the antinociceptive profiles of coumarin were examined in ICR mice. Coumarin administered orally (from 1 to 10 mg/kg) showed an antinociceptive effect in a dose-dependent manner as measured in the acetic acid-induced writhing test. Duration of antinociceptive action of coumarin maintained at least for 60 min. But, the cumulative response time of nociceptive behaviors induced by a subcutaneous (s.c.) formalin injection, intrathecal (i.t.) substance P (0.7 µg) or glutamate (20 µg) injection was not affected by coumarin. In addition, intracerebroventricular (i.c.v.) or intrathecal (i.t.) administration with coumarin (10-40 µg) attenuated acetic acid-induced writhing response in a dose dependent manner. Intraperitoneal (i.p.) pretreatment with naloxone (an opioid receptor antagonist) attenuated antinociceptive effect induced by coumarin in the writhing test. Furthermore, i.c.v. or i.t. pretreatment with naloxone (5 µg) reversed the decreased acetic acid-induced writhing response. However, methysergide (a 5-HT serotonergic receptor antagonist) or yohimbine (an α2-adrenergic receptor antagonist) did not affect antinociception induced by coumarin in the writhing test. Our results suggest that coumarin exerts a selective antinociceptive property in the acetic acid-induced visceral-derived pain model. Furthermore, the antinociceptive effect of coumarin may be mediated by activation of central opioid receptors, but not serotonergic and adrenergic receptors.

Topics: Acetic Acid; Administration, Oral; Analgesics; Animals; Behavior, Animal; Coumarins; Formaldehyde; Glutamic Acid; Male; Mice; Mice, Inbred ICR; Naloxone; Narcotic Antagonists; Pain; Receptors, Opioid; Substance P

The most highly abused prescription drugs are opioids used for the treatment of pain. Physician-reported drug-seeking behavior has resulted in a significant health concern among doctors trying to adequately treat pain while limiting the misuse or diversion of pain medications. In addition to abuse liability, opioid use is associated with unwanted side effects that complicate pain management, including opioid-induced emesis and constipation. This has resulted in restricting long-term doses of opioids and inadequate treatment of both acute and chronic debilitating pain, demonstrating a compelling need for novel analgesics. Recent reports indicate that adaptations in endogenous substance P/neurokinin-1 receptor (NK1) are induced by chronic pain and sustained opioid exposure, and these changes may contribute to processes responsible for opioid abuse liability, emesis, and analgesic tolerance. Here, we describe a multifunctional mu-/delta-opioid agonist/NK1 antagonist compound [Tyr-d-Ala-Gly-Phe-Met-Pro-Leu-Trp-NH-Bn(CF3)2 (TY027)] that has a preclinical profile of excellent antinociceptive efficacy, low abuse liability, and no opioid-related emesis or constipation. In rodent models of acute and neuropathic pain, TY027 demonstrates analgesic efficacy following central or systemic administration with a plasma half-life of more than 4 hours and central nervous system penetration. These data demonstrate that an innovative opioid designed to contest the pathology created by chronic pain and sustained opioids results in antinociceptive efficacy in rodent models, with significantly fewer side effects than morphine. Such rationally designed, multitargeted compounds are a promising therapeutic approach in treating patients who suffer from acute and chronic pain.

Topics: Analgesics, Opioid; Animals; Ferrets; Injections, Intraventricular; Injections, Spinal; Male; Mice; Mice, Inbred ICR; Morphine; Naloxone; Pain; Pain Measurement; Rats; Rats, Sprague-Dawley; Receptors, Neurokinin-1; Spinal Nerves; Treatment Outcome

Morphine is the gold-standard pain reliever for severe acute or chronic pain but it also produces adverse side effects that can alter the quality of life of patients and, in some rare cases, jeopardize the vital prognosis. Morphine elicits both therapeutic and adverse effects primarily through the same μ opioid receptor subtype, which makes it difficult to separate the two types of effects. Here we show that beneficial and deleterious effects of morphine are mediated through different signalling pathways downstream from μ opioid receptor. We demonstrate that the TREK-1 K(+) channel is a crucial contributor of morphine-induced analgesia in mice, while it is not involved in morphine-induced constipation, respiratory depression and dependence-three main adverse effects of opioid analgesic therapy. These observations suggest that direct activation of the TREK-1 K(+) channel, acting downstream from the μ opioid receptor, might have strong analgesic effects without opioid-like adverse effects.

Topics: Analgesia; Analgesics, Opioid; Animals; Chlorocebus aethiops; Constipation; COS Cells; Crosses, Genetic; Dose-Response Relationship, Drug; Drug Tolerance; Female; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Morphine; Naloxone; Pain; Pain Management; Potassium Channels, Tandem Pore Domain; Receptors, Opioid, mu; Respiratory Insufficiency; Signal Transduction; Time Factors

Piperine, is the major active principal of black pepper. In traditional medicine, black pepper has been used as an analgesic, anti-inflammatory agent and in the treatment of epilepsy. This study was conducted to evaluate the in vivo analgesic and anticonvulsant effects of piperine in mice. The analgesic and anticonvulsant effects of piperine were studied in mice using acetic acid-induced writhing, tail flick assay, pentylenetetrazole (PTZ)- and picrotoxin (PIC)-induced seizures models. The intraperitoneal (i.p.) administration of piperine (30, 50 and 70 mg/kg) significantly inhibited (P<0.01) the acetic acid-induced writhing in mice, similar to the effect of indomethacin (20 mg/kg i.p.). In the tail flick assay, piperine (30 and 50 mg/kg, i.p.) and morphine (5 mg/kg, i.p.) caused a significant increase (P<0.01) in the reaction time of mice. Pre-treatment of animals with naloxone (5 mg/kg i.p.), reversed the analgesic effects of both piperine and morphine in the tail flick assay. Piperine (30, 50 and 70 mg/kg, i.p.) and standard drugs, valproic acid (200 mg/kg, i.p.), carbamazepine (30 mg/kg, i.p.) and diazepam (1 mg/kg, i.p.) significantly (P<0.01) delayed the onset of PTZ-and PIC-induced seizures in mice. These findings indicate that piperine exhibits analgesic and anticonvulsant effects possibly mediated via opioid and GABA-ergic pathways respectively. Moreover, piperine being the main constituent of black pepper, may be contributing factor in the medicinal uses of black pepper in pain and epilepsy.

Topics: Acetic Acid; Alkaloids; Analgesics; Animals; Anticonvulsants; Benzodioxoles; Hot Temperature; Male; Mice; Naloxone; Narcotic Antagonists; Pain; Pentylenetetrazole; Picrotoxin; Piper nigrum; Piperidines; Polyunsaturated Alkamides; Seizures

The pain threshold effects of a neurotensin NT (8 - 13) dipeptide analog (dilept), morphine, and their combination have been studied using the tail flick test in rats. The animals of another experimental group were administered with morphine in increasing doses (10 - 20 mg/kg, i.p.) for 5 days in order to induce the state of dependence. The physical dependence on morphine was evaluated in the open-field test by monitoring 16 specific behavioral signs of withdrawal syndrome (WS) induced by the opioid receptor antagonist naloxone, after which the WS total index was calculated. It was established, that dilept (1.6 mg/kg, i.p.) produced a mild analgesic effect via increasing the pain threshold by 34% (p < 0.01), did not effect on the morphine analgesic effect, and decreased the expression of morphine WS by 29.1 and 37.5% (p < 0.01) after a single or subchronic administration, respectively. These behavioral effects of dilept were accompanied by normalization of dopamine and serotonin turnover in the hypothalamus, frontal cortex, and striatum of experimental animals.

Topics: Animals; Dopamine; Frontal Lobe; Hypothalamus; Male; Morphine; Naloxone; Narcotic Antagonists; Narcotics; Neurotensin; Pain; Pain Threshold; Peptide Fragments; Proline; Rats; Serotonin; Severity of Illness Index; Substance Withdrawal Syndrome; Tyrosine

We have studied the analgesic activity of a morpholinoethylimidazobenzimidazole derivative (RU-1205) in comparison to butorphanol. It is established that the test compound exhibits a pronounced analgesic activity, which exceeded that ofbutorphanol six times in the hot-plate test and was comparable to the reference drug effect in the tail-flick and acetic acid-induced writhing tests. It is established that the analgesic action of RU-1205 is based on the kappa-opioidergic mechanism.

Topics: Analgesics; Animals; Animals, Outbred Strains; Benzimidazoles; Butorphanol; Male; Mice; Morpholines; Naloxone; Naltrexone; Narcotic Antagonists; Nociception; Pain; Pain Measurement; Rats; Receptors, Opioid, kappa

Ocimum gratissimum is used in popular medicine to treat painful diseases. The antinociceptive properties of O. gratissimum essential oil (OgEO) and two of its active principles (eugenol and myrcene) were tested in classic models of pain (hot plate test and formalin test). Adult male C57BL/6 J mice acutely received corn oil (control group, p.o.), morphine (positive control group, 5 mg/kg, i.p.), OgEO (10, 20, or 40 mg/kg, p.o.), eugenol or myrcene (both at 1, 5, or 10 mg/kg, p.o.). The highest doses of all tested drugs significantly increased the latency to lick the paw(s) in the hot plate test compared with the control group. OgEO at a dose of 40 mg/kg and eugenol and myrcene at a dose of 10 mg/kg were effective in minimizing animal pain in the first and second phases of the formalin test. The antinociceptive effect shown by all drugs tested in hot plate test was reverted by naloxone administration (1 mg/kg), indicating opiod system participation. These results demonstrate the beneficial effects of OgEO and its active principles against neurogenic and inflammatory pain. Our findings demonstrate that OgEO and its isolated active principles exhibited antinociceptive activity in murine pain models.

Topics: Acyclic Monoterpenes; Alkenes; Analgesics; Animals; Behavior, Animal; Eugenol; Male; Mice; Mice, Inbred C57BL; Monoterpenes; Morphine; Naloxone; Ocimum; Oils, Volatile; Pain; Pain Measurement

Artemisia scoparia (redstem wormwood) locally known as jhahoo or jaukay, is traditionally used in pain, inflammation and febrile conditions. So far, little or no scientific work has been reported to validate its folk uses in the alleviation of pain, fever and inflammation. The present study was designed to explore the analgesic, anti-inflammatory and antipyretic effects of the Artemisia scoparia hydromethanolic extract (ASHME), and to validate its traditional use in Asia.. This study made use of thermal (hot plate induced) and chemical (acetic acid induced) nociception models in mice. In addition, the mechanism of antinociception in hot plate test was further evaluated in the presence of caffeine (10mg/kg), naloxone (2mg/kg) and monosodium glutamate (1g/kg). While carrageenan induced rat paw edema and yeast induced mouse pyrexia models were used to test the anti-inflammatory and antipyretic activities.. Administration of single intraperitoneal doses (400mg/kg and 800 mg/kg) of ASHME significantly reduced the carrageenan induced paw edema in rats (P<0.05, P<0.001) by 54% and 74%, increased the thermal nociception time in the hot plate test up to 2- and 2.5-fold (P<0.01, P<0.001), inhibited the acetic acid induced writhings in mice by 41.12% and 61.53% (P<0.001), and attenuated the yeast induced pyrexia in mice by nearly 74% and 90% respectively (P<0.01, P<0.001). Caffeine (10mg/kg), naloxone (2mg/kg) and monosodium glutamate (1g/kg) significantly (P<0.001) abolished the anti-nociceptive response of ASHME (400mg/kg).. These findings suggest that the Artemisia scoparia hydromethanolic extract of ASHME possesses anti-nociceptive, anti-inflammatory and antipyretic potentials, which support its use, for the said conditions, in traditional medicine and should be further exploited for its use in clinical medicine.

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Antipyretics; Artemisia; Caffeine; Carrageenan; Edema; Female; Fever; Herb-Drug Interactions; Male; Methanol; Mice; Mice, Inbred BALB C; Naloxone; Pain; Phytotherapy; Plant Extracts; Rats; Rats, Sprague-Dawley; Sodium Glutamate

β-caryophyllene (BCP) is a common constitute of the essential oils of numerous spice, food plants and major component in Cannabis. The present study investigated the contribution of peripheral cannabinoid (CB) and opioid systems in the antinociception produced by intraplantar (i.pl.) injection of BCP. The interaction between peripheral BCP and morphine was also examined.. The antinociceptive effect of i.pl. BCP was assayed by the capsaicin tests in mice. Antagonists for CB and opioid receptors, and antisera against β-endorphin were injected peripherally prior to i.pl. injection of BCP. Morphine in combination with BCP was injected subcutaneously or intrathecally.. The i.pl. injection of BCP dose-dependently attenuated capsaicin-induced nociceptive response. The antinociceptive effect produced by BCP was prevented by pretreatment with AM630, a selective CB2 receptor antagonist, but not by AM251, a selective CB1 receptor antagonist. Pretreatment with naloxone, an opioid receptor antagonist, and β-funaltrexamine, a selective μ-opioid receptor antagonist, reversed the antinociceptive effect of BCP. Pretreatment with naloxone methiodide, a peripherally acting antagonist for opioid receptors and antisera against β-endorphin, resulted in a significant antagonizing effect on BCP-induced antinociception. Morphine-induced antinociception was increased by a low dose of BCP. The increased effect of morphine in combination with BCP was antagonized significantly by pretreatment with naloxone.. The present results demonstrate that antinociception produced by i.pl. BCP is mediated by activation of CB2 receptors, which stimulates the local release from keratinocytes of the endogenous opioid β-endorphin. The combined injection of morphine and BCP may be an alternative in treating chemogenic pain.

Topics: Animals; Cannabinoids; Endorphins; Mice; Morphine; Naloxone; Naltrexone; Narcotic Antagonists; Nociception; Pain; Pain Measurement; Polycyclic Sesquiterpenes; Receptor, Cannabinoid, CB2; Sesquiterpenes

Geoffroea decorticans (chañar) fruits and their derivate product (arrope) have been traditionally used as food and a folk medicine for the treatment of a wide variety of diseases including bronchopulmonary disorders and to relieve dolorous process.. In order to evaluate the pharmacology action of this plant, studies were performed of antinociceptive and antioxidant activities.. The aqueous and ethanolic extracts and arrope of chañar were evaluated in various established pain models, including chemical nociception induced by subplantar formalin and intraperitoneal acetic acid and thermal nociception method, such as tail immersion test in rats. To examine the possible connection of the opioid receptor to the antinociceptive activity of extracts and arrope it was performed a combination test with naloxone, a non-selective opioid receptor antagonist.. The aqueous extract and arrope (1000 mg/kg) caused an inhibition of the pain in formalin test in the first phase, similar to morphine and decrease in the second phase. In a combination test using naloxone, diminished analgesic activity of aqueous extract and arrope were observed, indicating that antinociceptive activity is connected with the opioid receptor. The aqueous extract and arrope, caused an inhibition of the writhing response induced by acetic acid. Central involvement in analgesic profile was confirmed by the tail immersion test, in which the aqueous extract and arrope showed a significant analgesic activity by increasing latency time. The aqueous extract showed higher antioxidant activity than the arrope, it may be due to the cooking process.. This study has shown that the aqueous extract and arrope of Geoffroea decorticans (chañar) fruits, does possess significant antinociceptive effects. It is further concluded that aqueous extract with maximum inhibition of free radical is the most potent extract amount tested extracts. At the oral doses tested the aqueous extract and arrope were non-toxic. The present results justifies their popular use and constitutes the first validation study of the antinociceptive action.

Topics: Analgesics; Animals; Antioxidants; Disease Models, Animal; Fabaceae; Flavonoids; Fruit; Herb-Drug Interactions; Male; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Pharmaceutical Solutions; Phenols; Phytotherapy; Plant Extracts; Rats; Rats, Wistar

Apelin was identified as natural ligand for APJ, a G protein-coupled receptor. APJ is expressed in spinal cord and dorsal root ganglion. This study was designed to investigate the effects and mechanisms of intrathecally (i.t.) administered apelin-13 on nociceptive response in formalin test and tail-flick test. In formalin test, i.t. injection of apelin-13 (0.3-3 nmol/mouse) had no effect on the nociceptive response in either acute phase (0-10 min) or interphase (10-20 min), but significantly produced hyperalgesic effect in late phase (20-30 min) at the dose of 3 nmol/mouse. The APJ receptor antagonist apelin-13(F13A) and GABAA receptor antagonist bicuculline methiodide, but not opioid receptor antagonist naloxone, significantly blocked the hyperalgesia caused by apelin-13 in late phase, indicating that i.t. apelin-13- induced hyperalgesia was mediated by APJ and GABAA receptor, rather than opioid receptor. However, in tail-flick test, i.t. injected apelin-13 (1 and 3 nmol/mouse) induced a significant antinociceptive effect, which was significantly antagonized by apelin-13(F13A) and naloxone, suggesting APJ and opioid receptor were involved in the antinociception of spinal apelin-13.

Topics: Amino Acid Sequence; Animals; Apelin Receptors; Injections, Spinal; Intercellular Signaling Peptides and Proteins; Male; Mice; Molecular Sequence Data; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Receptors, G-Protein-Coupled; Receptors, Opioid; Spinal Cord

In the present study, the antinociceptive profile of oligopeptidases B from Trypanosoma cruzi (OPTc) and Trypanosoma brucei (OPTb) were examined in mice evaluated by the acetic acid-induced writhing test. Both OPTc and OPTb injected intraperitoneally attenuated the writhing numbers in the acetic acid-induced writhing test. This effect was not dependent on the enzymatic activity, but the enzyme structure was important for this purpose. Intraperitoneal pretreatment with methysergide (5-HT serotonergic receptor antagonist) attenuated antinociceptive effect induced by both OPTc and OPTb in the writhing test. However, naloxone (opioid receptor antagonist) or yohimbine (α2-adrenergic receptor antagonist) did not affect antinociception induced by both oligopeptidases. Our results suggest that OPTc and OPTb show antinociceptive property in the writhing test. Furthermore, this antinociceptive effect may be mediated by serotonergic receptor but not opioidergic or α2-adrenergic receptors.

Topics: Adrenergic alpha-2 Receptor Antagonists; Analgesics; Animals; Male; Methysergide; Mice; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Receptors, Serotonin; Serine Endopeptidases; Serotonin Antagonists; Trypanosoma brucei brucei; Trypanosoma cruzi; Yohimbine

It has been demonstrated that opioid and cannabinoid receptor systems can produce similar signal transduction and behavioural effects. Neuropeptide FF (NPFF) belongs to an opioid-modulating peptide family. NPFF has been reported to play important roles in control of pain and analgesia through interactions with the opioid system. We were interested in whether the central and peripheral antinociception of cannabinoids could be influenced by supraspinal NPFF system. The present study examined the effects of NPFF and related peptides on the antinociceptive activities induced by the non-selective cannabinoid receptors agonist WIN55,212-2, given by supraspinal and intraplantar routes. In mice, the central and peripheral antinociception of WIN55,212-2 are mediated by cannabinoid CB(1) and CB(2) receptors, respectively. Interestingly, central administration of NPFF significantly reduced central and peripheral analgesia of cannabinoids in dose-dependent manners. In contrast, dNPA and NPVF (i.c.v.), two highly selective agonists for NPFF(2) and NPFF(1) receptors, dose-dependently augmented the antinociception caused by intracerebroventricular and intraplantar injection of WIN55,212-2. Additionally, pretreatment with the NPFF receptors selective antagonist RF9 (i.c.v.) markedly reduced the cannabinoid-modulating activities of NPFF and related peptides in nociceptive assays. These data provide the first evidence for a functional interaction between NPFF and cannabinoid systems, indicating that activation of central NPFF receptors interferes with cannabinoid-mediated central and peripheral antinociception. Intriguingly, the present work may pave the way for a new strategy of using combination treatment of cannabinoid and NPFF agonists for pain management. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'.

Topics: Analgesia; Analgesics; Animals; Benzoxazines; Indoles; Male; Mice; Morpholines; Naloxone; Naphthalenes; Oligopeptides; Pain; Pain Measurement; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2

This study investigated the potential antinociceptive efficacy of a novel synthetic curcuminoid analogue, 2,6-bis-(4-hydroxy-3-methoxybenzylidene)cyclohexanone (BHMC), using chemical- and thermal-induced nociception test models in mice. BHMC (0.03, 0.1, 0.3 and 1.0 mg/kg) administered via intraperitoneal route (i.p.) produced significant dose-related inhibition in the acetic acid-induced abdominal constriction test in mice with an ID(50) of 0.15 (0.13-0.18) mg/kg. It was also demonstrated that BHMC produced significant inhibition in both neurogenic (first phase) and inflammatory phases (second phase) of the formalin-induced paw licking test with an ID(50) of 0.35 (0.27-0.46) mg/kg and 0.07 (0.06-0.08) mg/kg, respectively. Similarly, BHMC also exerted significant increase in the response latency period in the hot-plate test. Moreover, the antinociceptive effect of the BHMC in the formalin-induced paw licking test and the hot-plate test was antagonized by pre-treatment with the non-selective opioid receptor antagonist, naloxone. Together, these results indicate that the compound acts both centrally and peripherally. In addition, administration of BHMC exhibited significant inhibition of the neurogenic nociception induced by intraplantar injections of glutamate and capsaicin with ID(50) of 0.66 (0.41-1.07) mg/kg and 0.42 (0.38-0.51) mg/kg, respectively. Finally, it was also shown that BHMC-induced antinociception was devoid of toxic effects and its antinociceptive effect was associated with neither muscle relaxant nor sedative action. In conclusion, BHMC at all doses investigated did not cause any toxic and sedative effects and produced pronounced central and peripheral antinociceptive activities. The central antinociceptive activity of BHMC was possibly mediated through activation of the opioid system as well as inhibition of the glutamatergic system and TRPV1 receptors, while the peripheral antinociceptive activity was perhaps mediated through inhibition of various inflammatory mediators.

Topics: Analgesics; Animals; Curcumin; Cyclohexanones; Disease Models, Animal; Dose-Response Relationship, Drug; Inflammation; Inflammation Mediators; Inhibitory Concentration 50; Injections, Intraperitoneal; Male; Mice; Mice, Inbred BALB C; Naloxone; Narcotic Antagonists; Pain; Toxicity Tests, Acute

Chronic treatment of pain with opiate drugs can lead to analgesic tolerance and drug dependence. Although all opiate drugs can promote tolerance and dependence in practice, the severity of those unwanted side effects differs depending on the drug used. Although each opiate drug has its own unique set of pharmacological profiles, methadone is the only clinically used opioid drug that produces substantial receptor endocytosis at analgesic doses. Here, we examined whether moderate doses of methadone carry any benefits over chronic use of equianalgesic morphine, the prototypical opioid. Our data show that chronic administration of methadone produces significantly less analgesic tolerance than morphine. Furthermore, we found significantly reduced precipitated withdrawal symptoms after chronic methadone treatment than after chronic morphine treatment. Finally, using a novel animal model with a degrading μ-opioid receptor we showed that, although endocytosis seems to protect against tolerance development, endocytosis followed by receptor degradation produces a rapid onset of analgesic tolerance to methadone. Together, these data indicated that opioid drugs that promote receptor endocytosis and recycling, such as methadone, may be a better choice for chronic pain treatment than morphine and its derivatives that do not.

Topics: Analgesics, Opioid; Animals; Area Under Curve; Dose-Response Relationship, Drug; Drug Tolerance; Endocytosis; Gene Knock-In Techniques; Methadone; Mice; Mice, Inbred C57BL; Mice, Transgenic; Morphine; Mutation; Naloxone; Pain; Pain Measurement; Pain Threshold; Receptors, Opioid, mu; Substance Withdrawal Syndrome; Substance-Related Disorders

Topics: Analgesics, Opioid; Humans; Male; Naloxone; Oxycodone; Pain

Previous studies showed noxious unilateral forepaw electrical stimulation surprisingly evoked negative blood-oxygenation-level-dependent (BOLD), cerebral blood flow (CBF), and cerebral blood volume (CBV) fMRI responses in the bilateral striatum whereas the local neuronal spike and c-Fos activities increased. These negative responses are associated with vasoconstriction and appeared to override the increased hemodynamic responses that typically accompanied with increased neural activity. The current study aimed to investigate the role of μ-opioid system in modulating vasoconstriction in the striatum associated with noxious stimulation on a 4.7-Tesla MRI scanner. Specifically, we investigated: i) how morphine (a μ-opioid receptor agonist) affects the vasoconstriction in the bilateral striatum associated with noxious electrical forepaw stimulation in rats, and ii) how naloxone (an opioid receptor antagonist) and eticlopride (a dopamine D(2)/D(3) receptor antagonist) modulates the morphine effects onwards. Injection of morphine enhanced the negative striatal CBV responses to noxious stimulation. Sequential injection of naloxone in the same animals abolished the stimulus-evoked vasoconstriction. In a separate group of animals, injection of eticlopride following morphine also reduced the vasoconstriction. Our findings suggested that noxious stimulation endogenously activated opioid and dopamine receptors in the striatum and thus leading to vasoconstriction.

Topics: Animals; Cerebrovascular Circulation; Corpus Striatum; Dopamine Antagonists; Magnetic Resonance Imaging; Male; Morphine; Naloxone; Narcotic Antagonists; Narcotics; Pain; Rats; Rats, Wistar; Salicylamides; Synaptic Transmission; Vasoconstriction

The neuropeptide Substance P (SP), that has a high affinity for the neurokinin 1 (NK1) receptor, is involved in modulation of pain transmission. Although SP is thought to have excitatory actions and promote nociception in the spinal cord, the peptide induces analgesia at the supraspinal level. The aim of this study was to evaluate the role of supraspinal SP and the NK1 receptor in inflammatory pain induced by injection of carrageenan in the hind paw of the rat. There are two nociceptive behavioral responses associated with this pain state: mechanical allodynia and heat hyperalgesia. Because the NK1 receptor colocalizes with the MOP receptor in supraspinal sites involved in pain modulation, we also decided to study the possible involvement of the opioid system on SP-induced analgesia. We found that treatment with SP, at doses of 3.5, 5 and 7 μg/5 μl/rat i.c.v., clearly showed inhibition of allodynia and hyperalgesia. Pretreatment with the selective NK1 antagonist L-733,060 (10mg/kg i.p.) blocked the SP-induced analgesia, suggesting the involvement of the NK1 receptor. This SP-induced analgesia was significantly reduced by administration of the opioid antagonist naloxone (3mg/kg s.c.). This reduction occurred when SP was administered either before or after the carrageenan injection. These results suggest a significant antinociceptive role for SP and the NK1 receptor in inflammatory pain at the supraspinal level, possibly through the release of endogenous opioids.

Topics: Animals; Carrageenan; Dose-Response Relationship, Drug; Hyperalgesia; Infusions, Intraventricular; Injections, Spinal; Injections, Subcutaneous; Male; Naloxone; Narcotic Antagonists; Neurokinin-1 Receptor Antagonists; Nociception; Pain; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Neurokinin-1; Substance P

To compare the cost effectiveness of prolonged release oxycodone/naloxone (OXN) tablets (Targinact) and prolonged release oxycodone (OXY) tablets (OxyContin) in patients with moderate-to-severe non-malignant pain and opioid-induced constipation (OIC) from the perspective of the UK healthcare system.. A cohort model used data from a phase III randomised, controlled trial (RCT). It calculated the cost difference between treatments by combining the cost of pain therapy with costs of laxatives and other resources used to manage constipated patients. SF-36 scores were converted into EQ-5D utility values to calculate the quality-adjusted life-year (QALY) gains. Deterministic and probabilistic sensitivity analyses were performed.. The incremental cost of OXN versus OXY was £159.68 for the average treatment duration of 301 days. OXN gave an incremental QALY gain of 0.0273. The estimated incremental cost-effectiveness ratio (ICER) was £5841.56 per QALY. Sensitivity analyses gave a maximum ICER of £10,347.03. In some scenarios, OXN dominated with a cost saving of up to £4254.70. Probabilistic sensitivity analysis showed that OXN had approximately 96.6% probability of cost effectiveness at the £20,000 threshold.. The model was conservative in predicting the probability of constipation beyond the 12-week RCT period. UK cost of constipation data were limited and based on primary care physician opinion.. In the base case, direct treatment costs were slightly higher for patients treated with OXN than for those treated with OXY. However, patients treated with OXN experienced a quality of life gain, and had an ICER considerably below thresholds commonly applied in the UK. The model was most sensitive to the estimated cost of constipation with a number of realistic scenarios in the sensitivity analysis demonstrating a cost saving with OXN (OXN dominant). OXN is therefore estimated to be a cost-effective option for treating patients with severe non-malignant pain and OIC.

Topics: Analgesics, Opioid; Cohort Studies; Constipation; Cost-Benefit Analysis; Delayed-Action Preparations; Drug Combinations; Humans; Naloxone; Oxycodone; Pain; Quality of Life; Severity of Illness Index; United Kingdom

The zona incerta (ZI) is a subthalamic nucleus connected to several structures, some of them known to be involved with antinociception. The ZI itself may be involved with both antinociception and nociception. The antinociceptive effects of stimulating the ZI with glutamate using the rat tail-flick test and a rat model of incision pain were examined. The effects of intraperitoneal antagonists of acetylcholine, noradrenaline, serotonin, dopamine, or opioids on glutamate-induced antinociception from the ZI in the tail-flick test were also evaluated. The injection of glutamate (7 μg/0.25 μl) into the ZI increased tail-flick latency and inhibited post-incision pain, but did not change the animal performance in a Rota-rod test. The injection of glutamate into sites near the ZI was non effective. The glutamate-induced antinociception from the ZI did not occur in animals with bilateral lesion of the dorsolateral funiculus, or in rats treated intraperitoneally with naloxone (1 and 2 m/kg), methysergide (1 and 2 m/kg) or phenoxybenzamine (2 m/kg), but remained unchanged in rats treated with atropine, mecamylamine, or haloperidol (all given at doses of 1 and 2 m/kg). We conclude that the antinociceptive effect evoked from the ZI is not due to a reduced motor performance, is likely to result from the activation of a pain-inhibitory mechanism that descends to the spinal cord via the dorsolateral funiculus, and involves at least opioid, serotonergic and α-adrenergic mechanisms. This profile resembles the reported effects of these antagonists on the antinociception caused by stimulating the periaqueductal gray or the pedunculopontine tegmental nucleus.

Topics: Analgesics; Animals; Atropine; Glutamic Acid; Haloperidol; Male; Mecamylamine; Methysergide; Microinjections; Naloxone; Pain; Pain Measurement; Phenoxybenzamine; Rats; Rats, Wistar; Subthalamic Nucleus; Subthalamus

The leaves of Crassocephalum bauchiense have long been used in traditional Cameroonian medicine for the treatment of epilepsy, pain, inflammatory disorders, arthritis and intestinal pain.. In this study, we attempted to identify the possible antinociceptive action of the aqueous extract and the alkaloid fraction prepared from the leaves of Crassocephalum baucheiense.. Using acetic acid induced abdominal constrictions, formalin-, capsaisin- and glutamate-induced nociception, and hot plate assay procedures, the antinociceptive effects of the aqueous extract and the alkaloid fraction was assessed after oral administration in mice. Morphine sulfate was used as reference analgesic agent. Mice were submitted to the rota-rod task and open-field test in order to assess any non-specific muscle-relaxant or sedative effects of the extracts of Crassocephalum bauchiense. Male and female Swiss mice were used to assess acute toxicity of these extracts.. The aqueous extract and the alkaloid fraction of Crassocephalum bauchiense produced a significant antinociceptive effects in the acetic acid, formalin, glutamate, capsaicin and hot plate tests. These antinociceptive effects of Crassocephalum bauchiense were significantly attenuated by pretreatment with naloxone. The extracts of Crassocephalum bauchiense did not alter the locomotion of animals in the open-field or rotarod tests, which suggest a lack of a central depressant effect. The animals did not exhibit any acute toxicity to the aqueous extract and the alkaloid fraction, so it was not possible to calculate the LD(50).. The results confirm the popular use of Crassocephalum bauchiense as an antinociceptive, and contribute to the pharmacological knowledge of this species because it was shown that the aqueous extract and the alkaloid fraction of Crassocephalum bauchiense produced dose related antinociception in models of chemical and thermal nociception through mechanisms that involve an interaction with opioidergic pathway.

Topics: Acetic Acid; Administration, Oral; Alkaloids; Analgesics; Analgesics, Opioid; Animals; Asteraceae; Behavior, Animal; Capsaicin; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Formaldehyde; Glutamic Acid; Hot Temperature; Male; Mice; Morphine; Motor Activity; Naloxone; Narcotic Antagonists; Pain; Pain Threshold; Phytotherapy; Plant Extracts; Plant Leaves; Plants, Medicinal; Solvents; Time Factors; Water

Ginger (Zingiber officinale Roscoe), a well-known spice plant, has been used traditionally in the treatment of a wide variety of ailments such as opiates withdrawal-induced disorders. However, its influences on opioid tolerance and dependence have not yet been clarified.. Adult male Wistar rats were rendered tolerant to analgesic effect of morphine by injection of morphine (10 mg/kg, i.p.) twice daily for 8 days. To develop morphine dependence, rats given escalating doses of chronic morphine. To determine the effect of ginger on the development of morphine tolerance and dependence, different doses of ginger were administrated before morphine. The tail-flick and naloxone precipitation tests were used to assess the degree of tolerance and dependence, respectively.. Our results showed that chronic morphine-injected rats displayed tolerance to the analgesic effect of morphine as well as morphine dependence. Ginger (50 and 100 mg/kg) completely prevented the development of morphine tolerance. In addition, concomitant treatment of morphine with 100 and 150 mg/kg attenuated almost all of the naloxone-induced withdrawal sings which include weight lose, abdominal contraction, diarrhea, petosis, teeth chattering, and jumping. In addition, morphine-induced L-type calcium channel over-expression in spinal cord was reversed by 100 mg/kg ginger.. The data indicate that ginger extract has a potential anti-tolerant/anti-dependence property against chronic usage of morphine.

Topics: Analgesics, Opioid; Animals; Diarrhea; Drug Tolerance; Ethanol; Gene Expression; Male; Morphine; Morphine Dependence; Naloxone; Pain; Plant Extracts; Plant Roots; Rats; Rats, Wistar; RNA, Messenger; Spinal Cord; Substance Withdrawal Syndrome; Zingiber officinale

Topics: Analgesics, Opioid; Dose-Response Relationship, Drug; Drug Combinations; Humans; Naloxone; Narcotic Antagonists; Neoplasms; Oxycodone; Pain

Biphalin is an opioid linear octapeptide, which displays a broad affinity for all opioid receptors (μ, δ and κ), as well as exceptionally high antinociceptive activity. AM 94 is a biphalin analog and a selective agonist at μ and δ opioid receptors. This study investigated the antinociceptive profile of AM 94. All antinociception evaluations were made in adult male rats using the hot-plate test. AM 94 proved to induce greater and longer antinociception compared to biphalin following intracebroventricular (1 nmol/kg) and intravenous administration (1200 nmol/kg) as evaluated by % maximum possible effect (M.P.E.), when administered intracerebroventricularly and intravenously and sustained analgesia up to 210 min. The antinociceptive activities of biphalin and AM 94 were antagonized by naloxone (10mg/kg intraperitoneally). Our data suggest that AM 94 could be regarded as a novel pharmacologically active opioid compound for eliciting potent and sustained analgesia after central and peripheral administration.

Topics: Analgesics; Animals; Disease Models, Animal; Enkephalins; Injections, Intravenous; Injections, Intraventricular; Male; Naloxone; Narcotic Antagonists; Oligopeptides; Pain; Piperazines; Rats; Rats, Wistar; Time Factors

Pyrexia, algesia and inflammation are associated with several pathological conditions. Synthetic drugs available for the treatment of these conditions cause multiple unwanted effects. Several studies are ongoing worldwide to find natural healing agents with better safety profile. The current study was thus aimed at evaluating antipyretic, analgesic and anti-inflammatory activities of the methanolic extract of whole plant of V. betonicifolia (VBME).. VBME was employed to assess antipyretic activity in yeast induced hyperthermia. Analgesic profile was ascertained in acetic acid induced writhing, hot plat and tail immersion test. Nevertheless, the anti-inflammatory activity was tested in carrageenan induced paw edema and histamine induced inflammatory tests. BALB/c mice were used at test doses of 100, 200 and 300 mg/kg body weight intra peritoneally (i.p).. In yeast induced pyrexia, VBME demonstrated dose dependently (78.23%) protection at 300 mg/kg, similar to standard drug, paracetamol (90%) at 150 mg/kg i.p. VBME showed a dose dependent analgesia in various pain models i.e. acetic acid, hot plat and tail immersion having 78.90%, 69.96% and 68.58% protection respectively at 300 mg/kg. However, the analgesic action of VBME was completely antagonized by the injection of naloxone like opiate antagonists. Similarly carrageenan and histamine induces inflammation was significantly antagonized by VBME, 66.30% and 60.80% respectively at 300 mg/kg.. It is concluded that VBME has marked antipyretic, analgesic and anti-inflammatory activities in various animal models and this strongly supports the ethnopharmacological uses of Viola betonicifolia as antipyretic, analgesic and anti-inflammatory plant.

Topics: Acetaminophen; Acetic Acid; Analgesics; Animals; Anti-Inflammatory Agents; Antipyretics; Behavior, Animal; Carrageenan; Disease Models, Animal; Dose-Response Relationship, Drug; Edema; Female; Fever; Histamine; Hot Temperature; Inflammation; Male; Mice; Mice, Inbred BALB C; Naloxone; Narcotic Antagonists; Pain; Phytotherapy; Plant Extracts; Tail; Viola; Yeasts

Artificial sweeteners are low-calorie substances used to sweeten a wide variety of foods. At present they are used increasingly not only by diabetics, but also by the general public as a mean of controlling the weight. This study was carried out to evaluate and compare antinociceptive activity of the artificial sweeteners, aspartame and sucrose and to study the mechanisms involved in this analgesic activity.. Forty eight white albino Wistar rats were divided into two groups of 24 rats each. Group 1 received sucrose and group 2 received aspartame solution ad libitum for 14 days as their only source of liquid. On 14(th) day, both groups of rats were divided into 3 subgroups having 8 rats each. Group Ia and IIa served as control. Group Ib and IIb were given naloxone and Ic and IIc received ketanserin, the opioid and serotonergic receptor antagonists, respectively.. Tail withdrawal latencies (tail flick analgesiometer) and paw licking/jumping latencies (Eddy's hot plate method) were increased significantly in both aspartame and sucrose group. The analgesia produced by aspartame was comparable with sucrose. The opioid receptor antagonist naloxone and the 5-HT(2A/2C) serotonergic receptor antagonist ketanserin partly reversed the antinociceptive effect of these sweeteners.. Thus, the artificial sweetening agent aspartame showed antinociceptive activity like sucrose in rats. Reduction in antinociceptive activity of aspartame and sucrose by opioid and serotoninergic antagonists demonstrate the involvement of both opioid and serotonergic system.

Topics: Analgesics, Non-Narcotic; Analysis of Variance; Animals; Aspartame; Disease Models, Animal; Ketanserin; Naloxone; Narcotic Antagonists; Pain; Rats; Rats, Wistar; Serotonin Antagonists; Sucrose

The therapeutic action of opioid analgesics is compromised by peripheral adverse effects among which opioid-induced constipation (OIC) is the most disabling, with a prevalence reported to vary between 15 and 90 %. Although OIC is usually treated with laxatives, there is insufficient clinical evidence that laxatives are efficacious in this indication. In contrast, there is ample evidence from double- blind, randomized and placebo-controlled trials that peripheral opioid receptor antagonists (PORAs) counteract OIC. This specific treatment modality is currently based on subcutaneous methylnaltrexone for the interruption of OIC in patients with advanced illness, and a fixed combination of oral prolonged-release naloxone with prolonged-release oxycodone for the prevention of OIC in the treatment of non-cancer and cancer pain. Both drugs counteract OIC while the analgesic effect of opioids remains unabated. The clinical studies show that more than 50 % of the patients with constipation under opioid therapy may benefit from the use of PORAs, while PORA-resistant patients are likely to suffer from non-opioid-induced constipation, the prevalence of which increases with age. While the addition of naloxone to oxycodone seems to act by preventing OIC, the intermittent dosing of methylnaltrexone every other day seems to stimulate defaecation by provoking an intestinal withdrawal response. The availability of PORAs provides a novel opportunity to specifically control OIC and other peripheral adverse effects of opioid analgesics (e.g., urinary retention and pruritus). The continuous dosing of a PORA has the advantage of few adverse effects, while intermittent dosing of a PORA can be associated with abdominal cramp-like pain.

Topics: Age Factors; Analgesics, Opioid; Constipation; Defecation; Drug Combinations; Gastrointestinal Tract; Humans; Laxatives; Naloxone; Naltrexone; Narcotic Antagonists; Pain; Predictive Value of Tests; Prevalence; Quaternary Ammonium Compounds; Receptors, Opioid; Risk Factors

Babassu is the common Brazilian name of Orbignya speciosa Mart. (Arecaceae). The fruits are used for several disorders. In the present study, the antinociceptive effects of the ethanol extract (EE) and dichloromethane fraction (DF) obtained from leaves were investigated, as well as apigenin using nociception models (acetic acid-induced abdominal writhing, formalin, and hot plate).. Mice were treated with EE, DF (10, 30, and 100mg/kg, p.o.), apigenin (1mg/kg, p.o.), morphine (5mg/kg, s.c.), acetylsalicylic acid (100mg/kg, p.o.) or vehicle (0.1 ml, p.o.). The EE and DF reduced the contortions induced by acetic acid. Both also reduced the licking response in the formalin model. In the hot plate model, the antinociceptive effects were, at least, equal to that shown by morphine. To elucidate the antinociceptive mechanism of action of EE, DF, and apigenin the animals were pre-treated with atropine (nonselective muscarinic receptor antagonist, 1mg/kg, s.c.), naloxone (opioid receptor antagonist, 1mg/kg, s.c.), l-nitro arginine methyl ester (L-NAME, nitric oxide synthase inhibitor, 3mg/kg, s.c.) or mecamylamine (nicotinic receptor antagonist, 2mg/kg, s.c.) and evaluated in the hot plate model.. The antinociception produced by DF was abolished by atropine, naloxone or mecamylamine. The effect of apigenin was significantly blocked by atropine or naloxone.. The results obtained indicated that EE and DF have antinociceptive activity that is mediated, at least in part, by opioid and cholinergic systems. This effect can be attributed to the presence of apigenin, a flavonoid in the dichloromethane fraction.

Topics: Analgesics; Animals; Apigenin; Arecaceae; Aspirin; Atropine; Brazil; Disease Models, Animal; Dose-Response Relationship, Drug; Male; Mecamylamine; Mice; Morphine; Naloxone; Pain; Plant Extracts; Plant Leaves

Ultra-low dose naloxone has been shown to restore the antinociceptive effect of morphine in pertussis toxin (PTX)-treated rats by suppressing spinal microglia activation and inhibiting inflammatory cytokine expression. This study was further investigated the mechanism by which ultra-low dose naloxone promotes analgesia in pertussis toxin-treated rats.. Male Wistar rats were implanted with an intrathecal (i.t.) catheter and injected either saline or PTX (1 μg). Four days later, rats randomly received either saline, or ultra-low dose naloxone, or recombinant rat interleukin-10 (rrIL-10) (1 μg) injection followed by saline or morphine (10 μg) 30 min later. In some experiments, mouse anti-rat IL-10 antibody (10 μg) was injected intrathecally into PTX injected rats daily on days 4, 5, 6, and 7. On day 7, ultra-low dose naloxone was given 1h after antibody injection with or without subsequent morphine injection.. PTX injection induced notable thermal hyperalgesia and mechanical allodynia. Injection of ultra-low dose naloxone preserved the antinociceptive effect of morphine in PTX-treated rats and associated an increasing of IL-10 protein expression. Intrathecal injection rrIL-10 alone or in combination with morphine, not only reversed mechanical allodynia but also partially restored the antinociceptive effect of morphine; injection of anti-rat IL-10 antibody attenuated the effect of morphine plus ultra-low dose naloxone on mechanical allodynia and completely inhibited the antinociceptive effect of morphine.. These results indicate that intrathecal ultra-low dose naloxone induces IL-10 expression in spinal neuron and microglia, which suppresses PTX-induced neuroinflammation and restores the antinociceptive effect of morphine.

Topics: Analgesics, Opioid; Animals; Antibodies; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Therapy, Combination; Inflammation; Interleukin-10; Male; Mice; Microglia; Morphine; Naloxone; Narcotic Antagonists; Neurons; Pain; Pertussis Toxin; Random Allocation; Rats; Rats, Wistar; Recombinant Proteins; Spinal Cord; Up-Regulation

ETNOPHARMACOLOGICAL RELEVANCE: Aspidosperma cuspa (Kunth) Blake (Apocynaceae) is popularly known as "amargosa" or "cuspa", and its bark is used in folk medicine primarily for pain.. In the present study the acute toxicity, antinociceptive effect and alkaloids of the aqueous decoction extract of the Aspidosperma cuspa bark in mice was investigated.. Acute toxicity was tested using a variation of the method described by Lichfield and Wilcoxon. The antinociceptive activity was evaluated using the acetic acid induced writhing and tail-flick tests. The phytochemical analysis was performed.. Oral administration of the extract did not cause animal death (LD(50)>4 g/kg), and the histological analysis showed an absence of alterations in all organs examined. TD(50) of the extract was 0.5521 g/kg for male mice and 1.1565 g/kg for females. The aqueous extract at doses 276 mg/kg (p.o.) did not produce a significant inhibition of acetic acid-induced writhes, but showed a significant effect in tail-flick test. Naloxone, an opioid receptor antagonist, pretreatment inhibited significantly the antinociceptive activity of the extract. It is suggested that the aqueous decoction extract of the bark of Aspidosperma cuspa has an antinociceptive effect, and this may be mediated by opioid receptors. Three indole alkaloids (aspidocarpine, 11-methoxytubotaiwine and picraline) were isolated from the aqueous extract. The antinociceptive activity of the extract is presumed to be due to these compounds.

Topics: Acetic Acid; Analgesics, Opioid; Animals; Aspidosperma; Female; Hot Temperature; Indole Alkaloids; Male; Mice; Naloxone; Narcotic Antagonists; Pain; Phytotherapy; Plant Bark; Plant Extracts; Water

The neuropeptide oxytocin (OXT) contributes to the regulation of diverse cognitive and physiological functions including nociception. Indeed, OXT has been reported to be analgesic when administered directly into the brain, the spinal cord, or systemically. Although many authors have reported the analgesic effects of OXT, its mechanism has not been well elucidated. Recently, it has been also hypothesize that OXT, increasing intracellular concentration of calcium, could regulate the production of mediators, like endocannabinoids (eCB). It has been well documented that eCB are able to suppress pain pathways. The present study investigates the effect of OXT in paw carrageenan-induced pain. Intracerebroventricular (icv) administration of OXT, but neither intraperitoneal nor intraplantar route, induces an antihyperalgesic effect increasing paw withdrawal latency to mechanical or thermal stimuli. Our results clearly demonstrate that 3 and 6h following carrageenan challenge, central administration of OXT (30 ng/mouse) shows a significant antihyperalgesic activity. Moreover, for the first time, we demonstrate that CB1 receptor plays a key role in the antihyperalgesic effect of OXT. In fact our results show CB1 antagonist, but not the specific CB2 antagonist reduce OXT-induced antihyperalgesic effect. In addition, our data show that central OXT administration is able to reduce carrageenan-induced hyperalgesia but does not modify carrageenan-induced paw edema. Finally, using opioid antagonists we confirm an important role of opioid receptors. In conclusion, our experiments suggest that central administration of OXT reduces hyperalgesia induced by intraplantar injection of carrageenan, and this effect may work via cannabinoid and opioid systems.

Topics: Analgesics, Non-Narcotic; Animals; Carrageenan; Cyclooxygenase 2; Dose-Response Relationship, Drug; Edema; Hyperalgesia; Injections, Intraventricular; Male; Mice; Motor Activity; Naloxone; Narcotic Antagonists; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type II; Oxytocin; Pain; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Receptors, Opioid; Receptors, Oxytocin; Spinal Cord

Polypeptide toxins have played a central part in understanding physiological and physiopathological functions of ion channels. In the field of pain, they led to important advances in basic research and even to clinical applications. Acid-sensing ion channels (ASICs) are generally considered principal players in the pain pathway, including in humans. A snake toxin activating peripheral ASICs in nociceptive neurons has been recently shown to evoke pain. Here we show that a new class of three-finger peptides from another snake, the black mamba, is able to abolish pain through inhibition of ASICs expressed either in central or peripheral neurons. These peptides, which we call mambalgins, are not toxic in mice but show a potent analgesic effect upon central and peripheral injection that can be as strong as morphine. This effect is, however, resistant to naloxone, and mambalgins cause much less tolerance than morphine and no respiratory distress. Pharmacological inhibition by mambalgins combined with the use of knockdown and knockout animals indicates that blockade of heteromeric channels made of ASIC1a and ASIC2a subunits in central neurons and of ASIC1b-containing channels in nociceptors is involved in the analgesic effect of mambalgins. These findings identify new potential therapeutic targets for pain and introduce natural peptides that block them to produce a potent analgesia.

Topics: Acid Sensing Ion Channel Blockers; Acid Sensing Ion Channels; Analgesics; Animals; Drug Tolerance; Elapid Venoms; Injections, Spinal; Male; Mice; Mice, Inbred C57BL; Molecular Sequence Data; Morphine; Naloxone; Nociceptors; Oocytes; Pain; Peptides; Protein Subunits; Rats; Respiratory Insufficiency; Xenopus laevis

Carvacrol (5-isopropyl-2-methylphenol) is a monoterpenic phenol which is present in the essential oil of oregano and thyme. We have investigated the behavioural effects of carvacrol in animal models of pain, such as acetic acid-induced abdominal constriction, formalin and hot-plate tests in mice. The spontaneous motor activity of animals treated with carvacrol was investigated using open-field and rotarod tests.. Carvacrol was administered orally, at single doses of 50 and 100 mg/kg while indometacin (5 mg/kg), morphine (7.5 mg/kg) and diazepam (2 mg/kg) were used as standard drugs. Naloxone (1 mg/kg) and l-arginine (150 mg/kg) were used to elucidate the possible antinociceptive mechanism of carvacrol on acetic acid-induced abdominal constriction and formalin tests.. The results showed that carvacrol produced significant inhibitions on nociception in the acetic acid-induced abdominal constriction, formalin and hot-plate tests. In the open-field and rotarod tests carvacrol did not significantly impair the motor performance. The effect of the highest dose of carvacrol in mice in the acetic acid-induced abdominal constriction and formalin tests were not reversed by naloxone or l-arginine.. Based on these results, it has been suggested that carvacrol presents antinociceptive activity that may not act through the opioid system nor through inhibition of the nitric oxide pathway.

Topics: Abdominal Pain; Acetic Acid; Analgesics; Animals; Arginine; Behavior, Animal; Cymenes; Disease Models, Animal; Formaldehyde; Hot Temperature; Male; Mice; Mice, Inbred Strains; Monoterpenes; Motor Activity; Naloxone; Narcotic Antagonists; Oils, Volatile; Origanum; Pain; Phytotherapy; Plant Extracts; Thymus Plant

Proopiomelanocortin (POMC)-derived beta-endorphin1-31 from immune cells can inhibit inflammatory pain. Here we investigated cytokine signaling pathways regulating POMC gene expression and beta-endorphin production in lymphocytes to augment such analgesic effects.. Interleukin-4 dose-dependently elevated POMC mRNA expression in naïve lymph node-derived cells in vitro, as determined by real-time PCR. This effect was neutralized by janus kinase (JAK) inhibitors. Transfection of Signal Transducer and Activator of Transcription (STAT) 1/3 but not of STAT6 decoy oligonucleotides abolished interleukin-4 induced POMC gene expression. STAT3 was phosphorylated in in vitro interleukin-4 stimulated lymphocytes and in lymph nodes draining inflamed paws in vivo. Cellular beta-endorphin increased after combined stimulation with interleukin-4 and concanavalin A. Consistently, in vivo reduction of inflammatory pain by passively transferred T cells improved significantly when donor cells were pretreated with interleukin-4 plus concanavalin A. This effect was blocked by naloxone-methiodide.. Interleukin-4 can amplify endogenous opioid peptide expression mediated by JAK-STAT1/3 activation in mitogen-activated lymphocytes. Transfer of these cells leads to inhibition of inflammatory pain via activation of peripheral opioid receptors.

Topics: Animals; Cells, Cultured; Concanavalin A; Inflammation; Interleukin-4; Janus Kinase 3; Lymphocytes; Male; Naloxone; Pain; Pro-Opiomelanocortin; Quaternary Ammonium Compounds; Rats; Rats, Wistar; RNA, Messenger; STAT1 Transcription Factor; STAT3 Transcription Factor

Orexin A (OXA, hypocretin/hcrt 1) is a newly discovered potential analgesic substance. However, whether OXA is involved in acupuncture analgesia remains unknown. The present study was designed to investigate the involvement of spinal OXA in electroacupuncture (EA) analgesia.. A modified rat model of post-laparotomy pain was adopted and evaluated. Von Frey filaments were used to measure mechanical allodynia of the hind paw and abdomen. EA at 2/15 Hz or 2/100 Hz was performed once on the bilateral ST36 and SP6 for 30 min perioperatively. SB-334867, a selective orexin 1 receptor (OX1R) antagonist with a higher affinity for OXA than OXB, was intrathecally injected to observe its effect on EA analgesia.. OXA at 0.3 nmol and EA at 2/15 Hz produced respective analgesic effects on the model (P<0.05). Pre-surgical intrathecal administered of SB-334867 30 nmol antagonized OXA analgesia and attenuated the analgesic effect of EA (P<0.05). However, SB-334867 did not block fentanyl-induced analgesia (P>0.05). In addition, naloxone, a selective opioid receptor antagonist, failed to antagonize OXA-induced analgesia (P>0.05).. The results of the present study indicate the involvement of OXA in EA analgesia via OX1R in an opioid-independent way.

Topics: Abdomen; Acupuncture Points; Analgesia; Animals; Electroacupuncture; Fentanyl; Hindlimb; Hyperalgesia; Intracellular Signaling Peptides and Proteins; Laparotomy; Male; Naloxone; Narcotic Antagonists; Neuropeptides; Orexin Receptors; Orexins; Pain; Pain Management; Postoperative Complications; Rats; Rats, Sprague-Dawley; Receptors, G-Protein-Coupled; Receptors, Neuropeptide; Spine

Cholestasis is associated with analgesia. The histamine H(2) receptors control pain perception. The involvement of histamine H(2) receptors on modulation of nociception in a model of elevated endogenous opioid tone, cholestasis, was investigated in this study using zolantidine and cimetidine as two H(2) receptor antagonists and dimaprit as a selective H(2) receptor agonist. Cholestasis was induced by ligation of the main bile duct using two ligatures and transsection of the duct at the midpoint between them. A significant increase in tail-flick latencies was observed in cholestatic rats compared to non-cholestatic rats. Administration of zolantidine (10, 20 and 40 mg/kg) and cimetidine (25, 50 and 100 mg/kg) in the cholestatic group significantly increased tail-flick latencies while dimaprit (10 and 20 mg/kg) injection in the cholestatic group decreased tail-flick latencies compared to the saline treated cholestatic group. Antinociception produced by injection of zolantidine and cimetidine in cholestatic rats was attenuated by co-administration of naloxone. Drug injection in non-cholestatic rats did not alter tail-flick latencies compared to the saline treated rats at any of the doses. At the doses used here, none of the drugs impaired motor coordination as revealed by the rota rod test. These data show that the histamine H(2) receptor system may be involved in the regulation of nociception during cholestasis. According to the hypothesis that increasing the nociception threshold in cholestasis may lead to a decrease in the perception of pruritus, the provision of the drugs that increase the threshold to nociception may be a novel approach to the treatment of cholestatic pruritus.

Topics: Analgesia; Animals; Benzothiazoles; Cholestasis; Cimetidine; Dimaprit; Disease Models, Animal; Histamine H2 Antagonists; Male; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Pain Perception; Phenoxypropanolamines; Piperidines; Rats; Rats, Wistar; Receptors, Histamine H2; Rotarod Performance Test

Intracellular nucleotide-binding oligomerization domain (NOD)-like receptors, NOD1 and NOD2, recognize the diaminopimelic acid (DAP)-containing peptide moiety and muramyldipeptide (MDP) moiety of bacterial peptidoglycan, respectively. Muramyldipeptide has been reported to exert analgesic activity to decrease the frequency of acetic acid-induced writhing movements in mice. In this study, we demonstrated the analgesic activities of NOD1 as well as NOD2 agonists. Intravenous injection of NOD2-agonistic MDP, 6-O-stearoyl-MDP (L18-MDP), and MDP-Lys (L18) exhibited analgesic activity at 10, 50, and 2.0 µg/head, respectively, in BALB/c mice. NOD1-Agonistic FK156 (D-lactyl-L-Ala-D-Glu-meso-DAP-L-Gly) and FK565 (heptanoyl-D-Glu-meso-DAP-D-Ala) were also analgesic at 50 µg/head and 1.0 µg/head, respectively. The analgesic effect of FK565 appeared from 30 min, reached maximum activity at 8 h, and continued until 24 h. The FK565 exhibited activity by various administration routes; intravenous, intraperitoneal, intramuscular, sublingual (1.0 µg/head each), subcutaneous, intragastric (oral), intragingival (10 µg/ head each) and intracerebroventricular (0.01 µg/head). The analgesic activity of FK565 was observed even in tumor necrosis factor (TNF)-α knockout, interleukin (IL)-1α/β double knockout, and their triple knockout mice. Naloxane, a non-selective antagonist for the opioid receptor, completely inhibited the analgesic effect of FK565. These findings suggest that NOD1 and NOD2 activation induces an analgesic effect via opioid receptors in a TNF-α and IL-1α/β independent manner.

Topics: Acetic Acid; Acetylmuramyl-Alanyl-Isoglutamine; Analgesics; Animals; Diaminopimelic Acid; Drug Antagonism; Female; Interleukin-1; Male; Mice; Mice, Inbred BALB C; Mice, Knockout; Naloxone; Narcotic Antagonists; Nod1 Signaling Adaptor Protein; Nod2 Signaling Adaptor Protein; Oligopeptides; Pain; Pain Measurement; Time Factors; Tumor Necrosis Factor-alpha

We evaluated the effectiveness of intrathecal antagonists of α1- (WB4101) and α2- (idazoxan) adrenoceptors and serotonergic (methysergide), opioid (naloxone), muscarinic (atropine), GABA(A) (bicuculline) and GABA(B) (phaclofen) receptors in blocking 2- or 100-Hz electroacupuncture (EA)-induced analgesia (EAIA) in the rat tail-flick test. EA was applied bilaterally to the Zusanli and Sanyinjiao acupoints in lightly anesthetized rats. EA increased tail-flick latency, where the effect of 2-Hz EA lasted longer than that produced by 100-Hz EA. The 2-Hz EAIA was inhibited by naloxone or atropine, was less intense and shorter after WB4101 or idazoxan, and was shorter after methysergide, bicuculline, or phaclofen. The 100-Hz EAIA was less intense and shorter after naloxone and atropine, less intense and longer after phaclofen, shorter after methysergide or bicuculline, and remained unchanged after WB4101 or idazoxan. We postulate that the intensity of the effect of 2-Hz EA depends on noradrenergic descending mechanisms and involves spinal opioid and muscarinic mechanisms, whereas the duration of the effect depends on both noradrenergic and serotonergic descending mechanisms, and involves spinal GABAergic modulation. In contrast, the intensity of 100-Hz EAIA involves spinal muscarinic, opioid, and GABA(B) mechanisms, while the duration of the effects depends on spinal serotonergic, muscarinic, opioid, and GABA(A) mechanisms.. The results of this study indicate that 2- and 100-Hz EA induce analgesia in the rat tail-flick test activating different descending mechanisms at the spinal cord level that control the intensity and duration of the effect. The adequate pharmacological manipulation of such mechanisms may improve EA effectiveness for pain management.

Topics: Adjuvants, Anesthesia; Adrenergic alpha-Antagonists; Analgesia; Anesthetics, Intravenous; Animals; Atropine; Baclofen; Bicuculline; Biophysics; Dioxanes; Disease Models, Animal; Electroacupuncture; GABA Agents; Male; Methysergide; Models, Biological; Multivariate Analysis; Naloxone; Narcotic Antagonists; Pain; Pain Management; Pain Measurement; Rats; Rats, Wistar; Reaction Time; Serotonin Antagonists; Tail; Thiopental; Time Factors

The objectives of this work were to carry out a comparative chemical study and to evaluate the antinociceptive and anti-inflammatory activities of ethanol extracts (EtOHE) and vanilic acid (VA) from cultivated and wild Amburana cearensis A.C. Smith (Fabaceae), an endangered species used in Northeast Brazil for the treatment of asthma. The HPLC analysis of EtOHE, showed that coumarin (CM) and VA were the major constituents from the cultivated plant, while in the extract from the wild plant the major constituents were amburoside A (AMB) and CM. Pharmacological tests were performed with male Swiss mice or male Wistar rats acutely administered with 100-400mg/kg, p.o. of EtOHEs or 12.5-50mg/kg, p.o. of VA. EtOHEs from A. cearensis with 4, 7 or 9 months of cultivation significantly inhibited, from 32 to 64%, both phases of the formalin test in mice. Similar results were observed with the EtOHE from the wild species. VA significantly reduced both phases of the formalin test. This effect was partially reversed by naloxone. EtOHE from cultivated or wild A. cearensis inhibited the carrageenan (Cg)-induced mice paw edema. Furthermore, VA inhibited the paw edema and the leukocyte migration in rat peritoneal cavity induced by Cg. On the other hand, it did not inhibit the edema and the increase of vascular permeability induced by dextran in the rat paw. All together, these results indicate that the EtOHE from cultivated A. cearensis exhibit similar chemical and pharmacological profiles, as related to the wild plant. VA is, at least partially, responsible for these pharmacological effects. Its antinociceptive effect occurs by a mechanism partly dependent upon the opioid system, while the anti-inflammatory action was manifested in inflammatory processes dependent on polymorphonuclear cells and are probably related to the VA inhibition of cytokines as observed by others.

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Capillary Permeability; Carrageenan; Dextrans; Edema; Fabaceae; Formaldehyde; Leukocytes; Male; Mice; Naloxone; Pain; Peritoneum; Phytotherapy; Plant Extracts; Rats; Rats, Wistar; Vanillic Acid

Ligands acting at the same receptor can differentially activate distinct signal transduction pathways, which in turn, can have diverse functional consequences. Further, receptors expressed in different tissues may utilize intracellular signaling proteins in response to a ligand differently as well. The mu opioid receptor (MOR), which mediates many of the pharmacological actions of opiate therapeutics, is also subject to differential signaling in response to diverse agonists. To study the effect of diverse agonists on MOR signaling, we examined the effects of chronic opiate treatment on two distinct physiological endpoints, antinociceptive tolerance and physical dependence, in mice lacking the intracellular regulatory molecule, βarrestin2. While βarrestin2 knockout (βarr2-KO) mice do not become tolerant to the antinociceptive effects of chronic morphine in a hot plate test, tolerance develops to the same degree in both wild type and βarr2-KO mice following chronic infusion with methadone, fentanyl, and oxycodone. Studies here also assess the severity of withdrawal signs precipitated by naloxone following chronic infusions at three different doses of each opiate agonist. While there are no differences in withdrawal responses between genotypes at the highest dose of morphine tested (48 mg/kg/day), the βarr2-KO mice display several less severe withdrawal responses when the infusion dose is lowered (12 or 24 mg/kg/day). Chronic infusion of methadone, fentanyl, and oxycodone all lead to equivalent naloxone-precipitated withdrawal responses in both genotypes at all doses tested. These results lend further evidence that distinct agonists can differentially impact on opioid-mediated responses in vivo in a βarrestin2-dependent manner.

Topics: Analgesics, Opioid; Analysis of Variance; Animals; Arrestins; beta-Arrestins; Drug Tolerance; Fentanyl; Hot Temperature; Male; Methadone; Mice; Mice, Knockout; Morphine; Morphine Dependence; Naloxone; Narcotic Antagonists; Oxycodone; Pain; Pain Measurement; Pain Threshold; Receptors, Opioid, mu

Combination of opioid and potassium channel openers holds immense potential for the treatment for most acute and chronic pain. Therefore, the study was performed to assess the interaction between morphine and K(+) -channel openers. Swiss albino mice of either sex weighing between 25 and 30 g were used for the study. The study assesses the interaction between morphine and K(+) -channel openers (cromakalim, diazoxide and minoxidil), when administered intraperitoneally, using formalin and tail-flick tests in mice. Both morphine and K(+) -channel openers produced significant antinociception at higher doses in both the behavioral tests. Lower doses of morphine and K(+) -channel openers had no significant effect on tail-flick latency, while the same drugs had significant antinociceptive effect on formalin test. The combination of lower doses of morphine and K(+) -openers was observed to have significant antinociceptive effect in both the behavioral tests. Administration of naloxone prior to morphine or K(+) -channel openers antagonized the analgesic effect of morphine but not of K(+) -channel openers, whereas prior administration of glibenclamide antagonized the effect of both morphine and K(+) -channel openers. The study, therefore, suggests that the common site of action of morphine and K(+) -channel openers is at the levels of K(+) -channels rather than at the level of receptors. However, such interaction depends on the differential sensitivity to different pain stimulus.

Topics: Animals; Calcium Channel Agonists; Cromakalim; Diazoxide; Drug Interactions; Drug Therapy, Combination; Female; Glyburide; Injections, Intraperitoneal; Male; Mice; Mice, Inbred Strains; Minoxidil; Morphine; Naloxone; Pain; Pain Measurement; Potassium Channels

Acmella uliginosa (Sw.) Cass. is a medicinal herbaceous plant that is commonly used by the Malay community in Malaysia to relieve pain often associated with mouth ulcers, toothache, sore throat, and stomach ache.. The study was carried out to investigate the antinociceptive effect of the methanolic extract of A. uliginosa (Sw.) Cass. flowers (MEAU) using murine models of chemicals and thermal nociception.. Chemicals (acetic acid-induced abdominal constriction and formalin-, capsaicin-, glutamate-induced paw licking test) and thermal models (hot plate test) of nociception in mice were employed to evaluate the MEAU analgesic effect. The extract was given via oral administration at doses of 3, 10, 30 and 100 mg/kg.. It was demonstrated that MEAU produced significant antinociceptive response in all the chemical- and thermal-induced nociception models, which indicates the presence of both centrally and peripherally mediated activities. Furthermore, the reversal of antinociception of MEAU by naloxone suggests the involvement of opioid system in its centrally mediated analgesic activity. Moreover, MEAU-treated mice did not show any significant motor performance alterations. No mortality and signs of toxicity were recorded following treatment of the MEAU.. The results from the present study appear to support the folkloric belief in the medicinal properties of A. uliginosa (Sw.) Cass. which against pain at both central and peripheral levels, in which the central antinociception is probably due to the participation of the opioid receptors.

Topics: Analgesics; Animals; Asteraceae; Flowers; Hot Temperature; Malaysia; Male; Mice; Mice, Inbred ICR; Morphine; Naloxone; Pain; Phytotherapy; Plant Extracts; Rotarod Performance Test

Endomorphins (EMs) cannot be delivered into the central nervous system (CNS) in sufficient quantity to elicit antinociception when given systemically because they are severely restricted by the blood-brain barrier (BBB). In the present study, we investigated herein a series of EM-1 analogs with C-terminal linked by oligoarginine in order to improve the brain delivery and antinociception after systemic administration. Indeed, all these analogs decreased the opioid receptor affinity and in vitro pharmacological activity. Moreover, analogs 4, 7-9 produced a less potent antinociceptive activity after intracerebroventricular (i.c.v.) administration, with the ED(50) values about 11- to 13-fold lower potencies than that of EM-1. Nevertheless, our results revealed that EM-1 failed to induce any significant antinociception at a dose of 50μmol/kg after subcutaneous (s.c.) administration, whereas equimolar dose of these four analogs produced a little low but significant antinociceptive effects. Naloxone (10nmol/kg, i.c.v.) significantly blocked the antinociceptive effects, indicating an opioid and central mechanism. These results demonstrated that C-terminal of EM-1 linked to oligoarginine improved the brain delivery, eliciting potent antinociception following peripheral administration.

Topics: Analgesics, Opioid; Animals; Arginine; Brain; Chromatography, High Pressure Liquid; Female; Guinea Pigs; Ileum; Male; Mice; Mice, Inbred Strains; Muscle Contraction; Naloxone; Oligopeptides; Pain; Pain Measurement; Radioligand Assay; Rats; Rats, Wistar; Receptors, Opioid, delta; Receptors, Opioid, mu; Spectrometry, Mass, Electrospray Ionization; Vas Deferens

Ocimum basilicum L. is an aromatic herb used in Brazil to treat illnesses such as respiratory and rheumatic problems, vomiting, and pain. In the present study, the chemical composition, acute toxicity, and antinociceptive effects of the essential oil (EO) of the cultivar "Maria Bonita" obtained from O. basilicum L. PI 197442 genotype were evaluated in Swiss mice (20-35 g each). Lethal dose to cause 50 % death (LD50) was calculated from a dose-response curve (100-5000 mg/kg body wt.; n = 6) as 532 mg/kg body wt. In the acetic acid-induced writhing test (0.6 % i. p.), EO (50, 100, and 200 mg/kg body wt., n = 8, s. c.) was effective in reducing the abdominal contractions at all doses (48-78 %). In the hot-plate test, EO significantly increased the latency at 50 mg/kg body wt. at all times (37-52 %, n = 8, s. c.). However, the effects of morphine and EO at 50 mg/kg were reverted in the presence of naloxone, an opioid antagonist. In the formalin test, EO significantly reduced paw licking time in the first and second phases of pain at 200 mg/kg body wt. (38 and 75 %, respectively, n = 8, s. c.). The results suggested that the peripheral and central antinociceptive effects of EO are related to the inhibition of the biosynthesis of pain mediators, such as prostaglandins and prostacyclins, and its ability to interact with opioid receptors.

Topics: Analgesics; Analgesics, Opioid; Animals; Brazil; Female; Lethal Dose 50; Male; Mice; Morphine; Naloxone; Narcotic Antagonists; Nociceptors; Ocimum basilicum; Oils, Volatile; Pain; Pain Measurement; Plant Leaves; Plants, Medicinal

The leaves of Eriobotrya japonica Lindl. have been widely used as a traditional medicine for the treatment of many diseases including coughs and asthma. The present study was designed to validate the anti-inflammatory and antinociceptive properties of the n-BuOH fraction of E. japonica (LEJ) leaves.. The anti-inflammatory properties of LEJ were studied using IFN-γ/LPS activated murine peritoneal macrophage model. The antinociceptive effects of LEJ were assessed using experimental models of pain, including thermal nociception methods, such as the tail immersion test and the hotplate test, and chemical nociception induced by intraperitoneal acetic acid and subplantar formalin in mice. To examine the possible connection of the opioid receptor to the antinociceptive activity of LEJ, we performed a combination test with naloxone, a nonselective opioid receptor antagonist.. In the IFN-γ and LPS-activated murine peritoneal macrophage model, LEJ suppressed NO production and iNOS expression via down-regulation of NF-κB activation. It also attenuated the expression of COX-2 and the secretion of pro-inflammatory cytokines like TNF-α and IL-6. Moreover, LEJ also demonstrated strong and dose-dependent antinociceptive activity compared to tramadol and indomethacin in various experimental pain models. In a combination test using naloxone, diminished analgesic activities of LEJ were observed, indicating that the antinociceptive activity of LEJ is connected with the opioid receptor.. The results indicate that LEJ had potent inhibitory effects on the inflammatory mediators including nitric oxide, iNOS, COX-2, TNF-α and IL-6 via the attenuation of NF-κB translocation to the nucleus. LEJ also showed excellent antinociceptive activity in both central and peripheral mechanism as a weak opioid agonist. Based on these results, LEJ may possibly be used as an anti-inflammatory and an analgesic agent for the treatment of pains and inflammatory diseases.

Topics: Acetic Acid; Analgesics, Opioid; Animals; Anti-Inflammatory Agents; Cyclooxygenase Inhibitors; Dose-Response Relationship, Drug; Eriobotrya; Female; Formaldehyde; Hot Temperature; Indomethacin; Inflammation Mediators; Interferon-gamma; Lipopolysaccharides; Macrophages, Peritoneal; Male; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; Naloxone; Narcotic Antagonists; Pain; Phytotherapy; Plant Extracts; Plant Leaves; Receptors, Opioid

Emilia sonchifolia (L.) DC. (Asteraceae) is a medicinal plant traditionally used in Brazilian folk medicine to treat asthma, fever, cuts, wounds and rheumatism. This study was conducted to establish the antinociceptive properties of hydroethanolic extract from aerial parts of Emilia sonchifolia in mice using chemical and thermal models of nociception.. To evaluate the antinociceptive effect of Emilia sonchifolia hydroethanolic extract (EsHE) administered by oral route, peripheral (acetic acid-induced abdominal writhing and formalin), spinal (tail flick) and supra-spinal (hot plate) behavioral models of acute pain were used. High-performance liquid chromatography (HPLC) was used to determine the fingerprint chromatogram of the EsHE.. The EsHE at test doses of 100 and 300 mg/kg, p.o. clearly demonstrated antinociceptive activity in all tests. The extract had a stronger antinociceptive effect than morphine. Administration of the opioid receptor antagonist, naloxone, completely inhibited the antinociceptive effect induced by EsHE (100mg/kg). The presence of phenolic compounds in the extract of Emilia sonchifolia was confirmed using HPLC.. The extract of Emilia sonchifolia markedly exhibits opioid-mediated anti-nociceptive activity action in mice. Thus, may be useful in the treatment of inflammatory hyperalgesic disorders, which supports previous claims of its traditional use.

Topics: Acetic Acid; Analgesics, Opioid; Animals; Asteraceae; Behavior, Animal; Brazil; Disease Models, Animal; Formaldehyde; Hot Temperature; Male; Medicine, Traditional; Mice; Morphine; Naloxone; Pain; Phenols; Phytotherapy; Plant Components, Aerial; Plant Extracts

Polygonatum verticillatum All. is used traditionally as an analgesic and plant diuretic. The methanol extract of aerial parts of Polygonatum verticillatum (PA) was assessed in various experimental paradigms. The pain threshold in the form of abdominal constriction induced by acetic acid was significantly (p < 0.01) inhibited by PA at test doses (50, 100 and 200 mg/kg). In the formalin test, PA elicited a significant (p < 0.01) analgesic activity in both phases and strongly attenuated the formalin-induced flinching behaviour. The hot plate test was used to evaluate central involvement in the analgesic profile of PA. The PA significantly relieved thermal-induced pain. From a mechanistic point of view, the central antihyperalgesic activity was tested for antagonism with naloxone, but no antagonism was observed. The current investigations suggest that the active constituent(s) in PA has an analgesic profile with predominant peripheral activity which is augmented by an opioid independent central effect. In the diuretic assay, PA (300 and 600 mg/kg) showed mild insignificant diuretic activity. Our study rationalized the traditional use of Polygonatum verticillatum in the treatment of painful conditions.

Topics: Analgesics; Animals; Female; Male; Mice; Naloxone; Pain; Pain Measurement; Plant Components, Aerial; Plant Extracts; Polygonatum; Rats; Rats, Wistar; Toxicity Tests, Acute

The long-lasting post-surgical changes in nociceptive thresholds in mice, indicative of latent pain sensitization, were studied. The contribution of kappa opioid and N-methyl-d-aspartate (NMDA) receptors was assessed by the administration of nor-binaltorphimine or MK-801; dynorphin levels in the spinal cord were also determined. Animals underwent a plantar incision and/or a subcutaneous infusion of remifentanil (80μg/kg), and mechanical thresholds (von Frey) were evaluated at different times. On day 21, after complete recovery of mechanical thresholds and healing of the wound, one of the following drugs was administered subcutaneously: (-)-naloxone (1mg/kg), (+)-naloxone (1mg/kg), naloxone-methiodide (3mg/kg), or nor-binaltorphimine (5mg/kg). Another group received subcutaneous MK-801 (0.15mg/kg) before nor-binaltorphimine administration. Dynorphin on day 21 was determined in the spinal cord by immunoassay. In mice receiving remifentanil during surgery, the administration of (-)-naloxone or nor-binaltorphimine induced significant hyperalgesia even 5months after manipulation. Nociceptive thresholds remained unaltered after (+)-naloxone or naloxone-methiodide. On day 21 after manipulation, the administration of MK-801 prevented nor-binaltorphimine-induced hyperalgesia. No changes in dynorphin levels were observed before or after opioid antagonist administration. In conclusion, surgery produced latent pain sensitization evidenced by opioid antagonist-precipitated hyperalgesia. The effect was stereospecific, centrally originated, and mediated by kappa opioid receptors. The blockade of nor-binaltorphimine-induced hyperalgesia by MK-801, suggests that NMDA receptors are also involved. Our results show for the first time that surgery induces latent, long-lasting changes in the processing of nociceptive information that can be induced by non-nociceptive stimuli such as the administration of opioid antagonists.

Topics: Animals; Dizocilpine Maleate; Dynorphins; Hyperalgesia; Male; Mice; Naloxone; Naltrexone; Narcotic Antagonists; Pain; Pain Threshold; Piperidines; Postoperative Complications; Reaction Time; Receptors, N-Methyl-D-Aspartate; Receptors, Opioid, kappa; Remifentanil; Spinal Cord

Our recent investigations have shown that microinjection of three non-steroidal anti-inflammatory drugs (NSAIDs) analgin, ketorolac and xefocam into the central nucleus of amygdala produce tolerance to these drugs and cross-tolerance to morphine. We have observed the same phenomenon in midbrain periaqueductal grey matter and nucleus raphe magnus. The medullar nucleus raphe magnus (NRM) is one of important parts of CNS circuit that controls nociceptive transmission at the level of spinal cord. It is functionally involved in descending pain modulation, and mainly consists of serotoninergic neurons. The aim of this study was to examine opioid sensitivity of NSAIDs action in NRM of male rats. For this purpose 30 minutes later of NSAIDs administrations we microinjected μ-opioid antagonist naloxone and tested rats for tail flick and hot plate latencies. Our investigation showed that microinjection of naloxone in NRM significantly decreased antinociceptive effects of NSAIDs at the first day in the TF and HP latencies. At the second day, naloxone generally had trend effects in both TF and HP tests. These results strongly support the suggestion on endogenous opioid involvement in NSAIDs antinociception and tolerance. On the other hand, our evidence confirms once more that NRM is involved in the descending pain control circuit inhibiting spinal nocifensive reflexes.

Topics: Analgesia; Analgesics, Opioid; Animals; Anti-Inflammatory Agents, Non-Steroidal; Dipyrone; Drug Interactions; Drug Tolerance; Ketorolac; Male; Microinjections; Morphine; Naloxone; Nociceptors; Pain; Periaqueductal Gray; Piroxicam; Raphe Nuclei; Rats; Spinal Cord

Pediatric pain management underwent many changes since the undertreatment of pain in children was reported in the literature in 1980. Increasing data also suggest that long-term behavioural effects can be observed in children, following pain episodes as early as in the neonatal period. Therefore, the knowledge about safe and effective management of pain in children should be applied with greater effectiveness into clinical practice. Other advances in the field include the findings of long-term residual behavioural and metabolic effects induced by pain experienced during the critical periods of development in laboratory animals. Recent data in laboratory animals and clinical data in children suggest that early repeated and/or severe pain and other stressful procedures applied in the perinatal periods may produce not only behavioral, but also important hormonal, immune and metabolic long-term effects. In this paper we shall report data on some metabolic conditions described in adult humans following disruption of hormonal-metabolic programming produced in the peri-natal period. Quite similar signs can be found between animal models and human conditions, most of them being connected with hypothalamus-pituitary-adrenal hormones (HPA) dysfunction. In addition, some signs in animal models, such as overweight and abdominal overweight are prevented by treatment with the μ- and δ-opioid receptor antagonist naloxone during the lactating period. This indicates that some long-term consequences following stress received during the early phases of life in mammals may be bound to the HPA system dysregulation, whereas others are bound to different (e,g., opioid) endogenous brain receptors and/or neuromediators alteration.

Topics: Adult; Animals; Animals, Newborn; Child; Diabetes Mellitus, Type 2; Female; Hormones; Humans; Hypothalamo-Hypophyseal System; Infant, Newborn; Male; Mice; Models, Biological; Naloxone; Oligonucleotides, Antisense; Pain; Pituitary-Adrenal System; Pregnancy; Pro-Opiomelanocortin; Stress Disorders, Post-Traumatic; Stress, Physiological; Stress, Psychological; Translational Research, Biomedical

Periaqueductal gray (PAG) plays a very important role in pain modulation through endogenous opiate peptides including leucine-enkephalin (L-Ek), methionine-enkephalin (M-Ek), β-endorphin (β-Ep) and dynorphin A(1-13) (DynA(1-13)). Our pervious study has demonstrated that intra-PAG injection of oxytocin (OXT) increases the pain threshold, and local administration of OXT receptor antagonist decreases the pain threshold, in which the antinociceptive role of OXT can be reversed by pre-PAG administration of OXT receptor antagonist. The experiment was designed to investigate the effect of OXT on endogenous opiate peptides in the rat PAG during the pain process. The results showed that (1) the concentrations of OXT, L-Ek, M-Ek and β-Ep, not DynA(1-13) in the PAG perfusion liquid were increased after the pain stimulation; (2) the concentrations of L-Ek, M-Ek and β-Ep, not DynA(1-13) in the PAG perfusion liquid were decreased by the OXT receptor antagonist; (3) the increased pain threshold induced by the OXT was attenuated by naloxone, an opiate receptor antagonist; and (4) the concentrations of L-Ek, M-Ek and β-Ep, not DynA(1-13) in the PAG perfusion liquid were increased by exogenous OXT administration. The data suggested that OXT in the PAG could influence the L-Ek, M-Ek and β-Ep rather than DynA(1-13) to participate in pain modulation, i.e. OXT in the PAG participate in pain modulation by influencing the L-Ek, M-Ek and β-Ep rather than DynA(1-13).

Topics: Animals; beta-Endorphin; Catheterization; Dynorphins; Enkephalin, Leucine; Enkephalin, Methionine; Microinjections; Naloxone; Narcotic Antagonists; Oxytocin; Pain; Pain Measurement; Pain Threshold; Peptide Fragments; Periaqueductal Gray; Radioimmunoassay; Rats; Rats, Sprague-Dawley

We defined the nature of the pharmacological interaction between ginsenosides and morphine in a nociceptive state and clarified the role of the different types of opioid receptor in the effects of ginsenosides. An intrathecal catheter was placed in male Sprague-Dawley rats. Pain was induced by formalin injection into the hindpaw. Isobolographic analysis was used to evaluate drug interactions. Furthermore, a nonselective opioid receptor antagonist (naloxone), a μ opioid receptor antagonist (CTOP), a δ opioid receptor antagonist (naltrindole), and a κ opioid receptor antagonist (GNTI) were given intrathecally to verify the involvement of the opioid receptors in the antinociceptive effects of ginsenosides. Both ginsenosides and morphine produced antinociceptive effects in the formalin test. Isobolographic analysis revealed a synergistic interaction after intrathecal delivery of the ginsenosides-morphine mix. Intrathecal CTOP, naltrindole, and GNTI reversed the antinociceptive effects of ginsenosides. RT-PCR indicated that opioid receptors' mRNA was detected in spinal cord of naïve rats and the injection of formalin had no effect on the expression of opioid receptors' mRNA. Taken together, our results indicate synergistic antinociception following intrathecal coadministration of a ginsenosides/morphine mix in the formalin test, and that μ, δ, and κ opioid receptors are involved in the antinociceptive mechanism of ginsenosides.. This article concerns the antinociceptive activity of ginsenosides, which increases antinociception by morphine. Thus, a spinal combination of ginsenosides and morphine may be useful in the management of acute pain as well as facilitated state pain.

Topics: Analysis of Variance; Animals; Behavior, Animal; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Fixatives; Formaldehyde; Gene Expression Regulation; Ginsenosides; Injections, Spinal; Male; Morphine; Naloxone; Narcotic Antagonists; Narcotics; Pain; Pain Measurement; Rats; Rats, Sprague-Dawley; Receptors, Opioid; Reflex; Somatostatin

Several studies have shown that an oxycodone/naloxone combination (ratio 2:1) provides analgesia and less constipation in non-cancer patients receiving relatively low doses of this formulation. A case report of a cancer patient who was receiving increasing doses of oxycodone with an unexpected declining analgesia is presented. The substitution with the same doses (240 mg/day) of regular controlled-release oxycodone was effective in regaining adequate analgesia.

Topics: Aged; Analgesics, Opioid; Constipation; Delayed-Action Preparations; Dose-Response Relationship, Drug; Drug Combinations; Humans; Lung Neoplasms; Male; Naloxone; Narcotic Antagonists; Oxycodone; Pain; Treatment Outcome

The antioxidant and antinociceptive activities of Citrus limon essential oil (EO) were assessed in mice or in vitro tests. EO possesses a strong antioxidant potential according to the scavenging assays. Moreover, it presented scavenger activity against all in vitro tests. Orally, EO (50, 100, and 150  mg/kg) significantly reduced the number of writhes, and, at highest doses, it reduced the number of paw licks. Whereas naloxone antagonized the antinociceptive action of EO (highest doses), this suggested, at least, the participation of the opioid system. Further studies currently in progress will enable us to understand the action mechanisms of EO.

Topics: Administration, Oral; Analgesics; Animals; Antioxidants; Citrus; Disease Models, Animal; Free Radical Scavengers; Male; Mice; Naloxone; Oils, Volatile; Pain; Pain Measurement; Plant Extracts; Plant Leaves; Rutaceae

The antioxidant, antinociceptive, and anti-inflammatory activities of the ethanolic extract from leaves of Combretum duarteanum (EEC) were assessed in rodents through in vitro tests. The antioxidant activity was investigated by using thiobarbituric acid reactive species (TBARS), hydroxyl radical-scavenging, and scavenging activity of nitric oxide assays. The antinociceptive activity was investigated by using acetic acid-induced writhing, formalin, and hot-plate tests in mice. The anti-inflammatory activity was assessed in rats by using the carrageenan-induced hind-paw edema test and arachidonic acid-induced paw edema test. EEC possesses a strong antioxidant potential according to the TBARS, nitric oxide, and hydroxyl radical-scavenging assays; it also presented scavenger activity in all in vitro tests. After intraperitoneal injection, EEC (100, 200, and 400 mg/kg) significantly reduced the number of writhes (38.1%, 90.6%, and 97.8%, respectively) in a writhing test and the number of paw licks during phase 1 (30.5% and 69.5%, higher doses) and phase 2 (38.1%, 90.6%, and 97.8%, all doses) of a formalin test when compared with the control group. Naloxone (1.5 mg/kg, intraperitoneally) antagonized the antinociceptive action of EEC (400 mg/kg), and this finding suggests participation of the opioid system. Administration of 200 and 400 mg/kg (intraperitoneally) of EEC exhibited an anti-inflammatory activity in the carrageenin test, which was based on interference with prostaglandin synthesis. This finding was confirmed by the arachidonic acid test. Together, these results indicate that properties of EEC might be further explored in the search for newer tools to treat painful inflammatory conditions, including those related to pro-oxidant states.

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Antioxidants; Arachidonic Acid; Carrageenan; Combretum; Dose-Response Relationship, Drug; Edema; Ethanol; Hydroxyl Radical; Male; Mice; Naloxone; Nitric Oxide; Pain; Pain Measurement; Plant Extracts; Plant Leaves; Rats; Rats, Wistar; Reactive Oxygen Species; Rodentia; Thiobarbituric Acid Reactive Substances

Opioid-induced constipation (OIC) is a severe, persisting side-effect of opioid therapy. The Bowel Function Index (BFI(a), numerical analogue scale 0 - 100), calculated as the mean of three variables (ease of defaecation, feeling of incomplete bowel evacuation, and personal judgement of constipation) was developed to evaluate bowel function in opioid-treated patients with pain. This clinician-administered tool allows easy measurement of OIC from the patient's perspective. The purpose of this investigation was to define a reference range reflecting BFI values in non-constipated chronic pain patients who were recruited into a cross-sectional survey and asked for their perceptions of constipation. The BFI scores were assessed and compared with those of patients with confirmed OIC obtained from two previously published trials. Results were analysed and a reference range of BFI values of 0 - 28.8, into which 95% of non-constipated chronic pain patients fell, was defined. This permits discrimination between chronic pain patients with, or without, constipation.

Topics: Analgesics, Opioid; Chronic Disease; Constipation; Cross-Sectional Studies; Defecation; Female; Germany; Humans; Male; Middle Aged; Naloxone; Oxycodone; Pain; Quality of Life; Reference Values; Research Design; Surveys and Questionnaires

Nociceptin/orphanin FQ (N/OFQ), the endogenous ligand for the N/OFQ peptide (NOP) receptors, has been shown to be metabolized into some fragments. We examined to determine whether intrathecal (i.t.) N/OFQ (1-13), (1-11) and (1-7) have antinociceptive activity in the pain-related behavior after intraplantar injection of capsaicin. The i.t. administration of N/OFQ (0.3-1.2 nmol) produced an appreciable and dose-dependent inhibition of capsaicin-induced paw-licking/biting response. The N-terminal fragments of N/OFQ, (1-13) and (1-11), were antinociceptive with a potency lower than N/OFQ. Calculated ID₅₀ values (nmol, i.t.) were 0.83 for N/OFQ, 2.5 for N/OFQ (1-13) and 4.75 for N/OFQ (1-11), respectively. The time-course effect revealed that the antinociceptive effects of these N-terminal fragments lasted longer than those of N/OFQ. Removal of amino acids down to N/OFQ (1-7) led to be less potent than N/OFQ and its fragments, (1-13) and (1-11). Antinociception induced by N/OFQ or N/OFQ (1-13) was reversed significantly by i.t. co-injection of [Nphe¹]N/OFQ (1-13)NH₂, a peptidergic antagonist for NOP receptors, whereas i.t. injection of the antagonist did not interfere with the action of N/OFQ (1-11) and (1-7). Pretreatment with the opioid receptor antagonist naloxone hydrochloride did not affect the antinociception induced by N/OFQ and its N-terminal fragments. These results suggest that N-terminal fragments of N/OFQ are active metabolites and may modulate the antinociceptive effect of N/OFQ in the spinal cord. The results also indicate that N/OFQ (1-13) still possess antinociceptive activity through NOP receptors.

Topics: Analgesics; Animals; Behavior, Animal; Capsaicin; Dose-Response Relationship, Drug; Drug Interactions; Inhibitory Concentration 50; Injections, Spinal; Injections, Subcutaneous; Male; Mice; Mice, Inbred Strains; Naloxone; Narcotic Antagonists; Nociceptin; Opioid Peptides; Pain; Pain Measurement; Pain Perception; Peptide Fragments; Receptors, Opioid; Spinal Cord; Structure-Activity Relationship

To investigate whether the tetracyclic antidepressant mirtazapine has a pain-suppressing effect in healthy animals.. In the first step, Swiss albino female mice weighing 25-35 g were used. Eight groups each containing 8 mice were established as follows:- Control (saline), mirtazapine 5 mg/kg, 10 mg/kg, and 20 mg/kg, mirtazapine 10mg/kg and its combinations L-Nitro-L-Arginine Methyl Ester (L-NAME) 100 mg/kg, L-Arginine 100 mg/kg, naloxone 1 mg/kg, and cyproheptadine 50 ug/kg. This study was performed in the Department of Pharmacology, Faculty of Medicine, Eskisehir Osmangazi University, Eskisehir, Turkey during March, April, and May 2009. One hour after the drugs were given intraperitoneally, hot plate, tail clip, tail flick, and writhing tests were used for evaluating antinociceptive effects. In the second step, the brain hippocampus of Sprague Dawley type male rats weighing 250±20 g were isolated and 0.6 um hippocampus slices were obtained. In vitro groups were established as control, mirtazapine 3x10(-3)M, 4x10(-3)M, 5x10(-3)M, mirtazapine 4x10(-3)M and its combinations L-NAME, L-Arginine, naloxone, and cyproheptadine 4x10(-3)M.. Mirtazapine did not show central spinal analgesic activity, but had significant peripheral and biphasic central analgesic effects at the supraspinal level. In addition, there were no significant differences between the different groups in nitric oxide synthase levels on the brain slices.. The nitrergic pathway does not have an effect on the central antinociceptive activity of mirtazapine, while opiatergic and serotonergic pathways have a significant role.

Topics: Analysis of Variance; Animals; Antidepressive Agents, Tricyclic; Arginine; Behavior, Animal; Cyproheptadine; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Enzyme Inhibitors; Female; Gene Expression Regulation, Enzymologic; Hippocampus; In Vitro Techniques; Male; Mianserin; Mice; Mirtazapine; Naloxone; Narcotic Antagonists; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase Type I; Pain; Pain Measurement; Pain Threshold; Rats; Rats, Sprague-Dawley; Serotonin Antagonists

Over the past twenty years, neuroscience has changed our understanding of placebo analgesia. Often perceived by researchers as a response bias adding noise to the assessment of efficacy, in the patients' view, it is associated with charlatanism. The origin of the word, qualifying a patient's response to "please" the doctor, did not help its rightful appreciation. However, today the placebo analgesia is considered as a psychobiological phenomenon. Thanks to pharmacological manipulations and the development of functional brain imaging, the neural circuitry involved in this effect as well as the role of endorphins and dopamine have been identified. This article describes our current knowledge about this fascinating phenomenon: a psychological modulation can lead to a biological effect.

Topics: Aged; Analgesia; Chronic Disease; Dopamine; Endorphins; Female; Humans; Naloxone; Narcotic Antagonists; Neurosciences; Osteoarthritis, Knee; Pain; Placebo Effect; Placebos; Prefrontal Cortex; Treatment Outcome

Topics: Administration, Oral; Analgesics, Opioid; Chronic Disease; Constipation; Drug Combinations; Evidence-Based Medicine; Humans; Naloxone; Narcotic Antagonists; Oxycodone; Pain; Quality of Life; Switzerland; Treatment Outcome

The novel analgesic tapentadol HCl [(-)-(1R,2R)-3-(3-dimethylamino)-1-ethyl-2-methyl-propyl)-phenol hydrochloride] combines μ-opioid receptor (MOR) agonism and noradrenaline reuptake inhibition (NRI) in a single molecule and shows a broad efficacy profile in various preclinical pain models. This study analyzed the analgesic activity of tapentadol in experimental inflammatory pain. Analgesia was evaluated in the formalin test (pain behavior, rat and mouse), carrageenan-induced mechanical hyperalgesia (paw-pressure test, rat), complete Freund's adjuvant (CFA)-induced paw inflammation (tactile hyperalgesia, rat), and CFA knee-joint arthritis (weight bearing, rat). Tapentadol showed antinociceptive activity in the rat and mouse formalin test with an efficacy of 88 and 86% and ED(50) values of 9.7 and 11.3 mg/kg i.p., respectively. Tapentadol reduced mechanical hyperalgesia in carrageenan-induced acute inflammatory pain by 84% with an ED(50) of 1.9 mg/kg i.v. In CFA-induced tactile hyperalgesia, tapentadol showed 71% efficacy with an ED(50) of 9.8 mg/kg i.p. The decrease in weight bearing after CFA injection in one knee joint was reversed by tapentadol by 51% with an ED(25) of 0.9 mg/kg i.v. Antagonism studies were performed with the MOR antagonist naloxone and the α(2)-noradrenergic receptor antagonist yohimbine in the carrageenan- and CFA-induced hyperalgesia model. In the CFA model, the serotonergic receptor antagonist ritanserin was also tested. The effect of tapentadol was partially blocked by naloxone and yohimbine and completely blocked by the combination of both, but it was not affected by ritanserin. In summary, tapentadol showed antinococeptive/antihyperalgesic analgesic activity in each model of acute and chronic inflammatory pain, and the antagonism experiments suggest that both MOR activation and NRI contribute to its analgesic effects.

Topics: Adrenergic alpha-2 Receptor Antagonists; Analgesics; Analgesics, Opioid; Animals; Behavior, Animal; Carrageenan; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Freund's Adjuvant; Hyperalgesia; Inflammation; Male; Mice; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Phenols; Random Allocation; Rats; Rats, Sprague-Dawley; Receptors, Opioid, mu; Serotonin 5-HT2 Receptor Antagonists; Tapentadol

Celastrus orbiculatus, a woody vine of the Celastraceae family, has been widely used as a traditional medicine for the treatment of many diseases, including rheumatoid arthritis and odontalgia. In this study, we assessed the sedative and antinociceptive activities of the methanolic extract of Celastrus orbiculatus (MCO).. The antinociceptive effect of MCO was evaluated using several experimental pain models, including thermal nociception methods, such as the tail immersion and the hotplate tests, as well as chemical nociception induced by intraperitoneal acetic acid and subplantar formalin administration in mice. To verify the possible connection of the opioid receptor to the antinociceptive activity of MCO, we performed a combination test with naloxone, a nonselective opioid receptor antagonist. The sedative effect of MCO was studied using the pentobarbital-induced sleeping model.. MCO demonstrated strong and dose-dependent antinociceptive activity compared to tramadol and indomethacin in various experimental pain models. The combination test using naloxone revealed that the antinociceptive activity of MCO is associated with activation of the opioid receptor. MCO also caused decreased sleep latency and increased sleeping time in the pentobarbital-induced sleeping model; however, MCO alone did not induce sleep.. In the present study, MCO showed potent antinociceptive and sedative activities. Based on these results, MCO may be considered a valuable anti-nociceptive and hypnotic agent for the treatment of various diseases.

Topics: Acetic Acid; Animals; Celastrus; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Formaldehyde; Hypnotics and Sedatives; Indomethacin; Male; Mice; Mice, Inbred ICR; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Pain Threshold; Phenobarbital; Plant Extracts; Plants, Medicinal; Reaction Time; Sleep; Time Factors; Tramadol

To investigate the analgesic effect of cobratoxin (CTX), a long-chain α-neurotoxin from Thailand cobra venom, in a rat model of formalin-induced inflammatory pain.. Inflammatory pain was induced in SD rats via injecting 5% formalin (50 μL) into the plantar surface of their right hind paw. CTX and other agents were ip administered before formalin injection. The time that the animals spent for licking the injected paw was counted every 5 min for 1 h.. CTX (25, 34, and 45 μg/kg) exhibited a dose-dependent analgesic effect during the phase 1 (0-15 min) and phase 2 (20-60 min) response induced by formalin. Pretreatment with naloxone (0.5 or 2.5 mg/kg) did not block the analgesic effect of CTX. Pretreatment with atropine at 5 mg/kg, but not at 2.5 mg/kg, antagonized the analgesic effect of CTX. Treatment with the nonselective nAChR antagonist mecamylamine (3 mg/kg) inhibited the analgesic effects of CTX in Phase 1 and Phase 2 responses, while with the selective α7-nAChR antagonist methyllycaconitine (3 mg/kg) antagonized the effect of CTX only in the Phase 1 response. Treatment with the α7-nAChR agonist PNU282987 (3 mg/kg) significantly reduced the formalin-induced phase 2 pain response, but only slightly reduced the Phase 1 pain response.. The results suggest that CTX exerts an antinociceptive effect in formalin-induced inflammatory pain, which appears to be mediated by mAChR and α7-nAChR.

Topics: Aconitine; Adjuvants, Anesthesia; Analgesics; Animals; Antihypertensive Agents; Atropine; Cobra Neurotoxin Proteins; Drug Interactions; Formaldehyde; Male; Mecamylamine; Naloxone; Narcotic Antagonists; Nicotinic Antagonists; Pain; Rats; Rats, Sprague-Dawley; Receptors, Cholinergic

We investigated whether capsaicin induces itching in skin with existing inflammation. We induced skin inflammation by intradermal injection of complete Freund's adjuvant (CFA) in the neck of mice. Four days later, we injected capsaicin in the same area and counted the number of scratching bouts for 30 min. We examined potential effects on pain in parallel experiments in which CFA and capsaicin were intradermally injected into hind paws. We used the time spent licking the hind paws during the 15 min after capsaicin injection as an estimate of pain. Capsaicin injection into the skin pretreated with CFA, but not into healthy skin, induced scratching. The scratching behavior was reduced by pretreatment with naloxone or capsazepine, selective antagonists for transient receptor potential vanilloid receptor-1 (TRPV1), but not morphine or mepyramine, selective antagonists for histamine 1 receptor. In animals injected with capsaicin into the hind paws, licking behavior was significantly inhibited via a μ-receptor-dependent mechanism. Our results show that TRPV1 activation, which normally induces pain, evokes an itch-related response in the presence of inflammation. This model may be interesting for future studies to explore the mechanism of a painful stimuli-induced itch observed under pathological conditions.

Topics: Adjuvants, Immunologic; Animals; Anti-Inflammatory Agents, Non-Steroidal; Behavior, Animal; Capsaicin; Dimethyl Sulfoxide; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Freund's Adjuvant; Inflammation; Injections, Intradermal; Male; Mice; Mice, Inbred C57BL; Morphine; Naloxone; Pain; Pruritus; Receptors, Opioid, mu; Reflex; Sensory System Agents; Skin; Time Factors; TRPV Cation Channels

Byrsonima intermedia A. Juss. is popularly known as "murici pequeno" and is native to the Brazilian Cerrado. This species has been used as an antimicrobial, anti-hemorrhagic, anti-diarrheal and anti-inflammatory. Nevertheless, scientific information regarding Byrsonima intermedia is limited; there are no reports related to its possible anti inflammatory and antinociceptive effects. This study employed in vivo inflammatory and nociceptive models to evaluate the scientific basis for the traditional use of Byrsonima intermedia.. Carrageenan-induced paw edema, peritonitis and fibrovascular tissue growth induced by s.c. cotton pellet implantation tests were used to investigate the anti-inflammatory activity of Byrsonima intermedia aqueous extract (BiAE) in rats. Mechanical nociceptive paw, formalin and hot plate tests were used to evaluate the antinociceptive activity in mice. High-performance liquid chromatography (HPLC), phytochemistry screening and determination of total phenolics and flavonoids were used to determine the chemical profile of the BiAE.. BiAE at test doses of 30-300 mg/kg p.o. clearly demonstrated anti-inflammatory effects by reduced carrageenan-induced paw edema, by inhibited leukocyte recruitment into the peritoneal cavity and, in the model of chronic inflammation, by using the cotton pellet-induced fibrovascular tissue growth in rats. The extracts at test doses of 30-300 mg/kg p.o. clearly demonstrated antinociceptive activity in all tests. Administration of the opioid receptor antagonist naloxone completely inhibited the antinociceptive effect induced by BiAE (100 mg/kg).. BiAE markedly exhibits anti-inflammatory action in rats and antinociceptive activity in mice. Thus, it may be useful in the treatment of inflammatory hyperalgesic disorders, which supports previous claims of its traditional use.

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Behavior, Animal; Carrageenan; Chromatography, High Pressure Liquid; Cotton Fiber; Disease Models, Animal; Dose-Response Relationship, Drug; Edema; Flavonoids; Formaldehyde; Granuloma, Foreign-Body; Hot Temperature; Lipopolysaccharides; Male; Malpighiaceae; Mice; Motor Activity; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Pain Threshold; Peritonitis; Phenols; Plant Bark; Plant Extracts; Plant Stems; Plants, Medicinal; Rats; Rats, Wistar; Time Factors

The electrical stimulation of the occipital (OC) or retrosplenial (RSC) cortex produces antinociception in the rat tail-flick and formalin tests. This study examined the antinociceptive effects of stimulating the OC or RSC in a rat model of post-incision pain. The involvement of the anterior pretectal nucleus (APtN) as intermediary for the effect of OC or RSC stimulation was also evaluated because the OC and RSC send inputs to the APtN, which is implicated in antinociception and nociception. It is shown that a 15-s period of electrical stimulation of the OC or RSC significantly reduced post-incision pain for less than 10 min and at least 15 min, respectively. The injection of 2% lidocaine (0.25 μl), naloxone (10 ng/0.25 μl), methysergide (40 pg/0.25 μl), or atropine (100 ng/0.25 μl) into the APtN produced a further increase in post-incision pain. The effect of RSC stimulation was shorter and less intense in rats pretreated with lidocaine, methysergide or naloxone. The effect of OC stimulation was shorter and less intense in lidocaine-treated rats, but remained unchanged in rats pretreated with methysergide or naloxone in the APtN. The effects of stimulating the OC or RSC were not changed in rats treated with atropine. We conclude that stimulation-induced antinociception from the RSC or OC in rat post-incision pain activates distinct descending pain inhibitory pathways. The pathway activated from the RSC utilizes serotonergic and opioid mediation in the APtN, whereas stimulation of the OC utilizes a non-serotonergic, non-cholinergic and non-opioid mediation in the same nucleus.

Topics: Analgesics; Animals; Atropine; Cerebral Cortex; Electric Stimulation; Lidocaine; Male; Methysergide; Naloxone; Pain; Rats; Rats, Wistar

Tolerance to the analgesic effect of opioids complicates the management of persistent pain states. We tested whether the intrathecal infusion of small interfering RNA (siRNA) against β-arrestin 2 would reduce tolerance to chronic morphine use and the severity of precipitated morphine withdrawal.. Intrathecal β-arrestin 2 (2 μg siRNA per 10 μl per rat) was injected once daily for 3 days. Rats then received a continuous intrathecal infusion of morphine (2 nmol h⁻¹) or saline for 7 days. Daily tail-flick (TF) and intrathecal morphine challenge tests were performed to assess the effect of intrathecal β-arrestin 2 siRNA on antinociception and tolerance to morphine. Naloxone withdrawal (2 mg kg⁻¹) was performed to assess morphine dependence.. In the daily TF test, the antinociception of intrathecal morphine was increased and maintained in rats receiving β-arrestin 2 siRNA compared with the control group (morphine alone). In the probe response test, rats receiving morphine infusion with β-arrestin 2 siRNA treatment showed a significant left shift in their dose-response curve, as measured by per cent maximal possible effect (MPE), such that the AD₅₀ was significantly decreased by a factor of 5.6 when compared with that of morphine-infused rats. In the naloxone-induced withdrawal tests, rats receiving β-arrestin 2 siRNA injection with morphine infusion showed a significant reduction in four of the six signs of withdrawal.. We show here that intrathecal β-arrestin 2 siRNA in rats enhances analgesia and attenuates naloxone-induced withdrawal symptoms. This may warrant further investigation in the context of long-term use of intrathecal opioids for controlling chronic pain.

Topics: Analgesics, Opioid; Animals; Arrestins; beta-Arrestin 2; beta-Arrestins; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Drug Tolerance; Injections, Spinal; Male; Morphine; Morphine Dependence; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Rats; Rats, Sprague-Dawley; RNA, Small Interfering; Sodium Chloride; Substance Withdrawal Syndrome

Recently, paeoniflorin (PF) administered systemically was found to have analgesic effects against inflammatory pain and hypersensitivity in a naloxone-reversible manner. In the present study, we adopted intrathecal administration to evaluate whether PF has direct antinociceptive actions at the spinal level. Pain-related behaviors and spinal c-Fos expression were induced by subcutaneous injection of bee venom (BV) into one hind paw of a rat. Intrathecal pretreatment of PF resulted in an inhibition of the BV-induced persistent spontaneous nociception and partially suppressed the occurrence of both thermal and mechanical hypersensitivity. Moreover, the PF-produced antinociception was completely reversed by naloxone. We further evaluated the intrathecal effects of the drug on the BV-induced c-Fos expression. The result showed that intrathecal PF preconditioning was effective to suppress spinal c-Fos expression in both superficial (lamina I-II) and deep (lamina IV-VI) layers of the L(4-5) dorsal spine. This result showed that PF has a direct pharmacological action in the spinal cord dorsal horn via activation of opioid receptors.

Topics: Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Bee Venoms; Behavior, Animal; Benzoates; Bridged-Ring Compounds; Glucosides; Hot Temperature; Hyperalgesia; Injections, Spinal; Male; Monoterpenes; Naloxone; Narcotic Antagonists; Pain; Posterior Horn Cells; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Touch

Neuroplastic changes involved in latent pain sensitization after surgery are poorly defined. We assessed temporal changes in glucose brain metabolism in a postoperative rat model using positron emission tomography. We also investigated brain metabolism after naloxone administration.. Rats were given remifentanil anesthetic and underwent a plantar incision, with 1 mg/kg of (-)-naloxone subcutaneously administered on postoperative days 20 and 21. Using the von Frey test, mechanical thresholds were measured pre- and postoperatively at different time points in awake animals during F-fluorodeoxyglucose (F-FDG) uptake. Brain images were also obtained the day before mechanical testing, using a positron emission tomography R4 scanner (Concorde Microsystems, Siemens, Knoxville, TN). Differences in brain activity were assessed utilizing a statistical parametric mapping.. Surgery induced minor changes in F-FDG uptake in the cerebellum, hippocampus, and posterior cortex, which extended to the thalamus, hypothalamus, and brainstem on days 6 and 7. Changes were still present on day 21. Maximal postoperative hypersensitivity was observed on day 2. The administration of (-)-naloxone on day 21 induced significant hypersensitivity, greatly enhancing the effect on F-FDG uptake. In sham-operated rats, naloxone induced changes limited to the striatum and the cerebellum. Nonnociceptive stimulation with von Frey filaments had no effect on F-FDG uptake.. Surgery, remifentanil, and their combination induced long-lasting and significant metabolic changes in the pain brain matrix, with a positive correlation with hypersensitivity after naloxone. Changes in brain F-FDG precipitated by naloxone suggest that surgery under remifentanil anesthetic induces the greatest neuroplastic brain adaptations in opioid-related pathways involved in nociceptive processing and long-lasting pain sensitization.

Topics: Animals; Brain; Fluorodeoxyglucose F18; Glucose; Male; Naloxone; Pain; Pain Threshold; Piperidines; Positron-Emission Tomography; Postoperative Complications; Radiopharmaceuticals; Rats; Rats, Sprague-Dawley; Remifentanil

Centhaquin is a centrally acting hypotensive drug like clonidine. Clonidine also produces analgesia and hypothermia in mice and potentiates morphine analgesia. Clonidine analgesia is blocked by idazoxan and naloxone while it is potentiated by BQ123 and sulfisoxazole. This study was conducted to determine the analgesic and hypothermic properties of centhaquin, and to assess whether it potentiates morphine analgesia. Yohimbine (α(2)-adrenergic antagonist), idazoxan (imidazoline/α(2)-adrenergic antagonist), naloxone (opioid antagonist), and BQ123 and sulfisoxazole (endothelin ET(A) antagonists) were used to study the involvement of these receptors in centhaquin analgesia and hypothermia.. Analgesic (tail flick and hot-plate tests) latencies and body temperatures were measured in male Swiss Webster mice treated with vehicle plus centhaquin, antagonists plus centhaquin or centhaquin plus morphine.. Centhaquin produced dose-dependent analgesia which was partially blocked by yohimbine, idazoxan and naloxone. BQ123 and sulfisoxazole did not affect centhaquin analgesia. Morphine analgesia was not potentiated by centhaquin. Centhaquin produced mild hypothermia which was not blocked by yohimbine, idazoxan, naloxone, BQ123 or sulfisoxazole.. This is the first report demonstrating the analgesic activity of centhaquin. The α(2)-adrenergic, imidazoline and opioid receptors are involved in mediating centhaquin analgesia. Endothelin ET(A) receptors do not play a role in centhaquin analgesia; centhaquin does not augment morphine analgesia.

Topics: Adrenergic alpha-2 Receptor Antagonists; Analgesics; Analgesics, Opioid; Animals; Antihypertensive Agents; Body Temperature; Drug Interactions; Endothelin A Receptor Antagonists; Hot Temperature; Idazoxan; Imidazoline Receptors; Male; Mice; Morphine; Naloxone; Narcotic Antagonists; Pain; Piperazines; Receptor, Endothelin A; Receptors, Adrenergic, alpha-2; Receptors, Opioid; Yohimbine

Topics: Analgesia; Female; Humans; Naloxone; Narcotic Antagonists; Neurosciences; Osteoarthritis, Knee; Pain; Placebo Effect; Placebos; Prefrontal Cortex

Cannabinoid 2 receptor (CB2R) agonists attenuate inflammatory pain but the precise mechanism implicated in these effects is not completely elucidated. We investigated if the peripheral nitric oxide-cGMP-protein kinase G (PKG)-ATP-sensitive K(+) (KATP) channels signaling pathway triggered by the neuronal nitric oxide synthase (NOS1) and modulated by opioids, participates in the local antinociceptive effects produced by a CB2R agonist (JWH-015) during chronic inflammatory pain.. In wild type (WT) and NOS1 knockout (NOS1-KO) mice, at 10 days after the subplantar administration of complete Freund's adjuvant (CFA), we evaluated the antiallodynic (von Frey filaments) and antihyperalgesic (plantar test) effects produced by the subplantar administration of JWH-015 and the reversion of their effects by the local co-administration with CB2R (AM630), peripheral opioid receptor (naloxone methiodide, NX-ME) or CB1R (AM251) antagonists. Expression of CB2R and NOS1 as well as the antinociceptive effects produced by a high dose of JWH-015 combined with different doses of selective L-guanylate cyclase (ODQ) or PKG (Rp-8-pCPT-cGMPs) inhibitors or a KATP channel blocker (glibenclamide), were also assessed. Results show that the local administration of JWH-015 dose-dependently inhibited the mechanical and thermal hypersensitivity induced by CFA which effects were completely reversed by the local co-administration of AM630 or NX-ME, but not AM251. Inflammatory pain increased the paw expression of CB2R and the dorsal root ganglia transcription of NOS1. Moreover, the antinociceptive effects of JWH-015 were absent in NOS1-KO mice and diminished by their co-administration with ODQ, Rp-8-pCPT-cGMPs or glibenclamide.. These data indicate that the peripheral antinociceptive effects of JWH-015 during chronic inflammatory pain are mainly produced by the local activation of the nitric oxide-cGMP-PKG-KATP signaling pathway, triggered by NOS1 and mediated by endogenous opioids. These findings suggest that the activation of this pathway might be an interesting therapeutic target for the treatment of chronic inflammatory pain with cannabinoids.

Topics: Analgesics; Analgesics, Opioid; Animals; Cannabinoid Receptor Agonists; Cannabinoid Receptor Antagonists; Cyclic GMP; Glyburide; Indoles; KATP Channels; Mice; Mice, Knockout; Naloxone; Nitric Oxide; Nitric Oxide Synthase Type I; Pain; Piperidines; Pyrazoles; Quaternary Ammonium Compounds; Receptors, Cannabinoid; Signal Transduction; Thionucleotides

Topics: Aged, 80 and over; Analgesics, Opioid; Combined Modality Therapy; Drug Combinations; Female; Guideline Adherence; Humans; Naloxone; Oxycodone; Pain; Pain Measurement

Antinociceptive and anti-inflammatory activities of hydroalcoholic extract of Teucrium Oliverianum were investigated by formalin test model. This study was conducted in on the male Wistar rats, weighting 150-180 g. The animals were divided into seven groups (n = 7) and received 200, 400, 600 and 800 mg kg(-1) of hydroalcoholic extract of teucrium oliverianum intraperitoneally, respectively. Negative control group received normal saline (5 mL kg(-1)) and the positive control groups received 2.5 mg kg(-1) morphine and 300 mg kg(-1) aspirin, intraperitoneally respectively. The results showed that all doses of extract have significant analgesic effect (p < 0.05) in all studies times in comparison with negative control. The best result achieved with 600 mg kg(-1) of extract. The result revealed that the analgesic effect of the extract (600 mg kg(-1)) \\was less than aspirin (300 mg kg(-1)) on the second phase of pain and less than morphine (2.5 mg kg(-1)) in both phases of the pain, more than aspirin in first phase of pain. One group of animals was treated with naloxone (1 mg kg(-1), i.p.) and suitable dose of extract (600 mg kg(-1), i.p.). Also, Naloxone inhibited analgesic effect of alcoholic extract of Teucrium Oliverianum. It can be concluded that the alcoholic extract of Teucrium oliverianum may exert its effect through opioid receptors, stimulating GABAergic system or promotes the release of endogenous opipeptides or decreasing free radicals.

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Ethanol; Male; Medicine, Traditional; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Plant Extracts; Rats; Rats, Wistar; Teucrium; Water

Amanzio and Benedetti (J Neurosci 1999; 19: 484-494) first addressed the conditions necessary for the activation of opioid and non-opioid placebo responses in human. Here, we investigated whether placebo analgesia is subdivided into opioid and non-opioid components in mice by using the model of hot-plate test. Drug conditioning was performed by the combination of the conditioned cue stimulus with the unconditioned drug stimulus, either opioid agonist morphine hydrochloride or non-opioid aspirin. Placebo analgesic responses were evoked by an exposure to a conditioned cue previously paired with drug conditioning. Morphine conditioning produced placebo responses that were completely antagonised by naloxone. By contrast, the conditioned cue after aspirin conditioning elicited a placebo effect that was not blocked by naloxone. Therefore, we first evoked opioid and non-opioid placebo responses in mice that were either naloxone-reversible or naloxone-insensitive, depending on the drug used in conditioning procedure. These findings support that the mechanisms underlying placebo analgesia may depend on the drug conditioning that was originally performed. The present procedure of mice may serve as a model for further understanding of the opioid and non-opioid mechanisms underlying placebo responses.

Topics: Analgesia; Analgesics, Opioid; Animals; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Conditioning, Classical; Cues; Female; Hot Temperature; Mice; Mice, Inbred ICR; Morphine; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Placebo Effect; Random Allocation; Reaction Time

The midbrain neural basis underlying each phase of behavior in the formalin test has not been clarified. The present study was designed to investigate neuronal responses to formalin-induced 2-phase pain and morphine-induced antinociception in the nucleus cuneiformis (CnF) that is part of the descending pain modulatory system. Formalin-induced neuronal activities were recorded from the CnF during first and second phases of the formalin test, using an extracellular single-unit recording technique. Our results showed that: 1) the majority of neurons in the CnF displayed monophasic excitatory responses in the first or second phase after formalin injection, except a small portion of neurons which did not exhibit any responses; 2) unit activity of CnF neurons was suppressed after subcutaneous (sc) morphine administration and resumed by naloxone; 3) the increased neuronal firing induced by sc formalin could be suppressed by a single dose of sc morphine; and 4) the response patterns of many CnF neurons changed by preinjection of morphine during 2 phases of the formalin test. Our findings suggest that the diverse activity pattern in the spontaneous background of CnF neurons may have different roles in the transmission of nociceptive information induced by the peripheral noxious stimuli (eg, formalin).. Growing evidence shows the involvement of nucleus cuneiformis in the descending pain modulatory system. Further elucidation of the pain modulatory system could potentially lead to better understanding of pain modulation as well as development of new clinical treatments and/or strategies.

Topics: Action Potentials; Analgesics, Opioid; Animals; Behavior, Animal; Central Nervous System Agents; Formaldehyde; Male; Mesencephalon; Microelectrodes; Morphine; Naloxone; Narcotic Antagonists; Neurons; Pain; Pain Measurement; Rats; Rats, Inbred Strains

In the present study, the rhizome essential oil from Zingiber zerumbet (Zingiberaceae) was evaluated for antinociceptive activity using chemical and thermal models of nociception, namely, the acetic acid-induced abdominal writhing test, the hot-plate test and the formalin-induced paw licking test. It was demonstrated that intraperitoneal administration of the essential oil of Z. zerumbet (EOZZ) at the doses of 30, 100 and 300 mg/kg produced significant dose-dependent inhibition of acetic acid-induced abdominal writhing, comparable to that of obtained with acetylsalicylic acid (100 mg/kg). At the same doses, the EOZZ produced significant dose-dependent increases in the latency time in the hot-plate test with respect to controls, and in the formalin-induced paw licking test, the EOZZ also significantly reduced the painful stimulus in both neurogenic and inflammatory phase of the test. In addition, the antinociceptive effect of the EOZZ in the formalin-induced paw licking test as well as hot-plate test was reversed by the nonselective opioid receptor antagonist, naloxone suggesting that the opioid system was involved in its analgesic mechanism of action. On the basis of these data, we concluded that the EOZZ possessed both central and peripheral antinociceptive activities which justifying its popular folkloric use to relieve some pain conditions.

Topics: Acetic Acid; Analgesics; Animals; Behavior, Animal; Dose-Response Relationship, Drug; Formaldehyde; Male; Mice; Mice, Inbred BALB C; Naloxone; Narcotic Antagonists; Oils, Volatile; Pain; Plant Extracts; Rats; Rats, Sprague-Dawley; Reaction Time; Receptors, Opioid; Rhizome; Zingiberaceae

In this study, the effects of intraperitoneal (i.p.) injection of crocin in the absence and presence of subcutaneous (s.c.) injections of morphine and naloxone were investigated on the formalin test in rats. The formalin test was induced by intra-plantar (i.pl.) injection of formalin (50 microL, 1%), and the time spent licking and biting of the injected paw was measured for 1 h. Formalin induced a marked biphasic (first phase: 0-5 min and second phase: 15-45 min) pain response. Morphine (1 mg/kg, s.c.) significantly (p < 0.05) suppressed both phases of pain. Naloxone (2 mg/kg, s.c.) alone did not change the intensity of pain, but pretreatment with naloxone (2 mg/kg) significantly (p < 0.05) prevented morphine (1 mg/kg)-induced antinociception. Crocin at doses of 50, 100 and 200 mg/kg significantly (p < 0.05) attenuated pain. Crocin (100 mg/kg, i.p.) significantly (p < 0.05) increased the morphine (1 mg/kg, s.c.)-induced antinociception. Naloxone (2 mg/kg) did not reverse the suppressive effect of crocin (100 mg/kg) on pain. Crocin at a dose of 400 mg/kg significantly (p < 0.05) suppressed locomotor activities. These findings indicate that morphine through a naloxone-sensitive mechanism produced analgesia. Crocin produced a dose-dependent antinociceptive effect. In addition, crocin increased morphine-induced antinociception, but naloxone did not change the antinociceptive effect of crocin.

Topics: Analgesia; Analgesics, Opioid; Animals; Carotenoids; Male; Morphine; Motor Activity; Naloxone; Pain; Pain Measurement; Rats; Rats, Wistar

The analgesic effect induced by opiates is often potentiated during experimental inflammatory processes. We describe here that lower doses of systemic morphine are necessary to increase thermal withdrawal latencies measured in both hind paws of mice acutely inflamed with carrageenan than in healthy ones. This bilateral potentiation seems mediated through spinal opioid receptors since it is inhibited by the intrathecal (i.t.), but not intraplantar (i.pl.) administration of the opioid receptor antagonist naloxone-methiodide, and also appears when morphine is i.t. administered. Furthermore, the i.pl. administration of the nitric oxide (NO) synthase inhibitor, L-NMMA, or the K (ATP) (+) -channel blocker, glibenclamide, to carrageenan-inflamed mice inhibits the enhanced effect of systemic morphine in the paw that receives the injection of the drug, without affecting the potentiation observed in the contralateral one. The i.pl. administration of L-NMMA also partially antagonised the analgesic effect induced by i.t. morphine in inflamed mice. Finally, the increased analgesic effect evoked by the i.pl. administration of the NO donor SIN-1 either in the inflamed or in the contralateral paw of carrageenan-inflamed mice suggests that enhanced responsiveness to the peripheral analgesic effect of NO may be also underlying the bilateral potentiation of morphine-induced analgesia in acutely inflamed mice.

Topics: Acute Disease; Analgesia; Animals; Carrageenan; Glyburide; Inflammation; Injections, Spinal; Mice; Molsidomine; Morphine; Naloxone; Nociceptors; omega-N-Methylarginine; Pain; Quaternary Ammonium Compounds; Spinal Cord; Temperature

Co-infusion of ultra-low dose naloxone and morphine attenuates morphine tolerance through the prevention of mu opioid receptor-Gs protein coupling. We previously demonstrated that chronic intrathecal infusion of morphine leads to tolerance and spinal neuroinflammation. The aim of present study was to examine the possible mechanisms by which ultra-low dose naloxone modulates spinal neuroinflammation, particularly the role of anti-inflammatory cytokine interleukin 10 (IL-10). Morphine tolerance was induced in male Wistar rats by intrathecal infusion of morphine (15 microg/h) for 5 days, and co-infusion of naloxone (15 pg/h) was used to evaluate the impact on spinal cytokine expression. Recombinant rat IL-10 (rrIL-10) or anti-rat IL-10 antibody was injected to elucidate the effect of IL-10 on morphine tolerance. Our results showed that co-infusion of naloxone (15 pg/h) with morphine not only attenuated tolerance, shifting the AD(50) from 89.2 to 11.7 microg but also inhibited the increased expression of pro-inflammatory cytokine (TNF-alpha, IL-1beta, and IL-6) caused by chronic intrathecal morphine infusion. The increase of IL-10 protein and mRNA were 1.5- and 3-fold, respectively, compared to that in morphine-infused rat spinal cords. A combination of daily rrIL-10 (1 microg) injection with morphine infusion produced, in a less potent, preservative antinociception and inhibited pro-inflammatory cytokine production compared to ultra-low dose naloxone co-infusion, and the effect of ultra-low dose naloxone co-infusion was inhibited by daily intrathecal anti-rat IL-10 antibody injection. These results demonstrate that IL-10 contributes to the attenuation of pro-inflammatory cytokine expression caused by ultra-low dose naloxone/morphine co-infusion and thus the attenuation of morphine tolerance.

Topics: Analgesics, Opioid; Analysis of Variance; Animals; Antibodies, Neutralizing; Cytokines; Dose-Response Relationship, Drug; Drug Interactions; Drug Tolerance; Inflammation; Injections, Spinal; Interleukin-10; Male; Morphine; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Pain Threshold; Rats; Rats, Wistar; Receptors, Opioid, mu; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Spinal Cord; Up-Regulation

Endokinins are novel tachykinins encoded on the human TAC4 and consist of Endokinin A (EKA), B (EKB), C (EKC) and D (EKD). To date, the function of Endokinins in pain processing was not fully understood. Therefore the aim of this study was to investigate the effects of Endokinin A/B (EKA/B, the common C-terminal decapeptide in EKA and EKB) and Endokinin C/D (EKC/D, the common C-terminal duodecapeptide in EKC and EKD) on pain modulation at supraspinal level in mice. Intracerebroventricular (i.c.v.) administration of EKA/B (1, 3, 12, 20nmol/mouse) dose dependently induced potent analgesic effect. This effect could be fully antagonized by SR140333B but not SR48968C or SR142801. Naloxone could also block the analgesic effect, suggesting that this analgesic effect is related to opioid receptors. However, i.c.v. administration of EKA/B (10, 30, 100pmol/mouse) caused hyperalgesic effect significantly, with a "U" shape curve. Interestingly, the hyperalgesic effect induced by EKA/B could be attenuated by SR140333B, SR142801 but not SR48968C. I.c.v. administration of EKC/D (1, 3, 12, 20nmol/mouse) also dose dependently induced analgesic effect, which could not be blocked by SR48968C or SR142801 or naloxone. But to our astonishment, it could be significantly enhanced by SR140333B. More interestingly, the hyperalgesic effect induced by EKA/B could be significantly attenuated by EKC/D. In addition, the analgesic effect induced by co-administration of EKA/B and EKC/D was much less stronger than the effect of either EKA/B or EKC/D.

Topics: Analgesics; Animals; Antipsychotic Agents; Benzamides; Humans; Hyperalgesia; Injections, Intraventricular; Male; Mice; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Peptide Fragments; Piperidines; Receptors, Tachykinin; Tachykinins; Tropanes

The antinociceptive profile of St. John's Wort (SJW) was investigated in mice in a condition of acute thermal and chemical pain, together with the mechanism that might underlie this effect. A dried extract of SJW induced a prolonged antinociception that persisted for 120 minutes after administration. The thermal antinociception was prevented by naloxone and by the protein kinase C (PKC) activator PMA, whereas the chemical antinociception was prevented by PMA, remaining naloxone insensitive. A chloroform (CHL) and a methanol (MET) fraction, obtained to investigate the involvement of the SJW main components, hyperforin and hypericin/flavonoid, respectively, increased pain threshold with a time course comparable to the dried extract. The CHL antinociception was prevented by naloxone, whereas the MET antinociception was antagonized by PMA. Purified hyperforin and hypericin showed an antinociceptive efficacy comparable to CHL and MET, respectively. Conversely, flavonoids were devoid of any effect. The administration of yohimbine and atropine did not modify SJW, CHL and MET antinociception. These results indicate that both CHL and MET fractions mediate the SJW-induced antinociception. In particular, the presence of hypericin was fundamental to induce both thermal and chemical antinociception through the inhibition of the PKC activity, whereas hyperforin selectively produced a thermal opioid antinociception.. This article presents evidence of a persistent thermal and chemical antinociception of SJW that is mainly mediated by PKC-inhibiting mechanisms. These findings identify important targets for a longer-acting activation of endogenous pain systems and should potentially help clinicians who seek safe, tolerable, and prolonged treatments for pain relief.

Topics: Acetic Acid; Analgesics; Analgesics, Opioid; Animals; Anthracenes; Chromatography, High Pressure Liquid; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Routes; Drug Administration Schedule; Drug Compounding; Hypericum; Male; Mice; Naloxone; Naltrexone; Narcotic Antagonists; Pain; Pain Measurement; Pain Threshold; Perylene; Phorbol Esters; Phytotherapy; Protein Kinase C; Quercetin; Somatostatin; Spectrometry, Mass, Electrospray Ionization; Statistics, Nonparametric; Time Factors

In our previous study, Endokinin A/B (EKA/B, the common C-terminal decapeptide in Endokinin A and Endokinin B) was found to induce analgesic effect at high dose and nociception at low dose, while Endokinin C/D (EKC/D, the common C-terminal duodecapeptide in Endokinin C and Endokinin D) has analgesic effect only. So in this study an attempt was undertaken to investigate the interaction of EKA/B and EKC/D with Endomorphin-1 (EM-1) on antinociceptive effect at supraspinal level. Results showed that the antinociceptive effect of EM-1 was enhanced by high dose of EKA/B and abolished by low dose of EKA/B, while EKC/D could only enhance the analgesic effect. Mechanism studies showed that EKA/B blocked the antinociception of EM-1 by activating neurokinin-1 receptor (NK(1)), whose specific antagonist, SR140333B could fully block EKA/B-induced attenuation on the analgesic response of EM-1. Surprisingly, EKC/D could also block the same EKA/B-induced attenuation. Taken together, the different effects of EKA/B and EKC/D on the antinociception of EM-1 may pave the way for a new strategy on investigating the interaction between tachykinins and opioids on pain modulation.

Topics: Analgesics, Opioid; Animals; Humans; Male; Mice; Naloxone; Narcotic Antagonists; Neurokinin-1 Receptor Antagonists; Oligopeptides; Pain; Pain Measurement; Protein Isoforms; Protein Precursors; Tachykinins; Tropanes

The central nucleus of amygdala (CeA) is a very important brain structure involved in multiple physiological functions, especially in pain modulation. There are high densities of galanin and galanin receptors found in the CeA. The present study was performed to explore the antinociceptive effects of galanin in the CeA of rats, and possible involvements of opioid receptors in the galanin-induced antinociception. Intra-CeA injection of galanin induced dose-dependent increases in hindpaw withdrawal latencies (HWLs) to noxious thermal and mechanical stimulations in rats. Interestingly, the amtinociceptive effect induced by intra-CeA injection of galanin was blocked by intra-CeA injection of naloxone, a common opioid receptor antagonist, indicating an involvement of opioid receptors in the galanin-induced antinociception in the CeA of rats. Moreover, intra-CeA injection of either selective mu-opioid receptor antagonist beta-funaltrexamine (beta-FNA) or delta-opioid receptor antagonist naltrindole, but not kappa-opioid receptor antagonist nor-binaltorphimine (nor-BNI), significantly attenuated the galanin-induced increases in HWLs in the CeA of rats. Taken together, the results demonstrate that galanin induces antinociceptive effects in the CeA of rats, and both mu- and delta-opioid receptors are involved in the galanin-induced antinociception.

Topics: Amygdala; Animals; Galanin; Hindlimb; Hot Temperature; Male; Naloxone; Naltrexone; Narcotic Antagonists; Pain; Pain Measurement; Physical Stimulation; Rats; Rats, Wistar; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Time Factors

The relationship between pain severity and the extent of injury to a peripheral nerve remains elusive. In this study, we compared the pain behavior resulting from partial (1/3-1/2 thickness) and full L5 spinal nerve ligation (SNL) in rats. The decrease in paw withdrawal threshold (PWT) to mechanical stimuli in the hindpaw ipsilateral to the injury was comparable in the two groups on days 3-21 post-injury. However, the decreased PWT recovered earlier in the partial SNL group than in the full SNL group. These observations suggest that the duration of neuropathic pain behavior, but not the early development of mechanical allodynia, is dependent on the extent of nerve injury. On days 6 and 15 post-injury, when the mechanical allodynia was similar in the two groups, systemic morphine induced a greater reduction of mechanical allodynia in the partial SNL group than in the full SNL group. Furthermore, in partial SNL rats, at post-injury time points when they had largely recovered from the neuropathic pain state, systemic administration of naloxone hydrochloride (day 53) or naloxone methiodide (a non-selective peripherally acting opioid receptor antagonist; day 64) or intra-plantar injection of naloxone methiodide rekindled mechanical pain hypersensitivity in the ipsilateral hindpaw, suggesting a prolonged activation of endogenous opioidergic pain-inhibition. Therefore, partial SNL in rats may represent an efficient model for studying the mechanisms of neuropathic pain, testing effects of analgesic/antihyperalgesic drugs, and understanding endogenous pain-inhibitory mechanisms that lead to reversal of the pain behavior with time.

Topics: Analgesics, Opioid; Animals; Constriction, Pathologic; Disease Models, Animal; Ligation; Lumbosacral Region; Male; Morphine; Naloxone; Narcotic Antagonists; Pain; Peripheral Nervous System Diseases; Physical Stimulation; Rats; Rats, Sprague-Dawley; Spinal Nerves; Touch

Habituation to repetitive painful stimulation may represent an important protection mechanism against the development of chronic pain states. However, the exact neurobiological mechanisms of this phenomenon remain unclear. In this study we (i) explore the somatotopic specificity of pain attenuation over time and (ii) investigate the role of the endogenous opioid system in its development. We investigated 24 healthy volunteers with a paradigm of daily painful stimulation of the left volar forearm for 1 week. Habituation was assessed by comparing pain-related responses (ratings and thresholds) between days 1 and 8. To test whether a repetition-dependent attenuation of pain is restricted to the site of stimulus application or induces additional systemic effects indicative of a central mechanism, we also measured pain-related responses at the contralateral arm and the left leg. To assess the role of the endogenous opioid system in this mechanism, we used the opioid-receptor antagonist naloxone in a double-blind design. Repetitive painful stimulation over several days resulted in a significant habituation to pain at the site of daily stimulation. In addition, we also observed significant pain attenuation at the non-stimulated limbs. This effect was less pronounced at the untreated arm compared to the treated arm and even weaker in the leg, displaying a significant Stimulation-Site x Time interaction. The development of pain habituation was unaffected by the opioid antagonist naloxone. Taken together, these results strongly support the role of central components in the mechanism of pain habituation that do not directly involve the endogenous opioid system.

Topics: Adult; Habituation, Psychophysiologic; Humans; Male; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Pain Threshold; Physical Stimulation; Time Factors; Young Adult

Bowdichia virgilioides Kunth (Family Fabaceae) is a plant that is distributed widely in the tropical and subtropical regions of the world. In the northeast region of Brazil, where B. virgilioides is called "sucupira-preta," the stem bark is used in folk medicine to treatment of inflammatory and painful diseases. This study aimed to evaluate the antinociceptive activity of the aqueous extract of the dried stem bark of B. virgilioides. The aqueous extract of B. virgilioides in doses of 50, 100, 200, and 400 mg/kg was administered orally 1 hour prior to pain induction. Only the doses of 200 and 400 mg/kg produced an inhibition by 61% and 74%, respectively, in the number of abdominal writhings induced by acetic acid. This antinociceptive effect was not reversed by pretreatment with naloxone, indicating that the effect is not associated with the activation of opioid receptors. In the formalin test, using the two highest doses, the extract had no effect in the first phase but produced an analgesic effect on the second phase with the inhibition of licking time (P < .001). In the hot plate test, no effect was seen at the dose of 400 mg/kg p.o. Our findings show that B. virgilioides contains pharmacologically active constituents that possess antinociceptive activity justifying its popular therapeutic use in treating conditions associated with the painful conditions.

Topics: Acetic Acid; Analgesics; Animals; Behavior, Animal; Fabaceae; Formaldehyde; Male; Mice; Naloxone; Narcotic Antagonists; Pain; Phytotherapy; Plant Bark; Plant Extracts; Plant Stems

The activation of CB(2) receptors induces analgesia in experimental models of chronic pain. The present experiments were designed to study whether the activation of peripheral or spinal CB(2) receptors relieves thermal hyperalgesia and mechanical allodynia in two models of bone cancer pain.. NCTC 2472 osteosarcoma or B16-F10 melanoma cells were intratibially inoculated to C3H/He and C57BL/6 mice. Thermal hyperalgesia was assessed by the unilateral hot plate test and mechanical allodynia by the von Frey test. AM1241 (CB(2) receptor agonist), AM251 (CB(1) receptor antagonist), SR144528 (CB(2) receptor antagonist) and naloxone were used. CB(2) receptor expression was measured by Western blot.. AM1241 (0.3-10 mg.kg(-1)) abolished thermal hyperalgesia and mechanical allodynia in both tumour models. The antihyperalgesic effect was antagonized by subcutaneous, intrathecal or peri-tumour administration of SR144528. In contrast, the antiallodynic effect was inhibited by systemic or intrathecal, but not peri-tumour, injection of SR144528. The effects of AM1241 were unchanged by AM251 but were prevented by naloxone. No change in CB(2) receptor expression was found in spinal cord or dorsal root ganglia.. Spinal CB(2) receptors are involved in the antiallodynic effect induced by AM1241 in two neoplastic models while peripheral and spinal receptors participate in the antihyperalgesic effects. Both effects were mediated by endogenous opiates. The use of drugs that activate CB(2) receptors could be a useful strategy to counteract bone cancer-induced pain symptoms.

Topics: Analgesics; Animals; Bone Neoplasms; Camphanes; Cannabinoids; Cell Line, Tumor; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Ganglia, Spinal; Humans; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Naloxone; Osteosarcoma; Pain; Pain Measurement; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB2; Spinal Cord

Diffuse noxious inhibitory controls (DNIC) can be produced by different types of conditioning stimuli, but the analgesic properties and underlying mechanisms remain unclear. The aim of this study was to differentiate the induction of DNIC analgesia between noxious electrical and inflammatory conditioning stimuli.. First, rats subjected to either a supramaximal electrical stimulation or an injection of high-dose formalin in the hind limb were identified to have pain responses with behavioral evidence and spinal Fos-immunoreactive profiles. Second, suppression of tail-flick latencies by the two noxious stimuli was assessed to confirm the presence of DNIC. Third, an opioid receptor antagonist (naloxone) and an alpha2-adrenoreceptor antagonist (yohimbine) were injected, intraperitoneally and intrathecally respectively, before conditioning noxious stimuli to test the involvement of descending inhibitory pathways in DNIC-mediated analgesia.. An intramuscular injection of 100 microl of 5% formalin produced noxious behaviors with cumulative pain scores similar to those of 50 microl of 2% formalin in the paw. Both electrical and chemical stimulation significantly increased Fos expression in the superficial dorsal horns, but possessed characteristic distribution patterns individually. Both conditioning stimuli prolonged the tail-flick latencies indicating a DNIC response. However, the electrical stimulation-induced DNIC was reversed by yohimbine, but not by naloxone; whereas noxious formalin-induced analgesia was both naloxone- and yohimbine-reversible.. It is demonstrated that DNIC produced by different types of conditioning stimuli can be mediated by different descending inhibitory controls, indicating the organization within the central nervous circuit is complex and possibly exhibits particular clinical manifestations.

Topics: Adrenergic alpha-Antagonists; Afferent Pathways; Analgesia; Analysis of Variance; Animals; Area Under Curve; Conditioning, Psychological; Electric Stimulation; Formaldehyde; Immunohistochemistry; Male; Naloxone; Narcotic Antagonists; Neural Inhibition; Pain; Rats; Rats, Sprague-Dawley; Yohimbine

Pain complaints are common among individuals with opioid dependence. However, few studies investigate pain during opioid detoxification or the impact this pain has on continued opioid use. This secondary analysis utilized data from two Clinical Trials Network randomized controlled trials of buprenorphine-naloxone for short-term opioid detoxification to examine the extent to which pain was associated with continued opioid use during and immediately following a 13-day detoxification protocol. At follow-up, more severe pain was associated with a greater number of self-reported days of opioid use during the prior 30 days (p < .05) but was not associated with urine toxicology results collected at follow-up. These results, although mixed, have potentially important clinical implications for assessing and addressing pain during opioid detoxification. Pain that is experienced during and immediately following medically monitored detoxification may be associated with continued opioid use. These findings lend further support for continued research on pain among patients with opioid dependence.

Topics: Adult; Analgesics, Opioid; Buprenorphine; Buprenorphine, Naloxone Drug Combination; Drug Combinations; Female; Follow-Up Studies; Humans; Male; Middle Aged; Naloxone; Narcotic Antagonists; Opioid-Related Disorders; Pain; Randomized Controlled Trials as Topic; Severity of Illness Index; Substance Withdrawal Syndrome

Several species of the genus Hypericum (Guttiferae) have been used for analgesic purposes all over the world and some of them have demonstrated to possess this effect in rodents. This study describes the antinociceptive effect of the cyclohexane extract from aerial parts of H. polyanthemum (POL) as well as of benzopyrans, 6-isobutyryl-5,7-dimethoxy-2,2-dimethyl-benzopyran (HP1), 7-hydroxy-6-isobutyryl-5-methoxy-2,2-dimethyl-benzopyran (HP2), and 5-hydroxy-6-isobutyryl-7-methoxy-2,2-dimethyl-benzopyran (HP3), which are the main components of POL. The antinociceptive effect was evaluated through hot-plate and writhing tests in mice, and the opioid system involvement was assessed by using naloxone (2.5 mg/kg, s.c.) antagonism. In the hot-plate test, POL (45, 90, 180 mg/kg, p.o) showed a dose-dependent effect, and out of the benzopyrans only HP1 (30, 60, 90 mg/kg, i.p.) was active. Its effect was also dose-dependent, with the maximum reached at 60 mg/kg. HP1 60 mg/kg (p.o.) also inhibited acetic acid-induced writhing in 58%. The pretreatment with naloxone abolished the antinociceptive effect of HP1 60 mg/kg (i.p) in the hot plate. Furthermore, the H. polyanthemum cyclohexane extract and HP1 did not affect the mice performance in the rota-rod apparatus suggesting that at antinociceptive doses they do not present gross neurotoxicity nor induce motor impairment. From these data it is reasonable to assume that the benzopyran HP1 accounts for the H. polyanthemum cyclohexane extract antinociceptive effect, and this effect is, at least in part, mediated by an opioid-like mechanism.

Topics: Acetic Acid; Analgesics, Opioid; Animals; Behavior, Animal; Benzopyrans; Dose-Response Relationship, Drug; Hot Temperature; Hypericum; Male; Mice; Mice, Inbred Strains; Naloxone; Narcotic Antagonists; Pain; Phytotherapy; Plant Components, Aerial; Plant Extracts

Chronic pain has a marked negative impact on quality of life. Opioid treatment is often effective in controlling this pain, but it has numerous side-effects, particularly affecting bowel function.. The objective of the study was to evaluate the efficacy and safety of combined prolonged-release (PR) oxycodone and naloxone for the treatment of chronic pain under conditions of daily practice.. This is a multi-center, prospective, non-interventional, observational study. Analgesic efficacy and bowel function were assessed in patients suffering from long-lasting, severe chronic pain of different etiology (cancer and non-cancer) treated with combined PR oxycodone/PR naloxone and observed for 4 weeks. Pain was evaluated using the Brief Pain Inventory (BPI-SF) and constipation symptoms due to opioid treatment using the Bowel Function Index (BFI). Descriptive data are presented based on observed cases, efficacy and tolerability data additionally based on completely documented patients (for each parameter at least more than 2000 patients).. This trial was registered with the German Federal Institute for Drugs and Medical Devices (BfArM), study code: OXN9002.. A total of 7836 patients were recruited in 6496 centers. Strongest pain was reduced by an average of 2.9 points on an 11-point numeric rating scale (p < 0.001, evaluation populations n = 4271 or 2454, respectively). A progressive rise of patients without pain during the 24 hours prior to each evaluation (first visit, 11.6%; final visit, 33.8%; p < 0.001, evaluation populations n = 4413 or 3014, respectively) was observed. Bowel function improved significantly, indicated by a decrease of the bowel function index from 38.2 +/- 30.9 to 15.1 +/- 18.6 (p < 0.001, evaluation population n = 7640 or 6769, respectively) on a numeric scale of 0-100. Opioid-pretreated patients presented a marked decrease of constipation from 71% at the first visit to 34.1% at the final visit (p < 0.001, evaluation populations n = 5751 or 5123, respectively). Efficacy and tolerability were reported as good or very good by 84% and 87% of patients (evaluation populations n = 7590 and 7577, respectively). There were 4526 adverse events in 1566 patients (20.0%) with 3386 classified as adverse drug reactions; 177 patients (2.3%) suffered serious adverse events which were classified as serious adverse drug reactions in 51 cases.. PR oxycodone/PR naloxone achieved good pain control and significantly reduced constipation and associated opioid-induced gastrointestinal symptoms in this observational 4-weeks-trial.

Topics: Aged; Aged, 80 and over; Analgesics, Opioid; Delayed-Action Preparations; Drug Therapy, Combination; Female; Germany; Humans; Intestines; Male; Middle Aged; Naloxone; Oxycodone; Pain; Prospective Studies; Quality of Life; Treatment Outcome

Vocalization generated by the application of a noxious stimulus is an integrative response related to the affective-motivational component of pain. The rostral ventromedial medulla (RVM) plays an important role in descending pain modulation, and opiates play a major role in modulation of the antinociception mediated by the RVM. Further, it has been suggested that morphine mediates antinociception indirectly, by inhibition of tonically active GABAergic neurons. The current study evaluated the effects of the opioids and GABA agonists and antagonists in the RVM on an affective-motivational pain model. Additionally, we investigated the opioidergic-GABAergic interaction in the RVM in the vocalization response to noxious stimulation. Microinjection of either morphine (4.4nmol/0.2microl) or bicuculline (0.4nmol/0.2microl) into the RVM decreased the vocalization index, whereas application of the GABA(A) receptor agonist, muscimol (0.5nmol/0.2microl) increased the vocalization index during noxious stimulation. Furthermore, prior microinjection of either the opioid antagonist naloxone (2.7nmol/0.2microl) or muscimol (0.25nmol/0.2microl) into the RVM blocked the reduction in vocalization index induced by morphine. These observations suggest an antinociceptive and pro-nociceptive role of the opioidergic and GABAergic neurotransmitters in the RVM, respectively. Our data show that opioids have an antinociceptive effect in the RVM, while GABAergic neurotransmission is related to the facilitation of nociceptive responses. Additionally, our results indicate that the antinociceptive effect of the opioids in the RVM could be mediated by a disinhibition of tonically active GABAergic interneurons in the downstream projection neurons of the descending pain control system; indicating an interaction between the opioidergic and GABAergic pathways of pain modulation.

Topics: Analgesics, Opioid; Animals; Bicuculline; GABA Agonists; GABA Antagonists; gamma-Aminobutyric Acid; Guinea Pigs; Male; Medulla Oblongata; Morphine; Muscimol; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Vocalization, Animal

Topics: Analgesics, Opioid; Buprenorphine; Buprenorphine, Naloxone Drug Combination; Drug Tolerance; Humans; Methadone; Naloxone; Opioid-Related Disorders; Pain; Pain Measurement

Opioids provide effective analgesia in adult patients with painful inflammatory diseases. The proposed mechanism of action is the activation of peripheral opioid receptors, which may be up-regulated in such conditions. Here, by using a chronic inflammation model, namely subplantar injection of Complete Freund's adjuvant, we show a peripheral synergistic interaction between the histamine H(3) receptor agonist R-(alpha)-methylhistamine and fentanyl on the inhibition of thermal hyperalgesia and of peripheral substance P accumulation. Firstly, dose-related effects obtained for the subplantar antinociceptive effect of fentanyl (0.05-1 microg) in the presence of a fixed dose of R-(alpha)-methylhistamine (12.5 microg) showed a shift to the left when compared to that obtained with fentanyl alone. In a similar way, the subcutaneous administration of fentanyl (0.005-0.1mg/kg) plus a fixed dose of R-(alpha)-methylhistamine (0.5mg/kg) induced a supra additive effect on the inhibition of substance P accumulation in the hind-paw skin of inflamed mice. Interestingly, when a neurokinin-1 receptor antagonist was co-administered, the antinociceptive effects of the combined treatment were potentiated. The peripheral adjuvant effect of R-(alpha)-methylhistamine on fentanyl antinociception and inhibition of substance P accumulation was also demonstrated by means of opioid and histamine H(3) receptors selective antagonists: first, naloxone blockade of fentanyl-mediated effects were partially reversed by co-administration of R-(alpha)-methylhistamine, and second, thioperamide partially antagonised the combined R-(alpha)-methylhistamine/fentanyl effects. Overall, our results clearly show that R-(alpha)-methylhistamine enhances fentanyl effects at peripheral sites, and that the control of substance P levels might be one of the mechanisms responsible of such interaction.

Topics: Analgesics; Animals; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Fentanyl; Freund's Adjuvant; Histamine Agonists; Hyperalgesia; Inflammation; Male; Methylhistamines; Mice; Naloxone; Pain; Piperidines; Receptors, Histamine H3; Skin; Substance P

Like other endogenous enkephalinase inhibitors, human opiorphin peptide (QRFSR) attenuates catabolism of enkephalins and appears to be a promising therapeutic, displaying antinociceptive action in several pain models. However, its opioid-like side-effect profile is insufficiently characterized. In the present set of experiments, acute intraperitoneal administration of opiorphin produced an antinociceptive effect in the tail-flick test in mice (0.3mg/kg) and this action was inhibited by opioid receptor antagonist naloxone (3mg/kg). Repeated treatment with opiorphin changed the antinociceptive response neither to itself nor to morphine, suggesting the lack of tolerance and morphine cross-tolerance, respectively. Repeated treatment with opiorphin (3mg/kg) also failed to produce opioid dependence. Opiorphin (0.3 or 1mg/kg) produced no rewarding effects in the conditioned place preference test. However, at the dose of 3mg/kg, the peptide produced antidepressant-like effect in the forced swim test, and it did not affect locomotor activity. The present set of results confirms the beneficial effects of opiorphin in pain management, and suggests a lack of opioid-like side effects as well as the presence of antidepressant-like actions of this peptide.

Topics: Analgesics, Opioid; Animals; Central Nervous System Agents; Conditioning, Classical; Depression; Humans; Locomotion; Male; Mice; Mice, Inbred C57BL; Morphine; Naloxone; Narcotic Antagonists; Neuropsychological Tests; Oligopeptides; Pain; Receptors, Opioid; Salivary Proteins and Peptides; Space Perception; Substance-Related Disorders

The present study examined the hyponociceptive effect of swimming exercise in a chemical behavioral model of nociception and the mechanisms involved in this effect. Male mice were submitted to swimming sessions (30 min/d for 5 days). Twenty-four hours after the last session, we noticed that swimming exercise decreased the number of abdominal constriction responses caused by acetic acid compared with the nonexercised group. The hyponociception caused by exercise in the acetic acid test was significantly attenuated by intraperitoneal (i.p.) pretreatment of mice with naloxone (a nonselective opioid receptor antagonist, 1 mg/kg), ρ-chlorophenylalanine methyl ester (PCPA, an inhibitor of serotonin synthesis, 100 mg/kg once a day for 4 consecutive days), and by bilateral adrenalectomy. Collectively, the present results provide experimental evidences indicating for the first time that high-intensity extended swimming exercise reduces pain-related behavior in mice. The mechanisms involve an interaction with opioid and serotonin systems. Furthermore, endogenous opioids released by adrenal glands probably are involved in this effect.. Our results indicate that high-intensity extended exercise endogenously controls acute pain by activation of opioidergic and serotonergic pathways. Furthermore, these results support the use of exercise as a nonpharmacological approach for the management of acute pain.

Topics: Acetic Acid; Animals; Behavior, Animal; Fenclonine; Irritants; Male; Mice; Naloxone; Narcotic Antagonists; Opioid Peptides; Pain; Pain Threshold; Serotonin; Swimming

Docosahexaenoic acid (DHA), an omega-3 polyunsaturated fatty acid (n-3 PUFAs), is an essential polyunsaturated fatty acid in the central nervous system, and possesses many physiological functions in neurodegenerative diseases. Previously, there are some reports that n-3 PUFAs contribute to pain relief. As the antinociceptive effect of DHA alone has not been reported, this study examined the antinociceptive effect of DHA on various pain stimuli. To evaluate the antinociceptive effect of DHA on thermal and chemical nociception, we employed the tail flick test, acetic acid writhing test and formalin test in mice. DHA was orally administrated at 5, 15 and 25 mmol/kg at 30 min before measurement. DHA administration dose-dependently exerted an antinociceptive effect against thermal and chemical stimulation in comparison to the control olive oil administration. These effects of DHA were abolished when mice were pretreated with naloxone, an opioid receptor antagonist. These findings suggest that DHA has opiod receptor-mediated pain control activities, and may provide valuable information towards an advanced therapeutic approach for pain control.

Topics: Acetic Acid; Analgesics; Animals; Behavior, Animal; Docosahexaenoic Acids; Dose-Response Relationship, Drug; Formaldehyde; Hot Temperature; Male; Mice; Naloxone; Narcotic Antagonists; Pain; Tail

Cholestasis is associated with changes including analgesia. The histaminergic system regulates pain perception. The involvement of histamine H(3) receptors in modulation of nociception in a model of elevated endogenous opioid tone, cholestasis, was investigated in this study using immepip and thioperamide as selective H(3) receptor agonist and antagonist respectively. Cholestasis was induced by ligation of main bile duct using two ligatures and transsection the duct between them. Cholestatic rats had increased tail-flick latencies (TFLs) compared to non-cholestatics. Administration of immepip (5 and 30mg/kg) and thioperamide (10 and 20mg/kg) to the cholestatic groups significantly increased and decreased TFLs compared to the saline treated cholestatic group. Immepip antinociception in cholestatic animals was attenuated by co-administration of naloxone. Immepip and thioperamide injections into non-cholestatic animals did not alter TFLs. At the doses used here, none of the drugs impaired motor coordination, as revealed by the rotarod test. The present data show that the histamine H(3) receptor system may be involved in the regulation of nociception during cholestasis in rats.

Topics: Animals; Behavior, Animal; Bile Ducts; Cholestasis; Histamine Agonists; Histamine H3 Antagonists; Imidazoles; Male; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Piperidines; Postural Balance; Rats; Rats, Wistar; Reaction Time; Receptors, Histamine H3

Although morphine is a very effective analgesic, its narrow therapeutic index and severe side effects limit its therapeutic use. Previous studies indicated that the pharmacological responses of opioids are modulated by genetic and pharmacological invalidation of tachykinin receptors. Here we address the role of substance P and neurokinin A, which are both encoded by the tachykinin 1 (tac1) gene, as modulators of opioid effects.. The analgesic and side effect potential of morphine was compared between wild-type and tac1 null mutant mice.. Morphine was a more potent analgesic in tac1 null mutant mice, that is, in the absence of substance P/neurokinin A signalling. Interestingly, the most serious side effect of acute morphine, that is respiratory depression, was reduced in tac1(-/-) animals. Comparing the addictive potential of morphine in wild-type and knockout animals we found that morphine preference was similar between the genotypes. However, the aversive effect of withdrawal precipitated by naloxone in morphine-dependent animals was significantly reduced in tac1 knockout mice. Behavioural sensitization, the underlying mechanism of addiction, was also significantly lower in tac1(-/-) mice.. The analgesic potential of morphine was increased in tac1 knockout mice. In contrast, both the ventilatory suppressing effect and the addictive potential of morphine were reduced. These results suggest that reducing activity of the tachykinin system may be a possible strategy to improve the pharmacological potential of morphine.

Topics: Analgesics, Opioid; Animals; Behavior, Addictive; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Morphine; Naloxone; Narcotic Antagonists; Neurokinin A; Pain; Pain Measurement; Respiratory Insufficiency; Substance P; Tachykinins

Neuropeptide S (NPS), a recently discovered bioactive peptide, was reported to regulate arousal, anxiety, locomotion, feeding behaviors, memory, and drug addiction. NPS receptor (NPSR) mRNA was found in several brain regions related to descending control system of pain, including the periaqueductal gray (PAG). Our previous study had shown that NPS could produce antinociception in mice. The present study was designed to evaluate whether NPS may produce antinociceptive effect observed in the mouse formalin test, a model of inflammatory pain. NPS (0.1-100 pmol) administrated intracerebroventricularly (i.c.v.) dose-dependently attenuated both first-phase and second-phase nociceptive behaviors induced by paw formalin injection. NPS (10 pmol, i.c.v.)-elicited antinociceptive effect was counteracted by co-injection with 1000 and 10,000 pmol [D-Val(5)]NPS, which alone induced neither hyperalgesia nor antinociception. The antinociception induced by NPS (10 pmol, i.c.v.) was not affected by naloxone (i.p., 10 mg/kg) and naloxone alone had no effect in the formalin test. In addition, compared to the saline (i.c.v.) treated group, NPS (10 pmol, i.c.v.) treated group increased c-Fos protein expression in nearly all subdivisions of the PAG in the formalin-injected mice. The above results revealed that NPS could produce antinociception in the formalin test through NPSR, which may be involved in the activation of PAG, suggesting that NPS-NPSR system may be a potential target for developing new analgesic drugs.

Topics: Analgesics; Animals; Behavior, Animal; Dose-Response Relationship, Drug; Male; Mice; Naloxone; Narcotic Antagonists; Neuropeptides; Pain; Pain Measurement; Periaqueductal Gray; Proto-Oncogene Proteins c-fos; Receptors, G-Protein-Coupled

The present study analyzes the involvement of the endogenous opioid system in the antinociceptive effects produced in mammals after alpha- or beta- scorpion toxin injections. The analgesic effects on mice of the alpha-anatoxin Amm VIII, a weak modulator of Na(v)1.2 channel, and the depressant insect-selective beta-toxin LqqIT2 were evaluated by intraperitoneal route. The two toxins increased hot plate and tail flick latencies in a dose-dependent manner. We also compared the effects of the toxins with those obtained after acetic acid administration or cold-water tail immersion, which both induce pain relief through the activation of diffuse noxious inhibitory controls (DNIC) and the release of endogenous opioids. The increased latencies obtained with the toxins, acetic acid, or cold-water tail immersion were partly reversed by the co-administration of the opioid receptor antagonist naloxone. Finally, AmmVIII, LqqIT2, or acetic acid, induced increased c-fos mRNA expression in spinal cord. This increase disappeared when the toxins were co-injected with acetic acid. In conclusion, we show for the first time that an alpha-anatoxin exhibits a potent analgesic activity and confirm that depressant beta-toxins are able to reduce nociception. We hypothesize that pain relief induced by these scorpion toxins may implicate the activation of an endogenous opioid system and may be partly the result of a counter irritation phenomenon, which could be due to the activation of DNIC.

Topics: Analgesics, Opioid; Animals; Male; Mice; Naloxone; Narcotic Antagonists; Opioid Peptides; Pain; Scorpion Venoms; Sodium Channels; Spinal Cord

A profound tachyphylaxis of the acute nocifensive flinching (pain) response to subcutaneous injection of endothelin-1 (ET-1) into the hind paw footpad is shown by the reduced response to a second injection. Flinching from the second injection was 20% +/- 5%, 57% +/- 18%, 79% +/- 35%, and 100% +/- 17% of that from the first injection (both 200 micromol/L, 2 nmol) at respective intervals of 24, 30, 48, and 72 h. Inhibition of afferent impulses by local anesthesia of the sciatic nerve, reducing initial flinching to 6%-13% of control, did not affect the tachyphylaxis for the second injection at 24 h. There was no cross-desensitization between formalin and ET-1 injected sequentially into the same paw. Suppression of descending inhibitory effects from endogenous opiates by naloxone (5-8 mg/kg, i.p.), given 30 min before the second ET-1 injection, did not prevent tachyphylaxis. Diffuse effects caused by an initial subcutaneous ET-1 injection into the tail or forepaw resulted in sensitization of the response to ET-1 in the hind paw, rather than tachyphylaxis. In contrast, selective inhibition of local ETA receptors during the initial administration of ET-1, by the antagonist BQ-123 (3.2 mmol/L), reduced tachyphylaxis of nocifensive flinching. Therefore, prolonged pain tachyphylaxis is not due to reduced responsiveness of the CNS, but rather depends on the functional sensitivity or availability of peripheral ET(A) receptors.

Topics: Anesthetics; Animals; Central Nervous System; Endothelin A Receptor Antagonists; Endothelin-1; Foot; Formaldehyde; Hindlimb; Hyperalgesia; Male; Naloxone; Pain; Pain Measurement; Peptides, Cyclic; Rats; Rats, Sprague-Dawley; Sciatic Nerve; Tachyphylaxis; Time Factors; Touch

[Tyr(6)]-gamma2-MSH(6-12) with a short effecting time of about 20 min is one of the most potent rMrgC receptor agonists. To possibly increase its potency and metabolic stability, a series of analogues were prepared by replacing the Tyr(6) residue with the non-canonical amino acids 3-(1-naphtyl)-L-alanine, 4-fluoro-L-phenylalanine, 4-methoxy-L-phenylalanine and 3-nitro-L-tyrosine. Dose-dependent nociceptive assays performed in conscious rats by intrathecal injection of the MSH peptides showed [Tyr(6)]-gamma2-MSH(6-12) hyperalgesic effects at low doses (5-20 nmol) and analgesia at high doses (100-200 nmol). This analgesic activity is fully reversed by the kyotorphin receptor-specific antagonist Leu-Arg. For the two analogues containing in position 6, 4-fluoro-L-phenylalanine and 3-nitro-L-tyrosine, a hyperalgesic activity was not observed, while the 3-(1-naphtyl)-L-alanine analogue at 10 nmol dose was found to induce hyperalgesia at a potency very similar to gamma2-MSH(6-12), but with longer duration of the effect. Finally, the 4-methoxy-L-phenylalanine analogue (0.5 nmol) showed greatly improved hyperalgesic activity and prolonged effects compared to the parent [Tyr(6)]-gamma2-MSH(6-12) compound.

Topics: Analgesics; Animals; Dipeptides; gamma-MSH; Hyperalgesia; Male; Naloxone; Pain; Pain Measurement; Peptide Fragments; Rats; Rats, Wistar

Hofmeisteria schaffneri (Asteraceae) is a medicinal plant widely commercialized in the most important Markets of Mexico City for the treatment of gastro-intestinal complaints and skin afflictions.. The main goals of this study were to establish the potential acute toxicity and the antinociceptive activity in animal models of several preparations and compounds from Hofmeisteria schaffneri.. The aqueous and organic extracts as well as the essential oil of Hofmeisteria schaffneri were prepared by infusion, maceration and hydrodistillation, respectively. Investigation of the acute toxicity was accomplished by the Lorke method. The antinociceptive effect was assessed using the writhing and the hot plate tests. Natural compounds were isolated by standard phytochemical procedures. In addition, a few thymol esters were prepared by chemical synthesis. The stability of natural and synthetic esters was qualitatively analyzed by measuring their susceptibility to hydrolysis by pig liver estearase and mouse plasma at 37 degrees C.. The LD(50) for each preparation tested was higher than 5000 mg/kg revealing that they were not toxic to mice after exposure for short space of time. On the other hand, the extracts showed significant antinociceptive effect when tested in the hot plate model. The most active natural product as antinociceptive agent was hofmeisterin III (1) which also was the most stable in the stability study. Its pharmacological effect seems to be partially mediated by an opioid mechanism since naloxone inhibits its action. Using compound 1 as a lead molecule, several synthetic thymol esters were prepared and only compounds 13, 15 and 17 were antinoceptive at the dose of 1 mg/kg.. The present investigation provided evidence of the efficacy of several preparations of Hofmeisteria schaffneri as antinociceptive agents. The most active preparation was the essential oil which contained large amount of hofmeisterin III (1) and other thymol derivatives. Some novel synthetic analogs of hofmeisterin III with antinociceptive properties were discovered. The nature of the ester chain of these analogs did not have a clear impact on the antinociceptive activity. The phyto-preparations analyzed in this study were not toxic to mice according to the Lorke's test; therefore considering their long term use of the plant they might be secure for human consumption.

Topics: Analgesics; Animals; Asteraceae; Hot Temperature; Lethal Dose 50; Male; Mice; Mice, Inbred ICR; Naloxone; Narcotic Antagonists; Oils, Volatile; Pain; Phytotherapy; Plant Components, Aerial; Plant Extracts; Thymol

Little is known about analgesia in lower vertebrates such as the Speke's hinged tortoise (Kinixy's spekii), yet of late they are increasingly being adopted as pets. The effects of morphine (5, 7.5, 10 and 20 mg/kg), pethidine (10, 20, and 50 mg/kg) and naloxone (5 mg/kg) on nociception induced by the formalin test (12.5%, 100 microL) were studied in the Speke's hinged tortoise. Formalin induced a monophasic limb retraction behavioural response and its duration was recorded. The behaviour lasted for 16.4 +/- 0.8 min. Morphine (7.5, 10 and 20 mg/kg) and pethidine (20 and 50 mg/kg) induced significant decrease in the duration of limb retraction in the formalin test. The anti-nociceptive effects were naloxone (5 mg/kg) reversible. The data suggest that the formalin test is a good test for studying nociception and anti-nociception in tortoises and that the opioidergic system plays a role in the control of nociception in these animals.

Topics: Analgesics, Opioid; Animals; Dose-Response Relationship, Drug; Female; Male; Meperidine; Morphine; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Turtles

Long-term use of morphine can cause neuronal dystrophic changes in specific areas of the brain. These changes may underlie the mechanism for developing morphine antinociceptive tolerance and physical dependence. We evaluated the effect of tianeptine, an antidepressant with prominent neuroprotective and neuroplastic properties, on the development of morphine antinociceptive tolerance and physical dependence. Male C57BL/6 mice were rendered tolerant to or dependent on morphine by subcutaneously injecting them with morphine (10 mg/kg) and intraperitoneally with saline or tianeptine (1, 3, or 5 mg/kg) twice daily for 6 days. The mice were given a daily tail-flick test 1 h after the first morphine injection to evaluate the development of their tolerance to morphine antinociception. To evaluate their physical dependence on morphine, 3 h after the final morphine injection on day 6, naloxone-HCl-precipitated (2 mg/kg, intraperitoneally) withdrawal symptoms were counted for 30 min, and body weight was checked 1 h after the naloxone injection. Tianeptine per se produced no antinociception, neither did it modify the antinociception produced by morphine, nor did it evoke the behavioral responses different from those in the saline controls. The combination of tianeptine with morphine significantly reduced the development of morphine antinociceptive tolerance and suppressed the incidence of naloxone-precipitated withdrawal symptoms. We conclude that tianeptine is an effective inhibitor of morphine-induced antinociceptive tolerance and physical dependence in mice. Our results would imply that comedication with tianeptine and morphine might benefit those who need long-term morphine treatment.

Topics: Analgesics, Opioid; Animals; Antidepressive Agents, Tricyclic; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Tolerance; Male; Mice; Mice, Inbred C57BL; Morphine; Morphine Dependence; Naloxone; Narcotic Antagonists; Pain; Substance Withdrawal Syndrome; Thiazepines

Tuberoinfundibular peptide of 39 residues (TIP39) synthesizing neurons at the caudal border of the thalamus and in the lateral pons project to areas rich in its receptor, the parathyroid hormone 2 receptor (PTH2R). These areas include many involved in processing nociceptive information. Here we examined the potential role of TIP39 signaling in nociception using a PTH2R antagonist (HYWH) and mice with deletion of TIP39's coding sequence or PTH2R null mutation. Intracerebroventricular (icv) infusion of HYWH significantly inhibited nociceptive responses in tail-flick and hot-plate tests and attenuated the nociceptive response to hindpaw formalin injection. TIP39-KO and PTH2R-KO had increased response latency in the 55°C hot-plate test and reduced responses in the hindpaw formalin test. The tail-flick test was not affected in either KO line. Thermal hypoalgesia in KO mice was dose-dependently reversed by systemic administration of the cannabinoid receptor 1 (CB1) antagonist rimonabant, which did not affect nociception in wild-type (WT). Systemic administration of the cannabinoid agonist CP 55,940 did not affect nociception in KO mice at a dose effective in WT. WT mice administered HYWH icv, and both KOs, had significantly increased stress-induced analgesia (SIA). Rimonabant blocked the increased SIA in TIP39-KO, PTH2R-KO or after HYWH infusion. CB1 and FAAH mRNA were decreased and increased, respectively, in the basolateral amygdala of TIP39-KO mice. These data suggest that TIP39 signaling modulates nociception, very likely by inhibiting endocannabinoid circuitry at a supraspinal level. We infer a new central mechanism for endocannabinoid regulation, via TIP39 acting on the PTH2R in discrete brain regions.

Topics: Amidohydrolases; Animals; Cannabinoid Receptor Modulators; Formaldehyde; In Situ Hybridization; Injections, Intraventricular; Injections, Spinal; Male; Mice; Mice, Knockout; Naloxone; Narcotic Antagonists; Neuropeptides; Nociceptors; Pain; Pain Measurement; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptor, Parathyroid Hormone, Type 2; Rimonabant; RNA, Messenger; Signal Transduction; Stress, Psychological; Synapses; Vesicular Glutamate Transport Protein 2

We previously described a novel cyclic endomorphin-1 analog c[Tyr-D-Pro-D-Trp-Phe-Gly] (c[YpwFG]), acting as a mu-opioid receptor (MOR) agonist. This study reports that c[YpwFG] is more lipophilic and resistant to enzymatic hydrolysis than endomorphin-1 and produces preemptive antinociception in a mouse visceral pain model when injected intraperitoneally (i.p.) or subcutaneously (s.c.) before 0.6% acetic acid, employed to evoke abdominal writhing (i.p. ED(50)=1.24 mg/kg; s.c. ED(50)=2.13 mg/kg). This effect is reversed by the selective MOR antagonist β-funaltrexamine and by a high dose of the mu(1)-opioid receptor-selective antagonist naloxonazine. Conversely, the kappa-opioid receptor antagonist nor-binaltorphimine and the delta-opioid receptor antagonist naltrindole are ineffective. c[YpwFG] produces antinociception when injected i.p. after acetic acid (ED(50)=4.80 mg/kg), and only at a dose of 20mg/kg did it elicit a moderate antinociceptive response in the mouse, evaluated by the tail flick assay. Administration of a lower dose of c[YpwFG] (10mg/kg i.p.) apparently produces a considerable part of antinociception on acetic acid-induced writhes through peripheral opioid receptors as this action is fully prevented by i.p. naloxone methiodide, which does not readily cross the blood-brain barrier; whereas this opioid antagonist injected intracerebroventricularly (i.c.v.) is not effective. Antinociception produced by a higher dose of c[YpwFG] (20mg/kg i.p.) is partially reversed by naloxone methiodide i.c.v. administered. Thus, only at the dose of 20mg/kg c[YpwFG] can produce antinociception through both peripheral and central opioid receptors. In conclusion, c[YpwFG] displays sufficient metabolic stability to be effective after peripheral administration and demonstrates the therapeutic potential of endomorphin derivatives as novel analgesic agents to control visceral pain.

Topics: Analgesics; Animals; Injections, Intraperitoneal; Injections, Intraventricular; Injections, Subcutaneous; Mice; Naloxone; Naltrexone; Narcotic Antagonists; Oligopeptides; Pain; Peptides, Cyclic; Receptors, Opioid, mu

Repeated morphine treatment has been shown to induce transient receptor potential vanilloid type 1 (TRPV1) expression in the spinal cord, dorsal root ganglion (DRG), and sciatic nerve of a rat model. Increased TRPV1 expression may therefore play a role in morphine tolerance. In this study, we evaluated the hypothesis that blockage of TRPV1 may be useful as an adjunctive pain management therapy. We investigated whether blockage of TRPV1 by capsazepine, a TRPV1 antagonist, affected antinociception, development of tolerance, and physical dependence on morphine in mice.. Institute of Cancer Research mice were pretreated with capsazepine and post-treated with morphine acutely and repeatedly. Antinociception and its tolerance were assessed using the hot-plate test. Morphine dependence was examined through the manifestation of withdrawal symptoms induced by naloxone in morphine-dependent mice.. Acute capsazepine treatment (5 mg kg⁻¹, i.p.) potentiated the antinociceptive effects of morphine, as measured by the hot-plate test. Repeated co-treatment of capsazepine (2.5 mg kg⁻¹ i.p.) with morphine attenuated the development of tolerance to the antinociceptive effect of morphine. The development of morphine dependence was also reduced by capsazepine (1.25 or 2.5 mg kg⁻¹ i.p.).. Our results suggest that TRPV1 antagonists can be used adjunctively to morphine treatment because they strengthen morphine antinociception and prevent the development of tolerance, and also physical dependence, on morphine.

Topics: Analgesics, Opioid; Animals; Capsaicin; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Drug Synergism; Drug Tolerance; Male; Mice; Morphine; Morphine Dependence; Naloxone; Narcotic Antagonists; Pain; Substance Withdrawal Syndrome; TRPV Cation Channels

Capparis ovata Desf. (Capparaceae) grows widely in Turkey. Flower buds and fruits of the plant are used in folk medicine for their analgesic, antirheumatismal, and diuretic effects.. This study evaluated the possible antinociceptive effect of the methanol extract of C. ovata (CME) in mice.. The antinociceptive effect of methanol extract, prepared with the C. ovata flower buds, was studied at the doses of 50, 100, and 200 mg/kg (i.p.) using tail-immersion, hot-plate, and writhing tests in mice. Morphine sulfate (5 mg/kg; i.p.) and dipyrone (100 mg/kg; i.p.) were used as reference analgesic agents. Naloxone (5 mg/kg; i.p.) was also tested.. It was observed that the C. ovata extract had a significant antinociceptive effect in these tests. In the hot-plate and tail-immersion test results, the doses of 50, 100, and 200 mg/kg increased the percentage of the maximum possible effect (MPE%) value for nociception significantly according to the control value (P < 0.001). All doses of the extract decreased the number of acetic acid-induced abdominal constrictions in mice when compared with control group (P < 0.001). These effects were inhibited by pretreatment with naloxone.. Based on the results obtained, it can be concluded that CME is a potentially antinociceptive agent which acts as both at the peripheral and central levels.

Topics: Acetic Acid; Analgesics; Animals; Capparis; Dipyrone; Dose-Response Relationship, Drug; Flowers; Hot Temperature; Injections, Intraperitoneal; Male; Medicine, Traditional; Methanol; Mice; Morphine; Naloxone; Pain; Pain Measurement; Plant Extracts; Reaction Time; Solvents; Turkey

In this study, the effects of intraperitoneal (i.p.) and intracerebroventricular (i.c.v.) injection of crocin in separate and combined treatments with i.p. injections of morphine (an opioid receptor agonist) and naloxone (an opioid receptor antagonist) were investigated on acute corneal pain in rats. Acute corneal pain was induced by local application of a drop of 5 M NaCl solution on the corneal surface. The number of eye wipes was taken as a pain response, and counted during the first 30 s. Crocin injected i.p. and i.c.v. and morphine injected i.p. significantly (p < 0.05) decreased the number of eye wipes. Morphine (i.p.)-induced antinociception was significantly (p < 0.05) increased by the systemically and centrally injected crocin. The antinociceptive effects induced by i.p. and i.c.v. injections of crocin were not reversed by i.p. injection of naloxone. These findings indicated that both crocin and morphine attenuated hypertonic saline-induced corneal pain. The opioid receptors may not be involved in the analgesic mechanism of crocin.

Topics: Analgesics, Opioid; Animals; Carotenoids; Cornea; Drug Combinations; Injections, Intraperitoneal; Injections, Intraventricular; Male; Morphine; Naloxone; Pain; Pain Measurement; Rats; Rats, Wistar

Topics: Analgesics, Opioid; Animals; Behavior, Animal; Dose-Response Relationship, Drug; Endorphins; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Rats

Targinact (Napp Pharmaceuticals Ltd) is a modified-release combination product containing the strong opioid oxycodone plus the opioid antagonist naloxone. It is licensed for "severe pain, which can be adequately managed only with opioid analgesics".1 The summary of product characteristics (SPC) states that "naloxone is added to counteract opioid-induced constipation by blocking the action of oxycodone at opioid receptors locally in the gut". Advertising for the product claims "better pain relief", "superior GI [gastrointestinal] tolerability" and "improved quality of life" "compared to previous treatment in a clinical practice study (n=7836)". Here we consider whether Targinact offers advantages over using strong opioids plus laxatives where required.

Topics: Analgesics, Opioid; Constipation; Delayed-Action Preparations; Drug Combinations; Follow-Up Studies; Humans; Naloxone; Oxycodone; Pain; Randomized Controlled Trials as Topic

Mice deficient for the stable tubule only peptide (STOP) display altered dopaminergic neurotransmission associated with severe behavioural defects including disorganized locomotor activity. Endogenous morphine, which is present in nervous tissues and synthesized from dopamine, may contribute to these behavioral alterations since it is thought to play a role in normal and pathological neurotransmission.. In this study, we showed that STOP null brain structures, including cortex, hippocampus, cerebellum and spinal cord, contain high endogenous morphine amounts. The presence of elevated levels of morphine was associated with the presence of a higher density of mu opioid receptor with a higher affinity for morphine in STOP null brains. Interestingly, STOP null mice exhibited significantly lower nociceptive thresholds to thermal and mechanical stimulations. They also had abnormal behavioural responses to the administration of exogenous morphine and naloxone. Low dose of morphine (1 mg/kg, i.p.) produced a significant mechanical antinociception in STOP null mice whereas it has no effect on wild-type mice. High concentration of naloxone (1 mg/kg) was pronociceptive for both mice strain, a lower concentration (0.1 mg/kg) was found to increase the mean mechanical nociceptive threshold only in the case of STOP null mice.. Together, our data show that STOP null mice displayed elevated levels of endogenous morphine, as well as an increase of morphine receptor affinity and density in brain. This was correlated with hypernociception and impaired pharmacological sensitivity to mu opioid receptor ligands.

Topics: Analgesics, Opioid; Animals; Mice; Mice, Knockout; Microtubule-Associated Proteins; Morphine; Naloxone; Narcotic Antagonists; Nerve Tissue Proteins; Opiate Alkaloids; Pain; Receptors, Opioid, mu

The transdermal 7-day buprenorphine matrix patch provides a constant and user-friendly pain management when chronic musculoskeletal pain requires opioids. This analysis of clinical routine data evaluated the benefit of this treatment for patients previously receiving oral long-term treatment with weak opioids alone. Data of 310 patients previously treated with tramadol or tildate/naloxone and part of a multicentre observational study with 3295 patients were analyzed. In 89.7% of the 310 patients oral treatment with weak opioids was replaced by the 7-day buprenorphine patch due to insufficient analgesia. During treatment with the 7-day buprenorphine patch there was a clinically significant decrease of the mean pain intensity at rest during the day from 5.7 to 2.9, on physical effort during the day from 7.3 to 3.8 and at night from 5.2 to 2.3 (11-point NRS scale, p < or = 0.001). In addition, quality of life aspects such as mobility, self-reliance and quality of sleep improved, which are relevant for individual patient satisfaction with pain management. For patients with previous long-term tramadol or tilidate/naloxone treatment the switch to the 7-day buprenorphine matrix patch proved to be effective and safe for the management of chronic pain. The user-friendly 7-day application interval contributes to improving compliance and a reducing exposure to tablets.

Topics: Activities of Daily Living; Administration, Cutaneous; Aged; Aged, 80 and over; Analgesics, Opioid; Buprenorphine; Chronic Disease; Drug Substitution; Female; Germany; Humans; Long-Term Care; Male; Middle Aged; Naloxone; Pain; Pain Measurement; Prospective Studies; Quality of Life; Tilidine; Tramadol

Topics: Buprenorphine; Buprenorphine, Naloxone Drug Combination; Documentation; Humans; Naloxone; Opioid-Related Disorders; Pain; Patient Compliance; Practice Guidelines as Topic; Prescription Drugs

Data available on the role of the opioid systems of the naked mole-rat in nociception is scanty and unique compared to that of other rodents. In the current study, the effect of DAMGO, DPDPE and U-50488 and U-69593 on formalin-induced (20 microl, 10%) nociception were investigated. Nociceptive-like behaviors were quantified by scoring in blocks of 5 min the total amount of time (s) the animal spent scratching/biting the injected paw in the early (0-5 min) and in the late (25-60 min) phase of the test. In both the early and late phases, administration of 1 or 5 mg/kg of DAMGO or DPDPE caused a naloxone-attenuated decrease in the mean scratching/biting time. U-50488 and U-69593 at all the doses tested did not significantly change the mean scratching/biting time in the early phase. However, in the late phase U-50488 or U-69593 at the highest doses tested (1 or 5 mg/kg or 0.025 or 0.05 mg/kg, respectively) caused a statistically significant and naloxone-attenuated decrease in the mean scratching/biting time. The data showed that mu, delta or kappa-selective opioids causes antinociception in the formalin test in this rodent, adding novel information on the role of opioid systems of the animal on pain regulation.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics, Non-Narcotic; Analgesics, Opioid; Animals; Benzeneacetamides; Data Interpretation, Statistical; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, D-Penicillamine (2,5)-; Formaldehyde; Injections, Intraperitoneal; Male; Mole Rats; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Pyrrolidines; Rats; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu

Morphine-induced glial proinflammatory responses have been documented to contribute to tolerance to opioid analgesia. Here, we examined whether drugs previously shown to suppress glial proinflammatory responses can alter other clinically relevant opioid effects; namely, withdrawal or acute analgesia. AV411 (ibudilast) and minocycline, drugs with distinct mechanisms of action that result in attenuation of glial proinflammatory responses, each reduced naloxone-precipitated withdrawal. Analysis of brain nuclei associated with opioid withdrawal revealed that morphine altered expression of glial activation markers, cytokines, chemokines, and a neurotrophic factor. AV411 attenuated many of these morphine-induced effects. AV411 also protected against spontaneous withdrawal-induced hyperactivity and weight loss recorded across a 12-day timecourse. Notably, in the spontaneous withdrawal study, AV411 treatment was delayed relative to the start of the morphine regimen so to also test whether AV411 could still be effective in the face of established morphine dependence, which it was. AV411 did not simply attenuate all opioid effects, as co-administering AV411 with morphine or oxycodone caused three-to-five-fold increases in acute analgesic potency, as revealed by leftward shifts in the analgesic dose response curves. Timecourse analyses revealed that plasma morphine levels were not altered by AV411, suggestive that potentiated analgesia was not simply due to prolongation of morphine exposure or increased plasma concentrations. These data support and extend similar potentiation of acute opioid analgesia by minocycline, again providing converging lines of evidence of glial involvement. Hence, suppression of glial proinflammatory responses can significantly reduce opioid withdrawal, while improving analgesia.

Topics: Analgesia; Analgesics, Opioid; Animals; Anti-Bacterial Agents; Brain; Bronchodilator Agents; Dose-Response Relationship, Drug; Glial Fibrillary Acidic Protein; Immunohistochemistry; Injections, Intraperitoneal; Male; Minocycline; Morphine; Naloxone; Opioid-Related Disorders; Oxycodone; Pain; Pain Measurement; Pyridines; Rats; Rats, Sprague-Dawley; Substance Withdrawal Syndrome; Weight Loss

H-Dmt-D-Arg-Phe-Lys-NH(2) ([Dmt(1)]DALDA), a highly selective micro-opioid peptide, is potently analgesic after systemic and intrathecal administration but is less potent given intracerebroventricularly. This study was performed to further characterize the analgesic effects of [Dmt(1)]DALDA.. We compared the effects of [Dmt(1)]DALDA and morphine after systemic administration in two different acute pain tests, the tail flick test and the paw withdrawal test, and examined how antagonizing the spinal opioid actions would affect their analgesic effects.. [Dmt(1)]DALDA was markedly more potent in the tail flick test than in the hot plate test, while the potencies of morphine were similar in the two tests. Intrathecal naloxone completely blocked the effect of systemic [Dmt(1)]DALDA in the tail flick test, while it only partially blocked the effect of morphine. At higher doses that produced analgesia in the hot plate test, the effect of [Dmt(1)]DALDA in this test was only partially blocked by naloxone.. Systemic [Dmt(1)]DALDA has a unique analgesic property clearly different from that of morphine and it has a propensity to produce spinal analgesia.

Topics: Analgesics, Opioid; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Injections, Spinal; Male; Morphine; Naloxone; Narcotic Antagonists; Oligopeptides; Pain; Pain Measurement; Rats; Rats, Sprague-Dawley; Receptors, Opioid, mu

Allopurinol is a potent inhibitor of the enzyme xanthine oxidase, used primarily in the treatment of hyperuricemia and gout. It is well known that purines exert multiple effects on pain transmission. We hypothesized that the inhibition of xanthine oxidase by allopurinol, thereby reducing purine degradation, could be a valid strategy to enhance purinergic activity. The aim of this study was to investigate the anti-nociceptive profile of allopurinol on chemical and thermal pain models in mice.. Mice received an intraperitoneal (i.p.) injection of vehicle (Tween 10%) or allopurinol (10-400 mg kg(-1)). Anti-nociceptive effects were measured with intraplantar capsaicin, intraplantar glutamate, tail-flick or hot-plate tests.. Allopurinol presented dose-dependent anti-nociceptive effects in all models. The opioid antagonist naloxone did not affect these anti-nociceptive effects. The non-selective adenosine-receptor antagonist caffeine and the selective A(1) adenosine-receptor antagonist, DPCPX, but not the selective A(2A) adenosine-receptor antagonist, SCH58261, completely prevented allopurinol-induced anti-nociception. No obvious motor deficits were produced by allopurinol, at doses up to 200 mg kg(-1). Allopurinol also caused an increase in cerebrospinal fluid levels of purines, including the nucleosides adenosine and guanosine, and decreased cerebrospinal fluid concentration of uric acid.. Allopurinol-induced anti-nociception may be related to adenosine accumulation. Allopurinol is an old and extensively used compound and seems to be well tolerated with no obvious central nervous system toxic effects at high doses. This drug may be useful to treat pain syndromes in humans.

Topics: Adenosine; Adenosine A1 Receptor Agonists; Adenosine A1 Receptor Antagonists; Adenosine A2 Receptor Antagonists; Allopurinol; Analgesics; Animals; Capsaicin; Dose-Response Relationship, Drug; Glutamic Acid; Hot Temperature; Injections, Intraperitoneal; Male; Mice; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Pyrimidines; Triazoles; Uric Acid; Xanthine Oxidase; Xanthines

Previous investigation has shown that Thymus Vulgaris (TV) modulates pain. The aim of this work was to examine the role of TV on acute and chronic pain and compares its effect with dexamethasone (DEX) and stress (ST) by using hot plate, tail flick and formalin tests in mice. In this study male albino mice (25-30 g.) in 21 groups (n=147) were used. TV (100, 500 and 1000 mg/kg), DEX (0.5, 1 and 2 mg/kg) and vehicle (VEH) were injected 30 minutes before pain assessment tests. Stress was applied by 1 min swimming in cold water (18-22 degrees ). Acute and chronic pain was assessed by hot plate, tail flick and formalin tests. For assessment of the role of opioid receptors in antinoceception of TV extract, Naloxon (NAL, 2mg/kg, ip) as opioid receptor antagonist was injected before the injection of the more effective dose (500 mg/kg) of TV extract. Results indicated that TV, DEX and ST have analgesic effects in all tests (P<0.01 in comparison with control group). Above findings showed that TV extract, DEX and ST have modulatory effects on acute and chronic pain. Further research is required to determine the mechanisms by which TV extract has an inhibitory effect on pain sensation.

Topics: Analgesics; Animals; Dexamethasone; Disease Models, Animal; Dose-Response Relationship, Drug; Formaldehyde; Hot Temperature; Male; Mice; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Plant Extracts; Stress, Psychological; Thymus Plant

The rationale of this investigation was to examine the antinociceptive properties of the essential oil obtained from Rosmarinus officinalis aerial parts, using a rat model of arthritic pain. The essential oil (100, 300 and 600 mg/kg, I. P.) produced a dose-dependent antinociceptive effect, manifested as a significant reduction in the dysfunction in the pain-induced functional impairment model in the rat (PIFIR model), mainly at high doses. Chemical constituents of the essential oil were further analyzed by gas chromatography-mass spectrometry (GC/MS). The major compounds in the essential oil were alpha-pinene (14.10 %), camphene (11.47 %), beta-pinene (12.02 %), myrcene (3.31 %), alpha-phellandrene (7.87 %), eucalyptol (8.58 %), 2-bornanone (3.42 %), camphor (8.75 %), isoborneol (3.48 %), borneol (4.85 %) and borneol acetate (6.49 %). The antinociceptive effects of R. officinalis essential oil were tested in combination with 0.12 mg/kg WAY100635, s. c. (an antagonist of 5-HT(1A) receptors) or 1 mg/kg naloxone, i. p. (an antagonist of endogenous opioids receptors), demonstrating in both cases an inhibition of the antinociceptive response. This study suggests an involvement, at least in part, of the serotonergic system via 5-HT(1A) receptors and endogenous opioids in the antinociceptive effect of R. officinalis essential oil in the PIFIR model.

Topics: Analgesics; Animals; Arthritis; Chromatography, Gas; Male; Mass Spectrometry; Naloxone; Narcotic Antagonists; Oils, Volatile; Pain; Piperazines; Plant Components, Aerial; Plant Extracts; Pyridines; Rats; Rats, Wistar; Rosmarinus; Serotonin Antagonists; Terpenes; Uric Acid

Xylazine is an alpha(2)-adrenoceptor agonist extensively used in veterinary and animal experimentation. Evidence exists that alpha(2)-adrenoceptor agonists can activate opioid receptors via endogenous opioid release. Considering this idea and the multiple alpha(2) subtypes currently known (alpha(2A), alpha(2B), alpha(2C) and alpha(2D)), the aim of this study was to investigate which alpha(2) receptor subtype mediates xylazine-induced peripheral antinociception and possible opioid receptor and endogenous opioid involvement. The rat pressure test was used; the hyperalgesia was induced by intraplantar injection of prostaglandin E(2) (2 microg). Xylazine was administered locally (25, 50 and 100 microg) into the right hind paw of Wistar rat alone and after either alpha(2)-adrenoceptor antagonist yohimbine (5, 10 and 20 microg/paw), the alpha(2) antagonists to alpha(2A), alpha(2B), alpha(2C) and alpha(2D) subtypes (BRL 44 480, imiloxan, rauwolscine and RX 821002; 20 microg/paw, respectively) the opioid receptor antagonist naloxone (12.5, 25 and 50 microg) and the enkephalinase inhibitor bestatin (400 microg/paw). Intraplantar injection of xylazine (50 and 100 microg) induced peripheral antinociception; however, a dose of 25 microg/paw did not significantly reduce the hyperalgesic effect. Yohimbine, rauwolscine and naloxone prevented action of xylazine 100 microg/paw. BRL 44 480, imiloxan and RX 821002 were ineffective in blocking xylazine antinociception. Bestatin (400 microg/paw) potentiated the antinociceptive effect of xylazine 25 microg/paw. The present results provide evidence that the peripheral antinociceptive effect of xylazine probably results from activation of alpha(2C)-adrenoceptors and also by the release of endogenous opioids that act on their receptors.

Topics: Adrenergic alpha-2 Receptor Agonists; Adrenergic alpha-2 Receptor Antagonists; Analgesics; Animals; Dinoprostone; Dose-Response Relationship, Drug; Hyperalgesia; Idazoxan; Imidazoles; Leucine; Male; Naloxone; Opioid Peptides; Pain; Pain Measurement; Rats; Rats, Wistar; Xylazine; Yohimbine

Opiates are the mainstay of analgesia in the intensive care unit (ICU). Unfortunately, constipation is a common adverse effect associated with opioid use. Naloxone is a pure opiate antagonist that is frequently utilized in practice for the prophylaxis or treatment of opiate-induced constipation in the ICU. Despite extensive first pass metabolism in the liver there remains the potential for opiate reversal after oral administration. We sought to assess the safety of enteral naloxone in the ICU for the treatment of opiate-induced constipation.. Patients who were ordered enteral naloxone while in the ICU were identified through the Pharmacy's computer system. Patients were included in the data analysis if they had received at least one dose of enteral naloxone and had received standing opiates for at least 48 h prior to the initial naloxone dose. Patients were excluded from data analysis if the Richmond agitation-sedation scale (RASS) score was not utilized, they were paralysed or the medical record indicated that extubation was planned within the following 24 h. Data points were recorder at the following times with respect to each naloxone dose administered; time -2, -1, 0, 1, 2 and 4 h. The following data points were collected before and after each naloxone dose; blood pressure, heart rate, respiratory rate, RASS score, pain assessment score (recorded as present or absent), midazolam dose, propofol dose and fentanyl dose. In order to assess for possible opiate reversal the peak fentanyl, propofol and midazolam dose, vital sign value, RASS score and pain score were compared before and after each dose of naloxone.. The mean naloxone dose was 3.6 +/- 0.9 mg. There was no significant change in RASS score around the naloxone doses, -2.9 +/- 1.4 before and -2.8 +/- 1.6 after (P = 0.28). There were no significant changes in mean fentanyl, propofol or midazolam dose around naloxone administration. There were also no significant changes in heart rate, blood pressure and respiratory rate or in the presence of pain.. These results demonstrate that the administration of enteral naloxone to patients on intravenous opiates in the ICU setting was not associated with changes in sedation score, vital signs, fentanyl dose, midazolam dose or propofol dose.

Topics: Aged; Analgesics, Opioid; Constipation; Critical Care; Female; Fentanyl; Humans; Intubation, Gastrointestinal; Liver Function Tests; Male; Middle Aged; Naloxone; Narcotic Antagonists; Pain; Pain Measurement

Current strategies to reduce excess pain among hospitalized patients remain inadequate. New, effective approaches are urgently needed. In this prospective observational study of a performance-improvement intervention, we studied the effect of computer-generated, real-time alerts used by nurses on the rate of a medical error in pain management defined as lack of reassessment within 120 minutes from the last observation of severe pain. We also studied duration of severe pain events and frequency of treatment of opioid-related adverse effects. Analyses of 51,619 consecutive observations of severe pain were performed in monthly intervals. Significant decrease in error rate (delayed pain reassessment) was observed postintervention (mean+/-standard error [SE]: 35.8%+/-0.7%) compared with preintervention rate (56.2%+/-1.4%, P<0.0001). Among 6305 unique severe pain events examined during four months pre- and postintervention, time to resolution of severe pain decreased significantly (median time preintervention [January 2006] of 195 minutes compared with median time postintervention of 117, 106, and 101 minutes [January, April, and June 2007], P<0.0001). Hospital-wide, unanticipated monthly naloxone administration decreased postintervention (mean+/-SE: 1.48+/-0.21 per month per 1000 inpatients) compared with preintervention (2.69+/-0.35, P=0.0130). Hospital-wide implementation of real-time, computer-generated alerts identifying instances of delayed pain reassessment resulted in sustained reduction of error rate and faster resolution of severe pain without oversedation.

Topics: Analgesics, Opioid; Drug Therapy, Computer-Assisted; Hospitalization; Humans; Information Systems; Medical Errors; Naloxone; Narcotic Antagonists; Pain; Prospective Studies; Treatment Outcome

Gynandropsis gynandra (Capparidaceae) leaves are traditionally used in the treatment of pain. In order to evaluate the scientific validity of this, leaves were extracted successively to produce various extracts. These extracts were screened for antinociceptive activity using the hot plate test and acetic acid-induced writhing test in mice at a dose of 100 mg kg(-1), intraperitoneally. Ethanol and aqueous extracts were found most active in both the tests. The action was blocked by naloxone (1 mg kg(-1), s.c.) in the hot plate test, which suggests involvement of opioid receptors in the action. Flavonoids and tannins were observed in the active extracts, so we can say that they may responsible for the antinociceptive activity.

Topics: Acetic Acid; Analgesics; Animals; Cleome; Flavonoids; Injections, Intraperitoneal; Male; Mice; Naloxone; Pain; Plant Extracts; Plant Leaves; Tannins

We evaluated the effects of haloperidol and its metabolites on capsaicin-induced mechanical hypersensitivity (allodynia) and on nociceptive pain induced by punctate mechanical stimuli in mice.. Subcutaneous administration of haloperidol or its metabolites I or II (reduced haloperidol) dose-dependently reversed capsaicin-induced (1 microg, intraplantar) mechanical hypersensitivity of the hind paw (stimulated with a nonpainful, 0.5-g force, punctate stimulus). The order of potency of these drugs to induce antiallodynic effects was the order of their affinity for brain sigma-1 (sigma(1)) receptor ([(3)H](+)-pentazocine-labeled). Antiallodynic activity of haloperidol and its metabolites was dose-dependently prevented by the selective sigma(1) receptor agonist PRE-084, but not by naloxone. These results suggest the involvement of sigma(1) receptors, but discard any role of the endogenous opioid system, on the antiallodynic effects. Dopamine receptor antagonism also appears unlikely to be involved in these effects, since the D(2)/D(3) receptor antagonist (-)-sulpiride, which had no affinity for sigma(1) receptors, showed no antiallodynic effect. None of these drugs modified hind-paw withdrawal after a painful (4 g force) punctate mechanical stimulus in noncapsaicin-sensitized animals. As expected, the control drug gabapentin showed antiallodynic but not antinociceptive activity, whereas clonidine exhibited both activities and rofecoxib, used as negative control, showed neither.. These results show that haloperidol and its metabolites I and II produce antiallodynic but not antinociceptive effects against punctate mechanical stimuli and suggest that their antiallodynic effect may be due to blockade of sigma(1) receptors but not to dopamine receptor antagonism.

Topics: Analysis of Variance; Animals; Brain; Capsaicin; Disease Models, Animal; Dopamine Antagonists; Dose-Response Relationship, Drug; Female; Haloperidol; Hyperalgesia; Mice; Morpholines; Motor Activity; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Pain Threshold; Pentazocine; Physical Stimulation; Protein Binding; Radioligand Assay; Reaction Time; Receptors, sigma; Rotarod Performance Test; Sigma-1 Receptor; Tritium

Morphine and methadone are both high-affinity, potent mu-opioid peptide (MOP) receptor analgesics. In this report, we compared the antinociceptive potencies of these 2 drugs when administered subcutaneously (s.c.), intrathecally (i.t.), or intracerebroventricularly (i.c.v.) in both rat and mouse, using the tail-flick assay. We found that both morphine and methadone were potently antinociceptive when the drugs were administered s.c., showing comparable AD50 values in both species. However, the antinociception produced by methadone, when it was administered centrally, was much weaker than that produced by centrally administered morphine. Specifically, the AD50 value for methadone antinociception was more than 30-fold higher at both the i.t. and i.c.v. sites in mouse and not measurable in rat. Naloxone methiodide (NLX-M), a peripherally restricted antagonist, was used to further examine the relative contribution of central versus peripheral sites to morphine and methadone antinociception. NLX-M, when administered s.c., blocked the antinociceptive effect of either systemically or centrally administered methadone but had little effect on the antinociception produced by centrally administered morphine. Furthermore, centrally administered NLX-M significantly blocked antinociception produced by centrally administered morphine but not that produced by centrally administered methadone. Together, these results suggest that methadone antinociception is significantly dependent on an action of the drug at peripheral sites and could provide novel insight into the neural mechanisms that distinguish morphine versus methadone antinociception.. Methadone is often used as an alternative for pain management. The present study shows that a peripheral action plays a crucial role in methadone antinociception. This finding could have significant clinical relevance for the use of methadone versus morphine for the treatment of certain types of pain.

Topics: Analgesics, Opioid; Animals; Drug Administration Routes; Injections, Intraventricular; Injections, Spinal; Injections, Subcutaneous; Male; Methadone; Mice; Morphine; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Quaternary Ammonium Compounds; Rats; Rats, Sprague-Dawley; Receptors, Opioid; Species Specificity

Neuropeptide S (NPS), a recently identified bioactive peptide through reverse pharmacology approach, was reported to regulate arousal, anxiety, locomotor activity, feeding behaviors and drug reward. NPS receptor (NPSR) mRNA was found in the area related to the descending control system of pain, such as the periaqueductal gray (PAG), raphe nuclei, and lateral parabrachial nucleus (PBN), suggesting a possible role of the NPS-NPSR system in the regulation of pain transmission. In the present study, we evaluated the effects of NPS in pain modulation at the supraspinal level for the first time, using the tail withdrawal test and hot-plate test in mice. NPS (mouse, 0.01-1 nmol) injected intracerebroventricularly (i.c.v.) caused a significant increase of tail withdrawal latency and paw-licking/jumping latency in the tail withdrawal test and the hot-plate test, respectively. Antinociceptive effect elicited by NPS (0.1 nmol, i.c.v.) was not affected by naloxone (i.c.v., 10 nmol co-injection or i.p., 10 mg/kg, 10 min prior to NPS) in both tail withdrawal test and hot-plate test. However, at the doses, naloxone significantly inhibited the antinociceptive effect induced by morphine (i.c.v., 3 nmol). NPS (0.1 nmol, i.c.v.)-induced antinociception was inhibited by co-injection with 10 nmol, but not 3 nmol [D-Cys(tBu)(5)]NPS, a peptidergic antagonist identified more recently, while [D-Cys(tBu)(5)]NPS (3 and 10 nmol) alone induced neither hyperalgesia nor antinociception. These results revealed that NPS could produce antinociception through NPS receptor, but not opioid receptor, and NPS-NPSR system could be a potential target for developing new analgesic drugs.

Topics: Analgesics; Animals; Mice; Morphine; Naloxone; Narcotic Antagonists; Neuropeptides; Pain

The present study examined the antinociceptive effect of the ethanolic extract from Melissa officinalis L. and of the rosmarinic acid in chemical behavioral models of nociception and investigates some of the mechanisms underlying this effect. The extract (3-1000 mg/kg), given orally (p.o.) 1 h prior to testing, produced dose-dependent inhibition of acetic acid-induced visceral pain, with ID50 value of 241.9 mg/kg. In the formalin test, the extract (30-1000 mg/kg, p.o.) also caused significant inhibition of both, the early (neurogenic pain) and the late (inflammatory pain), phases of formalin-induced licking. The extract (10-1000 mg/kg, p.o.) also caused significant and dose-dependent inhibition of glutamate-induced pain, with ID50 value of 198.5 mg/kg. Furthermore, the rosmarinic acid (0.3-3 mg/kg), given p.o. 1 h prior, produced dose-related inhibition of glutamate-induced pain, with ID50 value of 2.64 mg/kg. The antinociception caused by the extract (100 mg/kg, p.o.) in the glutamate test was significantly attenuated by intraperitoneal (i.p.) treatment of mice with atropine (1 mg/kg), mecamylamine (2 mg/kg) or l-arginine (40 mg/kg). In contrast, the extract (100 mg/kg, p.o.) antinociception was not affected by i.p. treatment with naloxone (1 mg/kg) or D-arginine (40 mg/kg). It was also not associated with non-specific effects, such as muscle relaxation or sedation. Collectively, the present results suggest that the extract produced dose-related antinociception in several models of chemical pain through mechanisms that involved cholinergic systems (i.e. through muscarinic and nicotinic acetylcholine receptors) and the L-arginine-nitric oxide pathway. In addition, the rosmarinic acid contained in this plant appears to contribute for the antinociceptive property of the extract. Moreover, the antinociceptive action demonstrated in the present study supports, at least partly, the ethnomedical uses of this plant.

Topics: Acetic Acid; Analgesics; Animals; Arginine; Atropine; Cinnamates; Depsides; Dose-Response Relationship, Drug; Female; Formaldehyde; Glutamic Acid; Male; Mecamylamine; Melissa; Mice; Motor Activity; Naloxone; Nitric Oxide; Pain; Pain Threshold; Phytotherapy; Plant Extracts; Plant Leaves; Receptors, Muscarinic; Receptors, Nicotinic; Rosmarinic Acid

Although N-methyl-d-aspartate (NMDA) receptor antagonists potentiate antinociceptive effects induced by various exogenous opioids at the spinal, supraspinal, or peripheral level, less is known regarding the interaction between NMDA and endogenous opioids in antinociception. We therefore assessed the effects of NMDA receptor antagonists on endogenous opioids in antinociception at the peripheral level by testing the ability of the locally administered receptor antagonists to modify pain-related behavior induced by carrageenan injection into the knee joint. The NMDA receptor antagonist AP-5 or the exogenous opioid morphine was injected intra-articularly before carrageenan injection and 5h after carrageenan injection, respectively. We evaluated whether intra-articular injection of the opioid receptor antagonist naloxone reversed the analgesic effect of AP-5. In addition, we tested the effects of AP-5 on carrageenan-induced levels of the beta-endorphin protein in dorsal root ganglia (DRG), saphenous nerve and synovial membrane. We found that AP-5 prevented and morphine reversed carrageenan-induced pain-related behavior. Intriguingly, injection of naloxone 5h after carrageenan injection reversed the antinociceptive effects of AP-5 pre-treatment, although naloxone alone had no effect on carrageenan-induced pain-related behavior. Western blots showed that AP-5 pre-treatment followed by carrageenan injection resulted in a higher level of beta-endorphin protein in the DRG and saphenous nerve, but not in the synovial membrane, than that observed following saline control treatment. These results suggest that inhibition of the NMDA receptor unmasks antinociception induced by endogenous opioids at the peripheral level, partly through the increased protein level of the endogenous mu-opioid peptide beta-endorphin in DRG and saphenous nerve.

Topics: 2-Amino-5-phosphonovalerate; Analgesics, Opioid; Animals; Arthralgia; Arthritis; beta-Endorphin; Carrageenan; Drug Synergism; Excitatory Amino Acid Antagonists; Ganglia, Spinal; Male; Morphine; Naloxone; Narcotic Antagonists; Opioid Peptides; Pain; Pain Measurement; Pain Threshold; Peripheral Nerves; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Synovial Membrane

The present study investigated the inhibitory effect of cobratoxin (CTX) on pain-evoked discharge of neurons in thalamic parafascicular nucleus (Pf) of rats and analyzed some of the mechanisms involved in this effect. Intracerebroventricular injection (icv) of CTX at 0.56, 1.12 and 4.50 microg/kg resulted in a dose-dependent inhibitory effect on the pain-evoked discharges of Pf neurons. The inhibition of pain-evoked discharges of Pf neurons by CTX at high dose (4.50 microg/kg) persisted at least for 2h, while the inhibitory effect of morphine (40 microg) persisted no longer than 30 min. The inhibitory effect of CTX was reversed by pretreatment with atropine (icv, 5 microg). In contrast, icv injection of naloxone (4 microg) had no effect on CTX-induced inhibition. Furthermore, pretreatment with parachlorophenylalanine, a specific inhibitor of tryptophan hydroxylase, also significantly attenuated the inhibitory effect of CTX. The results suggested that: (a) CTX has a dose-dependent inhibitory effect on pain-evoked discharges of Pf neurons, confirming electrophysiologically the antinociceptive action of CTX; (b) the inhibitory effect of CTX has a longer duration compared to that of morphine; (c) central cholinergic and serotonergic systems, but not opioidergic system, are involved in the inhibitory effect of CTX.

Topics: Animals; Atropine; Cobra Neurotoxin Proteins; Evoked Potentials; Male; Naloxone; Neurons; Pain; Rats; Rats, Wistar; Receptors, Cholinergic; Receptors, Serotonin; Thalamic Nuclei

Buprenorphine displays attributes of opioids, but also some features distinct from them. We examined spinal and supraspinal signal transduction of buprenorphine-induced anti-nociception in mice compared with morphine and fentanyl.. The opioid receptor antagonist naloxone, Pertussis toxin (PTX), G(z) protein antisense and nociceptin/orphanin-FQ receptor agonist nociceptin, and antagonist, JTC-801, were injected supraspinally (intracerebroventricular) and spinally (intrathecal). Also the cell-permeable Ser/Thr protein phosphatase inhibitor okadaic acid was given supraspinally.. Spinal naloxone (20 microg) or PTX (1 microg) attenuated morphine, fentanyl and buprenorphine (s.c.) anti-nociception. Supraspinal naloxone or PTX attenuated morphine and fentanyl, but not buprenorphine anti-nociception. Spinal G(z) protein antisense did not alter buprenorphine, morphine or fentanyl anti-nociception and supraspinal G(z)-antisense did not alter morphine or fentanyl anti-nociception. However, supraspinal G(z)-antisense (not random sense) reduced buprenorphine anti-nociception. Peripheral JTC-801 (1 mgxkg(-1), i.p.) enhanced the ascending (3 mgxkg(-1)) and descending (30 mgxkg(-1)) portions of buprenorphine's dose-response curve, but only spinal, not supraspinal, nociceptin (10 nmolxL(-1)) enhanced buprenorphine anti-nociception. Intracereboventricular okadaic acid (0.001-10 pg) produced a biphasic low-dose attenuation, high-dose enhancement of buprenorphine(3 or 30 mgxkg(-1), s.c.) anti-nociception, but did not affect morphine or fentanyl anti-nociception.. Buprenorphine has an opioid component to its supraspinal mechanism of analgesic action. Our present results reveal an additional supraspinal component insensitive to naloxone, PTX and nociceptin/orphanin-FQ, but involving G(z) protein and Ser/Thr protein phosphatase. These data might help explain the unique preclinical and clinical profiles of buprenorphine.

Topics: Acetylcholine; Adrenergic alpha-Antagonists; Aminoquinolines; Analgesics, Opioid; Anesthetics, Local; Animals; Benzamides; Brain; Buprenorphine; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Inhibitors; Fentanyl; GTP-Binding Proteins; Injections, Intraventricular; Injections, Spinal; Male; Mice; Morphine; Naloxone; Narcotic Antagonists; Nociceptin; Nociceptin Receptor; Okadaic Acid; Oligonucleotides, Antisense; Opioid Peptides; Pain; Pain Measurement; Pain Threshold; Pertussis Toxin; Phosphoprotein Phosphatases; Piperazines; Pyridines; Receptor, Serotonin, 5-HT1A; Receptors, Opioid; Serotonin 5-HT1 Receptor Antagonists; Serotonin Antagonists; Signal Transduction; Yohimbine

Pfaffia glomerata (Spreng) Pedersen (Amaranthaceae) is a medicinal plant known in Brazil as "Paratudo" and "Brazilian ginseng" and is commonly used as tonic, antidiabetic and to treat gastric disorders.. This study evaluates the possible mechanism by which hydroalcoholic extract (HE) of Pfaffia glomerata exerts its antinociceptive effect.. The HE was evaluated in acetic acid and glutamate models of pain or by biting behavior following intrathecal (i.t.) administration of agonists of excitatory aminoacids (EAA) receptors glutamate and pro-inflammatory cytokines, IL-1beta and TNF-alpha in mice.. Oral administration of HE produced dose-dependent inhibition of acetic acid-induced visceral pain and glutamate-induced pain, with ID(50) of 64.6 (47.7-87.5)mg/kg and ID(50) of 370.8 (253.4-542.7)mg/kg, respectively. The HE (300 mg/kg, p.o.) antinociception, in the acetic acid test, was not affected by i.p. treatment of animals with naloxone. In addition, HE (300 mg/kg, p.o.) inhibited the pain-related behaviors induced by i.t. injection of trans-ACPD and TNF-alpha, but not by NMDA, AMPA, kainate or IL-1beta.. Our results suggest that inhibition of glutamatergic metabotropic receptors and TNF-alpha may account for the antinociceptive action reported for the HE in models of chemical pain used in this study.

Topics: Acetic Acid; Amaranthaceae; Analgesics; Animals; Behavior, Animal; Cycloleucine; Disease Models, Animal; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Female; Glutamic Acid; Injections, Spinal; Interleukin-1beta; Mice; Naloxone; Narcotic Antagonists; Pain; Phytotherapy; Plant Extracts; Plant Roots; Tumor Necrosis Factor-alpha

50% ethanol extract (ASE) of Amaranthus spinosus (whole plant) has been evaluated for antinociceptive and antiinflammatory activities.. Analgesic and antiinflammatory activities were studied by measuring nociception by formalin, acetic acid, hot plate, tail immersion method while inflammation was induced by carrageenan.. ASE had significant dose dependent percentage protection against acetic acid (0.6% of 10 ml) induced pain and the effects were also compared to aspirin, morphine and naloxone while formalin induced pain (0.05 ml of 2.5%) was significantly blocked only at higher dose (400mg/kg) in first phase. ASE significantly blocked pain emanating from inflammation at all the doses in second phase. The reaction time in hot plate was increased significantly and dose dependently where as pretreatment with naloxone rigorously reduced the analgesic potentials of ASE. Further in tail immersion test the same dose dependent and significant activity was observed. Aspirin had no effect on thermal induced pain i.e. hot plate and tail immersion tests but showed an effect on writhing test.. Our investigation show that Amaranthus spinosus possess significant and dose dependant antiinflammatory activity, it has also central and peripheral analgesic activity.

Topics: Acetic Acid; Amaranthus; Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Carrageenan; Disease Models, Animal; Dose-Response Relationship, Drug; Edema; Formaldehyde; Hot Temperature; Male; Mice; Naloxone; Narcotic Antagonists; Pain; Phytotherapy; Plant Extracts

Cocos nucifera cultivated in Brazil is known as "coco-da-Bahia" or "coqueiro-da-India". The tea from the husk fiber is widely used to several inflammatory disorders. Crude extract and fractions obtained from Cocos nucifera "common variety" were evaluated to test the anti-inflammatory and antinociceptive activities.. Crude extract (CE, 50, 100, and 150 mg/kg), fraction 1 (F1, molecular weight lesser than 1 kDa, 1, 10, and 50mg/kg), fraction 2 (F2, molecular weight higher than 1 kDa, 1, 10, and 50mg/kg), and the references drugs morphine (5mg/kg), acetilsalicilic acid (200mg/kg), prometazine (30 mg/kg), and metisergide (5mg/kg) were evaluated on models of analgesia and inflammation.. CE, F1, and F2 significantly develop peripheral and central antinociceptive activity but with less effect on supra-spinal regions of the brain. Administration of the opioid antagonist, naloxone (5mg/kg) inhibited the antinociceptive effect indicating that Cocos nucifera crude extract and fractions may be acting in opioid receptors. CE and F1 also inhibited rat paw edema induced by histamine, and serotonin.. results demonstrated that Cocos nucifera and its fractions have antinociceptive and anti-inflammatory activities which confirm the popular use of this plant in several inflammatory disorders.

Topics: Acetic Acid; Analgesics; Animals; Anti-Inflammatory Agents; Cocos; Edema; Fruit; Male; Mice; Naloxone; Narcotic Antagonists; Pain; Phytotherapy; Plant Extracts

In the present work, we studied the effect of laetispicine, an amide alkaloid isolated from the stems of Piper laetispicum (Piperaceae), in forced swimming, open field, acetic acid writhing and formalin tests in KM mice to assess antidepressant and antinociceptive effects. A significant and dose-dependent decrease in the immobility time, as evaluated by the forced swimming test, was observed after laetispicine administration (38.18, 39.79, 58.77 and 67.28% decreased at the doses of 5, 10, 20, 40mg/kg, respectively), suggesting an antidepressant effect. Furthermore, in the open field test, laetispicine at the given doses did not alter the number of crossings and rearing, as compared to controls. Results from writhing and formalin tests showed that laetispicine reduced the number of writhing in mice in a dose-dependent manner, attenuated the licking and spiting time of the injected paw in the first phase of formalin test. The antinociceptive effect of laetispicine was not affected by pre-treatment (i.p.) with naloxone (2mg/kg). In conclusion, we showed that laetispicine possessed significant antidepressant and antinociceptive properties, making this drug potentially useful in depression and pain.

Topics: Acetic Acid; Analgesics; Animals; Antidepressive Agents; Behavior, Animal; Benzodioxoles; Depression; Dose-Response Relationship, Drug; Female; Male; Mice; Naloxone; Pain; Pain Measurement; Phytotherapy; Piper; Plant Extracts; Swimming

Many studies have shown that hypothalamic paraventricular nucleus (PVN) plays a role in pain process, and endogenous opiate peptide system in the spinal cord is involved in nociception. This communication was designed to study the relationship between PVN and endogenous opiate system in the spinal cord in the rat. The results showed that in both the thoracic and the lumber spinal cord, microinjection of 100 ng L-glutamate sodium into PVN could increase leucine-enkephalin (L-Ek), beta-endorphin (beta-Ep), dynorphinA(1-13) (DynA(1-13)) concentrations and PVN cauterization decreased L-Ek and beta-Ep concentrations. Pretreatment of the spinal cord with 5 microg naloxone, an opiate receptor antagonist could partly reverse the analgesia induced by microinjection of 100 ng L-glutamate sodium into PVN. The data suggested that PVN analgesia might be involved in the endogenous opiate peptide system in the spinal cord independently.

Topics: Analgesia; Animals; Glutamic Acid; Male; Microinjections; Naloxone; Narcotic Antagonists; Opioid Peptides; Pain; Pain Measurement; Paraventricular Hypothalamic Nucleus; Radioimmunoassay; Rats; Rats, Sprague-Dawley; Spinal Cord

The present study examined the antinociceptive effects of (O-methyl) N-benzoyl-tyramine (riparin I, ripI) isolated from the unripe fruit of Aniba riparia in chemical and thermal behavioral models of pain, such as acetic acid-induced abdominal writhing, formalin, and hot-plate tests in mice. Moreover, the involvement of the nitric oxide pathway as well as the opioid system in the antinociceptive action of ripI in the formalin test was investigated. RipI was administered both orally and intraperitoneally to male mice at single doses of 25 and 50 mg/kg. In the acetic acid-induced abdominal writhing, ripI decreased the number of writhings at both doses. In addition, in the formalin test, ripI reduced the paw licking time at both phases of the test. The effect of the highest dose of ripI in mice formalin test on the early phase was not reversed by naloxone (opioid receptor antagonist) but it was reversed by l-arginine (a nitric oxide precursor) in the late phase, suggesting that ripI may not act through opioid system and possibly acts through inhibition of nitric oxide pathway. In the hot-plate test, ripI increased the reaction time in the hot-plate test at the dose of 25 mg/kg, i.p., confirming the result found in the formalin test. Based on the obtained results, it is suggested that ripI presents antinociceptive activity that may be due to peripheral mechanisms (nitric oxide pathway) and central mechanisms, discarding the involvement of opioid system.

Topics: Acetic Acid; Administration, Oral; Analgesics; Analgesics, Opioid; Animals; Arginine; Behavior, Animal; Benzamides; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Inhibitors; Formaldehyde; Hot Temperature; Injections, Intraperitoneal; Lauraceae; Male; Mice; Morphine; Naloxone; Narcotic Antagonists; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Pain; Pain Measurement; Reaction Time; Time Factors; Tyramine

The antinociceptive effects of the selective noradrenaline reuptake inhibitor antidepressant reboxetine and its interaction with various opioid and noradrenaline receptor subtypes were evaluated. Reboxetine (i.p.) induced a weak dose-dependent antinociceptive effect in acute pain, using the hotplate model. The reboxetine-induced antinociception was significantly inhibited by the opioid receptor antagonists naloxone, nor-BNI, naltrindole and b-FNA, implying a non-selective role for the opioid receptors in the reboxetine's antinociceptive effect. The adrenergic antagonists yohimbine and phentolamine attenuated to some extent the reboxetine-induced antinociception, implying a minor adrenergic mechanism of antinociception. The addition of opioid or alpha2 agonists, did not potentiate the antinociception effect of reboxetine. Thus, it seems that reboxetine possesses a weak antinociceptive effect, mediated by non-selective opioid receptors and influenced somewhat by noradrenaline alpha2 receptors. These results suggest that reboxetine as monotherapy does not have sufficient efficacy in the management of acute pain. However, further research is needed in order to establish its possible use alone or in combination with other antidepressants or analgesics in the amelioration of chronic pain disorders.

Topics: Adrenergic Antagonists; Analgesics; Animals; Antidepressive Agents; Clonidine; Disease Models, Animal; Drug Interactions; Male; Mice; Mice, Inbred ICR; Morphine; Morpholines; Naloxone; Naltrexone; Narcotic Antagonists; Pain; Reboxetine; Receptors, Opioid, mu

Cytotoxic Necrotizing Factor 1 (CNF1) is a protein toxin from Escherichia coli that constitutively activates the Rho, Rac and Cdc42 GTPases. These regulatory proteins oscillate between a cytosolic GDP-bound inactive form and a membrane-linked GTP-bound active form, orchestrating the actin cytoskeleton assembly and dynamics. We herein describe, for the first time, the ability of CNF1 to potently counteract the formalin-induced inflammatory pain in mice. The analgesic response due to CNF1 requires both the sustained activation of the Rac GTPase, with consequent cerebral actin cytoskeleton remodeling, and the up-regulation of the mu-opioid receptors (MORs), the most important receptors controlling pain perception. The crucial role of Rac is proved by the lack of analgesic activity in mice challenged with a recombinant CNF1, in which the enzymatic activity was abolished by substituting serine with cysteine at position 866. The importance of MORs is proved by the inability of CNF1 to induce any analgesic effect in MORs knockout mice and by the ability of naloxone to antagonize the analgesic effects. Furthermore, it is worth noting that the analgesic effect in mice occurs after both peripheral and central administration of CNF1. Hence, taken altogether, our findings provide new insights into the comprehension of intracellular mechanisms involved in pain modulation, and indicate this bacterial protein toxin as a novel tool in the field of pain control. Conceivably, this might pave the way for new therapeutic strategies.

Topics: Analgesics; Animals; Bacterial Toxins; Cell Line, Tumor; Cerebellum; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Inhibitors; Escherichia coli Proteins; Formaldehyde; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Naloxone; Narcotic Antagonists; Neuroblastoma; NF-kappa B; p21-Activated Kinases; Pain; Pain Measurement; rac GTP-Binding Proteins; Receptors, Opioid, mu; rho GTP-Binding Proteins; Signal Transduction; Time Factors; Transfection; Up-Regulation

In comparison with cutaneous pain, the role of alpha(2)-adrenoceptor (alpha(2)-AR) agonists in visceral pain has not been extensively examined. We aimed to characterize the antinociceptive effect of IV dexmedetomidine on visceral pain in rats and to determine whether antinociception thus produced is mediated by opioid receptors.. Male Sprague Dawley rats (250-300 g) were instrumented with a venous catheter for drug administration and with enameled nichrome electrodes for electromyography of the external oblique muscles. Colorectal distension (CRD) was used as the noxious visceral stimulus, and the visceromotor response to CRD was quantified electromyographically before and 5, 15, 30, 60, 90, and 120 min after dexmedetomidine or clonidine administration. Antagonists were administered 10 min before dexmedetomidine. After confirmation of normal distribution of data, one-way analysis of variance with the Tukey-Kramer post hoc test was used for multiple comparison.. IV administration of dexmedetomidine (2.5-20 microg/kg) and clonidine (10-80 microg/kg) produced a dose-dependent reduction in visceromotor response with 50% effective dose values of 10.5 and 37.6 microg/kg, respectively. Administration of the nonspecific alpha(2)-AR antagonist yohimbine (1 mg/kg), but not the peripherally restricted alpha(2)-AR antagonist MK-467 (1 mg/kg), abolished the antinociceptive effect of dexmedetomidine (10 microg/kg). In addition, inhibition of opioid receptors by naloxone (1 mg/kg) attenuated the antinociceptive effect of dexmedetomidine.. Our data indicate that IV dexmedetomidine exerts pronounced antinociception against CRD-induced visceral pain and suggest that the antinociceptive effect of dexmedotimidine is mediated in part by opioid receptors, but peripheral alpha(2)-ARs are not involved.

Topics: Adrenergic alpha-Agonists; Adrenergic alpha-Antagonists; Analgesics, Non-Narcotic; Animals; Catheterization; Clonidine; Colon; Data Interpretation, Statistical; Dexmedetomidine; Dose-Response Relationship, Drug; Injections, Intravenous; Male; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Physical Stimulation; Quinolizines; Rats; Rats, Sprague-Dawley; Receptors, Opioid; Rectum; Yohimbine

Cholestasis is associated with increased activity of the endogenous opioid system that results in analgesia. Endocannabinoid system can reduce pain sensitivity. Considering the interaction that has been shown between the endogenous opioid and endocannabinoid systems in nociception processing, we studied the effect of AM404, an endocannabinoid transport inhibitor, on modulation of nociception in cholestasis, a model of elevated endogenous opioid tone. Cholestasis was induced by ligation of the main bile duct using two ligatures and transection of the duct at the midpoint between them. A significant increase (P<0.01) in TF was observed in cholestatic rats compared to unoperated and sham rats. AM404 (10 mg/kg, i.p.) significantly increased TFL at 5, 30 min but not 60 min after injection in cholestatic animals compared to the vehicle treated cholestatic group (P<0.05, P<0.001, respectively). AM404 injection to unoperated and sham rats did not alter baseline TFL. The effect of AM404 in cholestatic rats was blocked by co-administration of a CB(1) receptor antagonist, AM251 (1 mg/kg, i.p.) but not by the CB2 receptor antagonist, SR144528 (1 mg/kg, i.p.). Naloxone injection blocked the antinociception induced by cholestasis in bile duct ligated group. Antinociception produced by injection of AM404 in cholestatics was also attenuated by co-administration of naloxone. These data show that AM404 potentiates antinociception induced by cholestasis and indicate that there are possible interactions between opioid and cannabinoid systems in this experimental model of elevated endogenous opioid tone. The inhibitory effects of AM404 in this model are mediated by cannabinoid CB(1) and not CB(2) receptors.

Topics: Animals; Arachidonic Acids; Biological Transport; Camphanes; Cannabinoid Receptor Modulators; Cholestasis; Endocannabinoids; Male; Naloxone; Opioid Peptides; Pain; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2

Pertussis toxin (PTX) treatment results in ADP-ribosylation of Gi-protein and thus in disruption of mu-opioid receptor signal transduction and loss of the antinociceptive effect of morphine. We have previously demonstrated that pretreatment with ultra-low dose naloxone preserves the antinociceptive effect of morphine in PTX-treated rats. The present study further examined the effect of ultra-low dose naloxone on mu-opioid receptor signaling in PTX-treated rats and the underlying mechanism. Male Wistar rats implanted with an intrathecal catheter received an intrathecal injection of saline or PTX (1 microg in 5 microl of saline), then, 4 days later, were pretreated by intrathecal injection with either saline or ultra-low dose naloxone (15 ng in 5 microl of saline), followed, 30 min later, by saline or morphine (10 microg in 5 microl of saline). Four days after PTX injection, thermal hyperalgesia was observed, together with increased coupling of excitatory Gs-protein to mu-opioid receptors in the spinal cord. Ultra-low dose naloxone pretreatment preserved the antinociceptive effect of morphine, and this effect was completely blocked by the mu-opioid receptor antagonist CTOP, but not by the kappa-opioid receptor antagonist nor-BNI or the delta-opioid receptor antagonist naltrindole. Moreover, a co-immunoprecipitation study showed that ultra-low dose naloxone restored mu-opioid receptor/Gi-protein coupling and inhibited the PTX-induced mu-opioid receptor/Gs-protein coupling. In addition to the anti-neuroinflammatory effect and glutamate transporter modulation previously observed in PTX-treated rats, the re-establishment of mu-opioid receptor Gi/Go-protein coupling is involved in the restoration of the antinociceptive effect of morphine by ultra-low dose naloxone pretreatment by normalizing the balance between the excitatory and inhibitory signaling pathways. These results show that ultra-low dose naloxone preserves the antinociceptive effect of morphine, suppresses spinal neuroinflammation, and reduces PTX-elevated excitatory Gs-coupled opioid receptors in PTX-treated rats. We suggest that ultra-low dose naloxone might be clinically valuable in pain management.

Topics: Analgesics, Opioid; Animals; Drug Therapy, Combination; GTP-Binding Protein alpha Subunits, Gi-Go; GTP-Binding Protein alpha Subunits, Gs; Male; Morphine; Naloxone; Narcotic Antagonists; Pain; Pertussis Toxin; Rats; Rats, Wistar; Receptors, Opioid, mu; Spinal Cord

Topics: Administration, Topical; Aged; Analgesics, Opioid; Buprenorphine; Cholestasis; Chronic Disease; Drug Combinations; Female; Humans; Injections, Intravenous; Naloxone; Narcotic Antagonists; Neoplasms; Pain; Pain Measurement; Palliative Care; Pruritus; Treatment Outcome

There have been many reports indicating the analgesic and anti-inflammatory effects of 3,4-dihydroxychalcones. We have designed and synthesized a rigid 3,4-dihydroxychalcone (RDHC) as a possible drug effecting inflammation and nociception. The analgesic and anti-inflammatory effects were evaluated by formalin and hot-plate tests, respectively. The results showed that RDHC induced significant antinociceptive and anti-inflammatory effects (P < 0.01). Maximum analgesia (63.7%) was observed at 37.5 mg/kg in the first phase of the formalin test. The effect of RDHC was higher in the chronic phase (inflammation phase) of the formalin test (86.4%, P < 0.01). In addition, a significant analgesia (maximum possible effect; MPE = 30.1%) was observed in the hot plate test 45 min after injection of 37.5 mg/kg RDHC (P < 0.01). As a result of our findings, this new RDHC could be suggested for further pharmacological studies.

Topics: Analgesics; Analgesics, Opioid; Animals; Anti-Inflammatory Agents; Aspirin; Chalcone; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Formaldehyde; Hot Temperature; Inflammation; Male; Mice; Molecular Structure; Morphine; Naloxone; Narcotic Antagonists; Pain; Pain Measurement

Antidepressant drugs act as potent inhibitors of norepinephrine and/or serotonin reuptake and are widely used with opioids for the treatment of chronic pain. The mechanism of this increased analgesic action is unclear. We compared the antinociceptive effects of the intrathecal administration of morphine with that of a nonselective (amitriptyline) or selective (maprotiline or citalopram) antidepressant drug using the thermal withdrawal test in rats. We also investigated the possible mechanisms involved in the interactions of these drugs.. Male Wistar rats were anesthetized with sevoflurane and administered morphine and antidepressant drugs, or saline, through intrathecal injection. The antinociceptive effect was evaluated using the thermal withdrawal test before and after drug administration. The time for the withdrawal reaction was expressed as percentage of maximum possible effect (MPE). Animals were also pretreated with yohimbine (a nonselective alpha2-adrenergic antagonist) and naloxone (a nonselective opioid antagonist) for mechanism of action studies. Pharmacologic interaction was evaluated using isobolographic analysis of simultaneous administration of fixed proportions of maprotiline and morphine.. Single intrathecal administration of morphine (2 microg), amitriptiline (125 microg), citalopram (144 microg), and maprotiline (1.25 microg) produced 51.6% +/- 8.9%, 10.3% +/- 3.2%, 33.8% +/- 5.2%, and 48.5% +/- 9.2% MPE, respectively. The antinociceptive effect of morphine was increased when combined with amitriptyline (91.3% +/- 4.6% MPE) and maprotiline (86.9% +/- 9.2% MPE) but not with citalopram (40.6% +/- 4.6% MPE). Coadministration of maprotiline increased the antinociceptive duration of morphine by 4-fold (from 120 to 480 min), which was reversed by pretreatment with the alpha-2 adrenoceptor inhibitor, yohimbine, and the mu-type opioid receptor antagonist, naloxone. Isobolographic analysis demonstrated a synergistic interaction between morphine and maprotiline.. Selective norepinephrine reuptake inhibitors can significantly increase the intensity and duration of morphine antinociceptive activity via both alpha(2)-adrenergic and opioid receptors. This interaction was not observed with the selective serotonin inhibitor, citalopram.

Topics: Adrenergic alpha-Antagonists; Adrenergic Uptake Inhibitors; Amitriptyline; Analgesics, Opioid; Animals; Antidepressive Agents, Second-Generation; Behavior, Animal; Citalopram; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Injections, Spinal; Male; Maprotiline; Morphine; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Pain Threshold; Rats; Rats, Wistar; Reaction Time; Selective Serotonin Reuptake Inhibitors; Time Factors; Yohimbine

Topics: Analgesics, Opioid; Delayed-Action Preparations; Drug Combinations; Humans; Naloxone; Narcotic Antagonists; Oxycodone; Pain; Pain Measurement

Topics: Analgesics, Opioid; Delayed-Action Preparations; Drug Combinations; Humans; Naloxone; Narcotic Antagonists; Osteoporosis; Oxycodone; Pain; Quality of Life

The authors have recently demonstrated that the high serum estradiol level during the proestrus phase of the estrous cycle and that the administration of estradiol or progesterone in ovariectomized female and of testosterone in orchiectomized male rats significantly decrease formalin-induced temporomandibular joint (TMJ) nociception. In this study, the authors investigate the contribution of endogenous opioids to this antinociceptive effect of gonadal hormones in the TMJ formalin test. The opioid receptor antagonist naloxone was administrated either in the surrounding of the trigeminal sensory complex or in the TMJ region. The antinociceptive effect induced by endogenous estradiol in proestrus females and by exogenous estradiol in ovariectomized females was blocked by the administration of naloxone in the surrounding of the trigeminal sensory complex, but not in the TMJ region. The antinociceptive effect induced by the administration of progesterone in ovariectomized females and of testosterone in orchiectomized males was blocked by the administration of naloxone either in the surrounding of the trigeminal sensory complex or in the TMJ region. The authors conclude that central and peripheral opioid mechanisms mediate the antinociceptive effect of progesterone and testosterone, and central opioid mechanisms mediate the antinociceptive effect of estradiol. These findings suggest that the enhanced pain perception during low gonadal hormone periods in women and animals may be mediated by a decrease in endogenous opioid activity. This suggestion helps explain the higher severity of some pain conditions, such as temporomandibular dysfunctions in women than in men, that have no hormonal fluctuations.

Topics: Analgesia; Analysis of Variance; Androgens; Animals; Dose-Response Relationship, Drug; Estradiol; Estrogens; Estrous Cycle; Female; Formaldehyde; Male; Naloxone; Narcotic Antagonists; Opioid Peptides; Ovariectomy; Pain; Pain Measurement; Progesterone; Progestins; Rats; Rats, Wistar; Temporomandibular Joint; Testosterone Propionate

The implementation of standard order sets for patient-controlled analgesia (PCA) is described.. A review of naloxone usage at the University of Minnesota Medical Center (UMMC) from January to June 2004 found that 8% of patients receiving PCA had severe respiratory depression. A subanalysis of each event found that 85% of these patients had never before received opioid therapy. To reduce the risk of respiratory depression with PCA, separate standard order sets were developed for patients new to or tolerant of opioid therapy. A major component of both order sets was the standardization of a 10-minute lockout interval between each PCA dose. Implementation of the new PCA order sets raised concerns among health care professionals at UMMC that medication safety may be improved at the cost of increased pain. After implementation of the order sets, prescriber compliance, pharmacist interventions, the frequency of adverse effects, and patients' pain management were evaluated. After implementation of standard order sets for patients receiving PCA, 57% of patients' pain was documented as being controlled, and the orders for 93% of patients were in compliance with the recommended dosage interval of > or =10 minutes. There were no reports of oversedation or respiratory depression requiring reversal with naloxone.. The implementation of standard order sets for PCA resulted in a dramatic decrease in the number of cases of severe respiratory depression and increased use of the order set for patients new to opioid therapy. Changing the order sets to improve medication safety did not appear to negatively affect patients' satisfaction with pain management.

Topics: Academic Medical Centers; Adolescent; Adult; Aged; Aged, 80 and over; Analgesia, Patient-Controlled; Humans; Medical Audit; Medical Order Entry Systems; Middle Aged; Minnesota; Naloxone; Narcotic Antagonists; Organizational Case Studies; Pain; Respiratory Insufficiency

In order to clarify the effect of age-related change in trigeminal nociception, phosphorylation of extracellular signal-regulated kinase (pERK) in trigeminal spinal subnucleus caudalis (Vc) and upper cervical spinal cord neurons were studied in the aged rats following subcutaneous capsaicin injection into the whisker pad. A large number of pERK-LI cells was expressed in the superficial laminae of Vc and upper cervical spinal cord in adult and aged rats following subcutaneous capsaicin injection into the whisker pad region. The number of pERK-LI cells was largest at about 2.0mm caudal from the obex and gradually decreased in their numbers in more rostral and caudal sections. The rostro-caudal distribution profile of pERK-LI cells expressed after subcutaneous capsaicin injection into whisker pad was similar in adult and aged rats. The number of pERK-LI cells was slightly, but not significantly larger in aged rats compared with that of adults. Pretreatment with naloxone significantly increased the number of capsaicin-induced pERK-LI cells in adult rats but not in aged rats. The present findings suggest that the descending modulation system impaired with advancing age, resulting in the abnormal pain sensation in aged rats.

Topics: Aging; Animals; Capsaicin; Extracellular Signal-Regulated MAP Kinases; Face; Naloxone; Narcotic Antagonists; Neural Pathways; Pain; Phosphorylation; Rats; Rats, Inbred F344; Sensory System Agents; Trigeminal Caudal Nucleus

It has been shown that the behavioural responses to chemically evoked visceral nociception are increased in transgenic mice lacking the kappa-opioid receptor (KOR). The aim of the present study was to evaluate the contribution of KOR in mechanically evoked visceral pain by performing colorectal distension (CRD) and monitoring the subsequent visceromotor response (VMR) in control mice (KOR(+/+)) and in mice lacking KOR (KOR(-/-)). Pseudo-affective visceral pain responses were evoked in conscious mice using increasing (10-80 mmHg) and repeated (12 x 55 mmHg) phasic CRD paradigms. The resulting VMR was determined by monitoring the electromyographic activity of the abdominal muscle. The increasing and repeated CRD paradigms, respectively, evoked similar responses in both KOR(+/+) and KOR(-/-) mice. The selective KOR-agonists U-69593 (5 and 25 mg kg(-1), s.c.) and asimadoline (25 mg kg(-1), s.c.) significantly decreased the VMR in KOR(+/+) mice, while having no effect in KOR(-/-) mice. In contrast, the selective mu-opioid receptor agonist fentanyl significantly reduced the VMR in both types of mice and appeared more efficacious in KOR(-/-) mice. The opioid receptor antagonist naloxone (0.3-30 mg kg(-1) s.c.) did not affect the response to CRD in C57BL/6 mice at any dose tested. In conclusion, the data confirm that the KOR agonists used in this study inhibit the VMR to CRD in mice by acting via KOR receptors. In addition, the data suggest that the endogenous opioid system is not likely to modulate the VMR to mechanically evoked visceral pain in mice.

Topics: Analgesics, Opioid; Animals; Colon; Dilatation, Pathologic; Electromyography; Female; Fentanyl; Humans; Mice; Mice, Inbred C57BL; Mice, Knockout; Naloxone; Narcotic Antagonists; Nociceptors; Pain; Pain Measurement; Receptors, Opioid, kappa; Receptors, Opioid, mu; Rectum

Although activated spinal cord glia contribute importantly to neuropathic pain, how nerve injury activates glia remains controversial. It has recently been proposed, on the basis of genetic approaches, that toll-like receptor 4 (TLR4) may be a key receptor for initiating microglial activation following L5 spinal nerve injury. The present studies extend this idea pharmacologically by showing that TLR4 is key for maintaining neuropathic pain following sciatic nerve chronic constriction injury (CCI). Established neuropathic pain was reversed by intrathecally delivered TLR4 receptor antagonists derived from lipopolysaccharide. Additionally, (+)-naltrexone, (+)-naloxone, and (-)-naloxone, which we show here to be TLR4 antagonists in vitro on both stably transfected HEK293-TLR4 and microglial cell lines, suppressed neuropathic pain with complete reversal upon chronic infusion. Immunohistochemical analyses of spinal cords following chronic infusion revealed suppression of CCI-induced microglial activation by (+)-naloxone and (-)-naloxone, paralleling reversal of neuropathic pain. Together, these CCI data support the conclusion that neuron-to-glia signaling through TLR4 is important not only for initiating neuropathic pain, as suggested previously, but also for maintaining established neuropathic pain. Furthermore, these studies suggest that the novel TLR4 antagonists (+)-naloxone and (-)-naloxone can each fully reverse established neuropathic pain upon multi-day administration. This finding with (+)-naloxone is of potential clinical relevance. This is because (+)-naloxone is an antagonist that is inactive at the (-)-opioid selective receptors on neurons that produce analgesia. Thus, these data suggest that (+)-opioid antagonists such as (+)-naloxone may be useful clinically to suppress glial activation, yet (-)-opioid agonists suppress pain.

Topics: Animals; Behavior, Animal; Biomarkers; Cell Line; Humans; Injections, Spinal; Male; Microglia; Naloxone; Naltrexone; Narcotic Antagonists; Pain; Pain Measurement; Rats; Rats, Sprague-Dawley; Signal Transduction; Toll-Like Receptor 4

The aqueous extract of Ficus deltoidea leaves was evaluated for possible antinociceptive activity in three models of nociception, namely, acetic acid-induced abdominal writhing, formalin and hot plate test. The results of the present study showed that intraperitoneal administration of the F. deltoidea leaves aqueous extract at the dose of 1, 50 and 100 mg/kg, 30 min prior to pain induction produced significant dose-dependent antinociceptive effect in all the models used, which indicating the presence of both central and peripherally mediated activities. Furthermore, the antinociceptive effect of the extract in the formalin and hot plate test was reversed by the non-selective opioid receptor antagonist naloxone suggesting that the endogenous opioid system is involved in its analgesic mechanism of action. Thus, the present results demonstrated that F. deltoidea leaves aqueous extract contains pharmacologically active constituents which possess antinociceptive activity justifying its popular therapeutic use in treating conditions associated with the painful conditions.

Topics: Acetic Acid; Analgesics; Analysis of Variance; Animals; Dose-Response Relationship, Drug; Ficus; Formaldehyde; Hot Temperature; Male; Mice; Mice, Inbred BALB C; Naloxone; Narcotic Antagonists; Pain; Phytotherapy; Plant Extracts; Plant Leaves; Rats; Rats, Sprague-Dawley

We previously reported the synthesis of three new opioid agonists as well as their in vitro and in vivo activity [Girón, R., Abalo, R., Goicoechea, C., Martín, M.I., Callado, L.F., Cano, C., Goya, P., Jagerovic, N. 2002. Synthesis and opioid activity of new fentanyl analogs. Life Sci. 71, 1023-1034]. One of them, N-[1-phenylpyrazol-3-yl]-N-[1-(2-phenethyl)-4-piperidyl)] propenamide (IQMF-4), showed an interesting antinociceptive activity. Intraperitoneally (i.p.) administered, it was as effective as fentanyl or morphine, being less potent than fentanyl but more so than morphine. The aim of the present work was to evaluate its antinociceptive effect by different routes of administration, using the hot plate test, and to investigate possible side effects, such as tolerance and withdrawal, in vitro, using the myenteric plexus-longitudinal muscle strip preparation from guinea pig ileum, and in vivo, using the hot plate test. IQMF-4 was more potent than morphine when administered per os (p.o.), but less potent when administered intracerebroventricularly (i.c.v.). By both routes, fentanyl is more potent that IQMF-4. When IQMF-4 was administered i.p., naloxone methiodide, a peripherally acting antagonist, was able to completely block its antinociceptive effect, whereas, after i.c.v. administration, the blockade was only partial. An interesting feature of the new compound is that it induces tolerance in vitro but not in vivo. Moreover, though in vitro withdrawal was not different from fentanyl or morphine, in vivo withdrawal symptoms were significantly less frequent in mice treated with IQMF-4 than in those treated with morphine or fentanyl. Although more assays are required, these results show that IQMF-4 appears to be a potent analgesic compound with an interesting peripheral component, and reduced ability to induce dependence.

Topics: Administration, Oral; Analgesics, Opioid; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Tolerance; Fentanyl; Guinea Pigs; Hot Temperature; Ileum; Injections, Intraperitoneal; Injections, Intraventricular; Male; Mice; Morphine; Muscle Contraction; Muscle, Smooth; Naloxone; Narcotic Antagonists; Opioid-Related Disorders; Pain; Pain Measurement; Pain Threshold; Piperidines; Propane; Quaternary Ammonium Compounds; Reaction Time; Substance Withdrawal Syndrome; Time Factors

The use of nicotinic agonists for analgesia is limited by their unacceptable side effects. Sazetidine-A is a new partial agonist nicotinic ligand that has very high selectivity for beta2-containing nicotinic acetylcholine receptors. It potently and selectively desensitizes alpha4beta2 nicotinic acetylcholine receptors without measurable effects on alpha3beta4 receptors. The authors investigated the analgesic effects of Sazetidine-A using the formalin model of chronic inflammatory pain.. The formalin test was conducted after rats received intraperitoneal saline, Sazetidine-A (0.125, 0.25, 0.5, 1, 2 mg/kg), or subcutaneous epibatidine (2.5-5-10 mug/kg). In other experiments, Sazetidine-A was preceded by naloxone (0.5 mg/kg) or mecamylamine (10 mg). Effects of Sazetidine-A and epibatidine on locomotor were tested in an open field, and seizure activity was measured using the Racine scale. Locus coeruleus neuron extracellular single-unit spontaneous discharge was recorded in anesthetized animals after Sazetidine-A and epibatidine.. Higher doses of Sazetidine-A (0.5, 1, or 2 mg/kg) induced analgesia, with pain scores significantly lower than those seen after saline, lower doses of Sazetidine-A, and epibatidine (P < 0.001). Naloxone did not antagonize the effects of Sazetidine-A, and mecamylamine had partial, dose-dependent antagonistic effects. Epibatidine excited locus coeruleus neurons, whereas Sazetidine-A had no effect on these neurons. Epibatidine and Sazetidine-A affected animals' locomotor activity for the initial 20 min. While analgesic doses of epibatidine caused seizures, no seizure activity or other neurologic complications were seen in animals that received as much as four times the minimum analgesic dose of Sazetidine-A.. Sazetidine-A seems to be a potent analgesic without causing neurologic side effects.

Topics: Analgesics; Animals; Azetidines; Bridged Bicyclo Compounds, Heterocyclic; Cholinergic Agents; Disease Models, Animal; Dose-Response Relationship, Drug; Male; Mecamylamine; Motor Activity; Naloxone; Narcotic Antagonists; Nicotinic Agonists; Nicotinic Antagonists; Pain; Pain Measurement; Pyridines; Rats; Rats, Sprague-Dawley; Receptors, Nicotinic; Sodium Chloride

The infusion or decoction of Mirabilis jalapa leaves is used in traditional medicine in Brazil to treat inflammatory and painful diseases.. The present study examined the antinociceptive effect of Mirabilis jalapa extracts from leaves and stems in models of pain in mice.. The crude hydroethanolic extract from leaves (CrdL) was more potent than the crude extract from stems (CrdS) to inhibit abdominal constrictions induced by acetic acid, with ID(50) values of 5.5 (2.3-13.1) and 18.0 (11.3-28.5) mg/kg, respectively. Among the fractions tested, the Eta fraction from leaves (Eta) was more effective (maximal inhibition of 83+/-8%) and potent (ID(50) of 1.1 (0.6-2.1) mg/kg) to induce antinociception. Eta and CrdL also possessed an antinociceptive effect in the tail-flick test. Pre-treatment with naloxone did not modify the antinociceptive effect of Eta, but co-administration with atropine completely prevented it. This suggests that the antinociceptive effect might depend on the cholinergic system. Instead, Eta was not able to alter the acetylcholinesterase activity in blood or spinal cord. Concerning side effects, Eta did not alter locomotor activity, body temperature, gastrointestinal transit and did not produce gastric lesions.. Our results demonstrate that Mirabilis jalapa presents antinociceptive activity in mice, which supports its folkloric use as an analgesic.

Topics: Acetylcholinesterase; Analgesics; Animals; Atropine; Body Temperature; Brazil; Disease Models, Animal; Gastrointestinal Transit; Inhibitory Concentration 50; Male; Medicine, Traditional; Mice; Mirabilis; Motor Activity; Naloxone; Pain; Pain Measurement; Plant Extracts; Plant Leaves; Plant Stems; Toxicity Tests

Crotoxin (CTX), a neurotoxin isolated from the venom of the South American rattlesnake Crotalus durissus terrificus, induces analgesia. In this study, we evaluated the antinociceptive effect of CTX in a model of neuropathic pain induced by rat sciatic nerve transection. Hyperalgesia was detected 2 h after nerve transection and persisted for 64 days. Immersion of proximal and distal nerve stumps in CTX solution (0.01 mM for 10 s), immediately after nerve transection, blocked hyperalgesia. The antinociceptive effect of CTX was long-lasting, since it was detected 2 h after treatment and persisted for 64 days. CTX also delayed, but did not block, neurectomy-induced neuroma formation. The effect of CTX was blocked by zileuton (100 mg/kg, p.o.) and atropine (10 mg/kg, i.p.), and reduced by yohimbine (2 mg/kg, i.p.) and methysergide (5 mg/kg, i.p.). On the other hand, indomethacin (4 mg/kg, i.v.), naloxone (1 mg/kg, i.p.), and N-methyl atropine (30 mg/kg, i.p.) did not interfere with the effect of CTX. These results indicate that CTX induces a long-lasting antinociceptive effect in neuropathic pain, which is mediated by activation of central muscarinic receptors and partially, by activation of alpha-adrenoceptors and 5-HT receptors. Eicosanoids derived from the lipoxygenase pathway modulate the action of crotoxin.

Topics: Analgesics, Non-Narcotic; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arachidonate 5-Lipoxygenase; Creatine Kinase; Crotoxin; Eicosanoids; Hyperalgesia; Indomethacin; Male; Motor Activity; Muscarinic Agonists; Muscarinic Antagonists; Naloxone; Narcotic Antagonists; Pain; Pain Threshold; Peripheral Nervous System Diseases; Rats; Receptors, Muscarinic; Sciatic Nerve; Serotonin

Previous work from our group showed that intrathecal (i.t.) administration of substances such as glutamate, NMDA, or PGE(2) induced sensitization of the primary nociceptive neuron (PNN hypernociception) that was inhibited by a distal intraplantar (i.pl.) injection of either morphine or dipyrone. This pharmacodynamic phenomenon is referred to in the present work as "teleantagonism". We previously observed that the antinociceptive effect of i.t. morphine could be blocked by injecting inhibitors of the NO signaling pathway in the paw (i.pl.), and this effect was used to explain the mechanism of opioid-induced peripheral analgesia by i.t. administration. The objective of the present investigation was to determine whether this teleantagonism phenomenon was specific to this biochemical pathway (NO) or was a general property of the PNNs. Teleantagonism was investigated by administering test substances to the two ends of the PNN (i.e., to distal and proximal terminals; i.pl. plus i.t. or i.t. plus i.pl. injections). We found teleantagonism when: (i) inhibitors of the NO signaling pathway were injected distally during the antinociception induced by opioid agonists; (ii) a nonselective COX inhibitor was tested against PNN sensitization by IL-1beta; (iii) selective opioid-receptor antagonists tested against antinociception induced by corresponding selective agonists. Although the dorsal root ganglion seems to be an important site for drug interactions, the teleantagonism phenomenon suggests that, in PNNs, a local sensitization spreads to the entire cell and constitutes an intriguing and not yet completely understood pharmacodynamic property of this group of neurons.

Topics: Analgesics, Opioid; Animals; Anti-Inflammatory Agents, Non-Steroidal; Dinoprostone; Dopamine; Drug Interactions; Enzyme Inhibitors; Indomethacin; Interleukin-1beta; Male; Morphine; Naloxone; Narcotic Antagonists; Nitric Oxide; Nociceptors; omega-N-Methylarginine; Oxadiazoles; Pain; Pyrrolidines; Quinoxalines; Rats; Rats, Wistar; Sensory Receptor Cells; Signal Transduction

Previous studies have provided evidence of the existence of a pain modulatory feedback pathway consisting of thalamic nucleus submedius (Sm)-ventrolateral orbital cortex-periaqueductal grey pathway, which is activated during acute pain and leads to depression of transmission of nociceptive information in the spinal dorsal horn. The aim of this study was to test the hypothesis that morphine microinjection into the Sm decreased spontaneous pain and bilateral thermal hyperalgesia, as well as ipsilateral mechanical allodynia, induced by subcutaneous injections of bee venom into the rat hind paw. Morphine (1.0, 2.5 or 5.0 microg in 0.5 microL) injected into the Sm, contralateral to the bee venom-injected paw, depressed spontaneous nociceptive behaviour in a dose-dependent manner. Furthermore, morphine significantly decreased bilateral thermal hyperalgesia and ipsilateral mechanical allodynia 2 h after bee venom injection. These morphine-induced effects were antagonized by 1.0 microg naloxone (an opioid antagonist) microinjected into the Sm 5 min before morphine administration. The results provided further support for the important role of the Sm and Sm-opioid receptors in inhibiting nociceptive behaviour and indicated for the first time that Sm opioid receptors were also effective in inhibiting the hypersensitivity provoked by bee venom-induced inflammation.

Topics: Analgesics, Opioid; Animals; Bee Venoms; Behavior, Animal; Brain Stem; Dose-Response Relationship, Drug; Hindlimb; Hyperalgesia; Inflammation; Injections, Subcutaneous; Male; Microinjections; Morphine; Naloxone; Narcotic Antagonists; Nociceptors; Pain; Pain Threshold; Rats; Rats, Sprague-Dawley; Reaction Time; Thalamic Nuclei; Time Factors

The aim of the present study was to evaluate the antinociceptive effect of the novel pyrazoline methyl ester: 4-methyl-5-trifluoromethyl-5-hydroxy-4,5-dihydro-1H-pyrazole methyl ester (MPF4).. The effect of MPF4 was assessed in two models of pain: arthritic pain caused by Complete Freund's Adjuvant (CFA) and postoperative pain caused by surgical incision in mice.. MPF4 given intraperitoneally (1.0 mmol/kg, i.p.) produced marked antinociception in inflammatory allodynia caused by CFA. The antinociceptive effect produced by MPF4 was reversed with the pre-treatment of animals with naloxone or naltrindole. Oral administration of MPF4 (1.0 mmol/kg, p.o), dipyrone (1.0 mmol/kg, p.o.) and morphine (0.026 mmol/kg, p.o.) also produced an anti-allodynic effect. However, none of the compounds evaluated reversed the paw edema produced by CFA. Moreover, MPF4, dipyrone and morphine also produced an anti-allodynic effect in the surgical incisional pain model. The maximal inhibitions obtained with preemptive drug treatment were 66+/-7%, 73+/-9% and 88+/-8% for MPF4 (1.0 mmol/kg, p.o.), dipyrone (1.0 mmol/kg, p.o.) and morphine (0.026 mmol/kg, p.o.), respectively. The maximal inhibitions obtained with curative drug treatment were 53+/-9%, 83+/-7% and 84+/-7%, for MPF4, dipyrone and morphine, respectively. Unlike indomethacin, MPF4 did not induce gastric lesions at the dose that caused the highest antinociception (1.0 mmol/kg, p.o). The anti-allodynic action of MPF4, dipyrone and morphine was not associated with impairment of motor activity.. The results of the present study suggest that MPF4 represents a potential target for the development of new drugs to treat persistent inflammatory pain.

Topics: Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Experimental; Dipyrone; Freund's Adjuvant; Indomethacin; Inflammation; Male; Mice; Morphine; Motor Activity; Naloxone; Naltrexone; Narcotic Antagonists; Pain; Pain, Postoperative; Postural Balance; Pyrazoles; Stomach Ulcer

Postsynaptic density (PSD)-93, a neuronal scaffolding protein, binds to and clusters N-methyl-D-aspartate receptor (NMDAR) subunits NR2A and NR2B at cellular membranes in vitro. However, the roles of PSD-93 in synaptic NR2A and NR2B targeting in the central nervous system and NMDAR-dependent physiologic and pathologic processes are still unclear. We report here that PSD-93 deficiency significantly decreased the amount of NR2A and NR2B in the synaptosomal membrane fractions derived from spinal cord dorsal horn and forebrain cortex but did not change their levels in the total soluble fraction from either region. However, PSD-93 deficiency did not markedly change the amounts of NR2A and NR2B in either synaptosomal or total soluble fractions from cerebellum. In mice deficient in PSD-93, morphine dose-dependent curve failed to shift significantly rightward as it did in wild type (WT) mice after acute and chronic morphine challenge. Unlike WT mice, PSD-93 knockout mice also showed marked losses of NMDAR-dependent morphine analgesic tolerance and associated abnormal sensitivity in response to mechanical, noxious thermal, and formalin-induced inflammatory stimuli after repeated morphine injection. In addition, PSD-93 knockout mice displayed dramatic loss of jumping activity, a typical NMDAR-mediated morphine withdrawal abstinence behavior. These findings indicate that impaired NMDAR-dependent neuronal plasticity following repeated morphine injection in PSD-93 knockout mice is attributed to PSD-93 deletion-induced alterations of synaptic NR2A and NR2B expression in dorsal horn and forebrain cortex neurons. The selective effect of PSD-93 deletion on synaptic NMDAR expression in these two major pain-related regions might provide the better strategies for the prevention and treatment of opioid tolerance and physical dependence.

Topics: Analgesics, Opioid; Animals; Central Nervous System; Drug Tolerance; Guanylate Kinases; Intracellular Signaling Peptides and Proteins; Male; Membrane Proteins; Mice; Mice, Knockout; Morphine; Naloxone; Nerve Tissue Proteins; Pain; Posterior Horn Cells; Prosencephalon; Receptors, N-Methyl-D-Aspartate; Synaptosomes

We present simple method to assess dental pain in the awake rat. Using a sensitive strain gauge we examined changes in bite strength and bite pattern in rats following dental injury. Rats with dental injury displayed a significant reduction in mean peak bite strength and an altered bite cluster pattern. Both changes in the dental injury rats were reversed by an analgesic dose of morphine, and this could be reversed with naloxone. These changes were not observed in naive control animals. This simple method significantly improves our ability to evaluate dental pain syndromes.

Topics: Analgesics, Opioid; Analysis of Variance; Animals; Bite Force; Dental Pulp; Dental Stress Analysis; Male; Morphine; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Random Allocation; Rats; Rats, Long-Evans; Time Factors

Acute administration of opioids produces analgesia, while chronic administration induces tolerance and dependence. Aquaporin 4 (AQP4) is most strongly expressed in astrocytes throughout central nervous system, and plays an important role in some pathophysiological processes in brain. However, whether AQP4 modulates opioid analgesia, tolerance and dependence or not remains unknown. In the present study, the effects of AQP4 deficiency on morphine analgesia, tolerance and physical dependence were investigated. (1) In hot-plate tests, ED(50) values of morphine analgesia were 3.77 and 3.96 mg/kg in male and female AQP4 knockout mice, which were lower than that in wild-type mice (5.23 and 5.20mg/kg in males and females). (2) Repeated treatment with morphine resulted in analgesic tolerance to morphine in wild-type mice, whereas the morphine tolerance was attenuated in AQP4 knockout mice treated as the same schedule. (3) After repeated morphine administration, naloxone precipitation induced significant abstinent jumping in wild-type mice, whereas naloxone-induced abstinent jumping was not observed in AQP4 knockout mice. This suggested that AQP4 deficiency inhibited the development of morphine physical dependence. (4) Repeated morphine administration down-regulated cerebral glutamate transporter 1 (GLT-1) expression in wild-type mice. However, the down-regulation of GLT-1 expression diminished in AQP4 knockout mice. Taken together, these results demonstrated that AQP4 deficiency potentiated morphine analgesia, attenuated morphine tolerance and physical dependence. The suppression of down-regulation of cerebral GLT1 expression might mediate the attenuation of AQP4 deficiency to morphine tolerance and dependence.

Topics: Analgesics, Opioid; Analysis of Variance; Animals; Aquaporin 4; Blotting, Western; Cerebral Cortex; Dose-Response Relationship, Drug; Drug Tolerance; Excitatory Amino Acid Transporter 2; Female; Hot Temperature; Male; Mice; Mice, Knockout; Morphine; Morphine Dependence; Naloxone; Pain; Pain Measurement; Substance Withdrawal Syndrome; Thermosensing

The possible characteristics of spinal interaction between sildenafil (phosphodiesterase 5 inhibitor) and morphine on formalin-induced nociception in rats was examined. Then the role of the opioid receptor in the effect of sildenafil was further investigated. Catheters were inserted into the intrathecal space of male Sprague-Dawley rats. For induction of pain, 50 microL of 5% formalin solution was applied to the hind-paw. Isobolographic analysis was used for the evaluation of drug interaction between sildenafil and morphine. Furthermore, naloxone was intrathecally given to verify the involvement of the opioid receptor in the antinociception of sildenafil. Both sildenafil and morphine produced an antinociceptive effect during phase 1 and phase 2 in the formalin test. The isobolographic analysis revealed an additive interaction after intrathecal delivery of the sildenafil-morphine mixture in both phases. Intrathecal naloxone reversed the antinociception of sildenafil in both phases. These results suggest that sildenafil, morphine, and the mixture of the two drugs are effective against acute pain and facilitated pain state at the spinal level. Thus, the spinal combination of sildenafil with morphine may be useful in the management of the same state. Furthermore, the opioid receptor is contributable to the antinocieptive mechanism of sildenafil at the spinal level.

Topics: Analgesics; Analgesics, Opioid; Animals; Behavior, Animal; Dose-Response Relationship, Drug; Drug Synergism; Formaldehyde; Injections, Spinal; Male; Morphine; Naloxone; Narcotic Antagonists; Pain; Pain Management; Pain Measurement; Phosphodiesterase Inhibitors; Piperazines; Purines; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Sulfones; Time Factors

Trigonopleura malayana L. (Euphorbiaceae) resin, locally known as Gambir Sarawak, has been used traditionally to alleviate pain associated with insect bites, muscle ache, toothache and minor injuries. The present study was carried out using various animal models to determine the antinociceptive and antiinflammatory activities of the T. malayana resin aqueous extract. Antinociceptive activity was measured using the abdominal constriction, hot plate and formalin tests, while antiinflammatory activity was measured using the carrageenan-induced paw edema test. The extract, obtained after 24 h of soaking the dried resin in distilled water, was prepared in doses of 0.3, 3 and 10 mg/kg and administered subcutaneously 30 min prior to the assays. The mechanism of action was also determined by prechallenging with naloxone (10 mg/kg), a nonselective opioid antagonist. The extract was found to exhibit significant (P < 0.05) and dose-dependent antinociceptive and antiinflammatory activities; naloxone failed to inhibit the former activity. In conclusion, the aqueous extract of T. malayana resin possesses nonopioid antinociceptive and antiinflammatory activities, thus supporting previous claims regarding its traditional use by the Malays to treat various ailments, particularly those related to pain.

Topics: Analgesics, Non-Narcotic; Animals; Anti-Inflammatory Agents, Non-Steroidal; Carrageenan; Edema; Euphorbiaceae; Injections, Subcutaneous; Lethal Dose 50; Male; Mice; Mice, Inbred BALB C; Models, Animal; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Phytotherapy; Plant Extracts; Rats; Rats, Sprague-Dawley; Resins, Plant

In a previous study, we showed that electroacupuncture (EA) applied to the SI-6 point on the contralateral forelimb produces long-lasting and powerful analgesia in pain caused by ankle sprain in a rat model. To investigate the underlying mechanism of EA analgesia, the present study tested the effects of various antagonists on known endogenous analgesic systems in this model. Ankle sprain was induced in anesthetized rats by overextending their right ankle with repeated forceful plantar flexion and inversion of the foot. When rats developed pain behaviors (a reduction in weight-bearing of the affected hind limb), EA was applied to the SI-6 point on the contralateral forelimb for 30 min under halothane anesthesia. EA significantly improved the weight-bearing capacity of the affected hind limb for 2h, suggesting an analgesic effect. The alpha-adrenoceptor antagonist phentolamine (2mg/kg, i.p. or 30 microg, i.t.) completely blocked the EA-induced analgesia, whereas naloxone (1mg/kg, i.p.) failed to block the effect. These results suggest that EA-induced analgesia is mediated by alpha-adrenoceptor mechanisms. Further experiments showed that intrathecal administration of yohimbine, an alpha(2)-adrenergic antagonist, reduced the EA-induced analgesia in a dose-dependent manner, whereas terazosin, an alpha(1)-adrenergic antagonist, did not produce any effect. These data suggest that the analgesic effect of EA in ankle sprain pain is, at least in part, mediated by spinal alpha(2)-adrenoceptor mechanisms.

Topics: Acupuncture Analgesia; Acupuncture Points; Adrenergic alpha-Antagonists; Analysis of Variance; Animals; Ankle Injuries; Cross-Over Studies; Disease Models, Animal; Double-Blind Method; Male; Naloxone; Narcotic Antagonists; Pain; Pain Management; Pain Measurement; Randomized Controlled Trials as Topic; Rats; Rats, Sprague-Dawley; Sprains and Strains; Time Factors

The analgesic and antiinflammatory properties of mollic acid glucoside (MAG), a 1 alpha-hydroxycycloartenoid extract from Combretum molle leaf, have been investigated in mice and rats. The effects of graded doses of mollic acid glucoside (MAG, 5-80 mg/kg i.p.) were examined against thermally- and chemically-induced nociceptive pain in mice. Furthermore, the effects of graded doses of the plant extract (MAG, 5-80 mg/kg p.o.) were also investigated on rat paw oedema induced by subplantar injections of fresh egg albumin (0.5 mg/kg). Morphine (MPN, 10 mg/kg i.p.) and diclofenac (DIC, 100 mg/kg i.p.) were used as reference analgesic and antiinflammatory agents for comparison, respectively. Like DIC (100 mg/kg i.p.) and MPN (10 mg/kg i.p.), MAG (5-80 mg/kg i.p.) produced dose-dependent, significant (p < 0.05-0.001) analgesic effects against thermally and chemically induced nociceptive pain in mice. The extractive (MAG, 5-80 mg/kg i.p.) also significantly reduced (p < 0.05-0.001) rat paw oedema induced by subplantar injections of fresh egg albumin in a dose-related fashion. However, the extract (MAG, 5-80 mg/kg i.p.) was found to be less potent than diclofenac (DIC) as an analgesic or antiinflammatory agent. Experimental evidence obtained from this laboratory animal study indicates that the Combretum molle leaf extractive (MAG) possesses analgesic and antiinflammatory properties, and thus lend pharmacological credence to the folkloric, ethnomedical uses of the plant's leaf in the management, control and/or treatment of painful, arthritic and other inflammatory conditions in some rural communities of southern Africa.

Topics: Acetic Acid; Analgesics; Animals; Anti-Inflammatory Agents; Combretum; Diclofenac; Edema; Female; Hindlimb; Male; Mice; Mice, Inbred BALB C; Molecular Structure; Morphine; Naloxone; Pain; Pain Measurement; Phytotherapy; Plant Extracts; Plant Leaves; Rats; Rats, Wistar; Saponins

Visceral pain is one of the most common forms of pain and for which new drugs would be welcome. The aim of this study was to investigate whether gabapentin inhibits induced abdominal contractions in mice and to examine the effect of its co-administration with morphine.. A total of 96 mice received acetic acid intraperitoneally after administration of saline or gabapentin (1, 5, 10, 50 and 100 mg kg(-1)) or morphine (0.25, 0.5, 1, 3 and 5 mg kg(-1)) or a combination of morphine and gabapentin. Other groups also received naloxone. The number of writhes were counted.. Both gabapentin and morphine reduced writhing in a dose-dependent manner. The number of writhes was decreased significantly by gabapentin (50 and 100 mg kg(-1)) and morphine (0.5, 1, 3 and 5 mg kg(-1)) (P < 0.001). Also, the lowest dose of morphine 0.25 mg kg(-1) when combined with low doses of gabapentin significantly decreased the number of writhes (P < 0.005). The combination of a low effective dose of gabapentin (50 mg kg(-1)) with a low dose of morphine decreased the writhing by 94% as compared to the controls. The antinociceptive effect of combined administration was not reversed by naloxone.. These data demonstrated the comparable efficacy of gabapentin with morphine in visceral pain. Also, the results showed that the combination of doses of gabapentin and morphine, which were ineffective alone, produced a significant analgesic effect in the writhing model of pain. This may be clinically important in the management of visceral pain.

Topics: Acetic Acid; Amines; Analgesics; Analgesics, Opioid; Analysis of Variance; Animals; Cyclohexanecarboxylic Acids; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Gabapentin; gamma-Aminobutyric Acid; Male; Mice; Morphine; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Sodium Chloride

The present study investigated the role of peripheral opioid receptors in mustard oil-induced nociceptive behavior and inflammation in the masseter muscles of lightly anesthetized rats. Experiments were carried out on male Sprague-Dawley rats weighing between 300 and 400 g. After initial anesthesia with sodium pentobarbital (40 mg/kg, i.p.), one femoral vein was cannulated and connected to an infusion pump for the intravenous infusion of sodium pentobarbital. The rate of infusion was adjusted to provide a constant level of anesthesia. Mustard oil (MO, 30 microl) was injected into the mid-region of the left masseter muscle via a 30-gauge needle. Intramuscularly-administered morphine significantly reduced shaking behavior but not MO-induced inflammation. Intramuscular pretreatment with naloxone, an opioid receptor antagonist, reversed antinociception produced by intramuscularly-administered morphine, while intracisternal administration of naloxone did not affect the antinociception of peripheral morphine. Pretreatment with d-Pen-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP), a mu opioid receptor antagonist, but not naltrindole, a delta opioid receptor antagonist, nor norbinaltorphimine (nor-BNI), a kappa opioid receptor antagonist, reversed intramuscularly-administered morphine-induced antinociception. These results indicate that intramuscularly-administered morphine produces antinociception in craniofacial muscle nociception and that this intramuscularly-administered morphine-induced antinociception is mediated by a peripheral mu opioid receptor. Our observations further support the clinical approach of administering opioids in the periphery for the treatment of craniofacial muscle nociception.

Topics: Analgesics; Anesthesia, General; Animals; Inflammation; Injections; Injections, Intramuscular; Male; Masseter Muscle; Morphine; Mustard Plant; Naloxone; Naltrexone; Narcotic Antagonists; Nociceptors; Pain; Plant Oils; Psychomotor Performance; Rats; Rats, Sprague-Dawley; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Single-Blind Method; Somatostatin

Crotoxin (Cro), the principal neurotoxic component of Crotalus durissus terrificus, has been previously reported to have a behavioral analgesic effect in rats and mice. The present study investigated electrophysiologically the effect of Cro on pain-evoked unit discharge of neurons in thalamic parafascicular nucleus (Pf) and underlying mechanisms of its effect. The electrical discharge of Pf neurons was recorded with the microelectrode technique in rats. Intracerebroventricular (i.c.v.) injection of Cro at 0.25, 0.45 and 0.65 microg/kg resulted in a dose-dependent inhibitory effect on the pain-evoked discharge of Pf neurons. The discharge frequency and the discharge duration significantly (P<0.05) decreased after Cro administration. This inhibitory effect was significantly (P<0.05) attenuated after pretreatment with para-chlorophenylalanine (pCPA), or electrolytic lesion of dorsal raphe (DR) nucleus. In contrast, i.c.v. injection of atropine (muscarinic receptor antagonist, 5 microg) or naloxone (opioid receptor antagonist, 4 microg) had no effect on Cro-induced inhibition of discharge of Pf neurons. The results suggested that Cro has an analgesic effect, which is mediated, at least partially, by the central serotonergic system.

Topics: Analgesics; Animals; Atropine; Crotoxin; Dose-Response Relationship, Drug; Intralaminar Thalamic Nuclei; Male; Naloxone; Narcotic Antagonists; Neurons; Pain; Parasympatholytics; Rats; Rats, Wistar; Time Factors

The 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) is an endogenous ligand of peroxisome proliferator-activated receptors gamma (PPAR-gamma) and is now recognized as a potent anti-inflammatory mediator. However, information regarding the influence of 15d-PGJ(2) on inflammatory pain is still unknown. In this study, we evaluated the effect of 15d-PGJ(2) upon inflammatory hypernociception and the mechanisms involved in this effect. We observed that intraplantar administration of 15d-PGJ(2) (30-300 ng/paw) inhibits the mechanical hypernociception induced by both carrageenan (100 mug/paw) and the directly acting hypernociceptive mediator, prostaglandin E(2) (PGE(2)). Moreover, 15d-PGJ(2) [100 ng/temporomandibular joint (TMJ)] inhibits formalin-induced TMJ hypernociception. On the other hand, the direct administration of 15d-PGJ(2) into the dorsal root ganglion was ineffective in blocking PGE(2)-induced hypernociception. In addition, the 15d-PGJ(2) antinociceptive effect was enhanced by the increase of macrophage population in paw tissue due to local injection of thioglycollate, suggesting the involvement of these cells on the 15d-PGJ(2)-antinociceptive effect. Moreover, the antinociceptive effect of 15d-PGJ(2) was also blocked by naloxone and by the PPAR-gamma antagonist 2-chloro-5-nitro-N-phenylbenzamide (GW9662), suggesting the involvement of peripheral opioids and PPAR-gamma receptor in the process. Similar to opioids, the 15d-PGJ(2) antinociceptive action depends on the nitric oxide/cGMP/protein kinase G (PKG)/K(ATP)(+) channel pathway because it was prevented by the pretreatment with the inhibitors of nitric-oxide synthase (N(G)-monomethyl-l-arginine acetate), guanylate cyclase]1H-(1,2,4)-oxadiazolo(4,2-alpha)quinoxalin-1-one[, PKG [indolo[2,3-a]pyrrolo[3,4-c]carbazole aglycone (KT5823)], or with the ATP-sensitive potassium channel blocker glibenclamide. Taken together, these results demonstrate for the first time that 15d-PGJ(2) inhibits inflammatory hypernociception via PPAR-gamma activation. This effect seems to be dependent on endogenous opioids and local macrophages.

Topics: Analgesics; Animals; Carrageenan; Cytokines; Formaldehyde; Hyperalgesia; Inflammation; Macrophages; Male; Naloxone; Narcotic Antagonists; Pain; PPAR gamma; Prostaglandin D2; Rats; Rats, Wistar; Receptors, Opioid; Skin; Tumor Necrosis Factor-alpha

The heat pain threshold was assessed in 32 healthy participants after a mild burn on the dorsal surface of each hand, after injection of an opioid antagonist (80 microg naloxone) or vehicle alone (0.2 mL saline) into the burnt skin of 1 hand, and after repeated painful immersion of this hand in cold water for up to 180 seconds. We hypothesized that sensitivity to heat would decrease at the burn-injured site after the immersions, due to local release of opioids into the burnt skin. Naloxone augmented cold-induced pain during the immersions in participants who tolerated the longest immersions, implying that release of endogenous opioids suppressed cold-pain. After the immersions, sensitivity to heat decreased at the burn-injured site in the immersed hand, but naloxone did not block this effect. Instead, naloxone altered sensitivity to heat in unburnt skin, implying that thermal hyperalgesia at sites of burn injury masked the modulatory effects of opioids. In particular, naloxone blocked a decrease in sensitivity to heat at an unburnt site on the contralateral hand of participants who tolerated the longest immersions, consistent with central or systemic opioid release. Naloxone reduced sensitivity to heat at unburnt sites in participants who tolerated medium-length immersions, suggesting that an increase in systemic or central opioid activity evoked thermal hyperalgesia in this group. In addition, in a small group of participants who tolerated only brief immersions, naloxone blocked decreases in sensitivity to heat at an unburnt site in the immersed hand. These findings suggest that repeated painful immersions trigger local opioid release in participants who tolerate only brief immersions, and elicit central or systemic opioid release in participants who tolerate longer immersions.. This article demonstrates that repeated immersion of the hand in painfully cold water increases opioid activity and that the increase in opioid activity exerts multiple opposing effects on sensitivity to heat. Individual differences in the response to opioids might contribute to individual differences in pain tolerance.

Topics: Adolescent; Adult; Burns; Female; Humans; Hyperalgesia; Injections, Subcutaneous; Male; Naloxone; Narcotic Antagonists; Nociceptors; Opioid Peptides; Pain; Pain Threshold; Sensory Receptor Cells; Skin Temperature

Transcutaneous electric nerve stimulation (TENS) is a noninvasive treatment used in physiotherapy practice to promote analgesia in acute and chronic inflammatory conditions. The aim of the present study was to investigate the action mechanism of TENS at high (HF: 130 Hz) and low (LF: 10 Hz) frequencies in an inflammation model produced by the injection of carrageenan in rat paws (Cg; 250 microg). After carrageenan administration (0 time), either HF or LF TENS was applied to the inflamed paw of rats for 20 minutes, and hyperalgesia was assessed hourly using the modified Randall-Selitto method (1957). HF and LF TENS inhibited the carrageenan-induced hyperalgesia by 100%. Pretreatment of animals with intraplantar naltrexone (Nx; 50 microg) reversed the analgesic effect of the LF TENS but did not alter the effect of HF TENS. The application of HF and LF TENS to the contralateral paw reversed the hyperalgesia of the inflamed paw similar to that observed when TENS was applied to the inflamed paw. However, LF TENS presented a longer-lasting analgesic effect than HF TENS. Our data demonstrate that HF and LF TENS induced antihyperalgesia. We also report that the antihyperalgesia provoked by LF TENS is partially due to the local release of endogenous opioids.. This study offers important information about physiotherapy practices aimed at pain relieving. TENS is a noninvasive treatment that promotes analgesia in acute and chronic inflammatory conditions. Scientists, patients, and the general population may benefit from this knowledge.

Topics: Analgesics; Animals; Carrageenan; Functional Laterality; Inflammation; Naloxone; Narcotic Antagonists; Opioid Peptides; Pain; Pain Management; Rats; Transcutaneous Electric Nerve Stimulation

Nicotine is neuronal stimulating drug in the central nervous system and elicits various effects through nicotinic acetylcholine receptors. As previously reported, nicotine has an antinociceptive effect through activation of endogenous opioid neurons. However, detailed mechanisms of nicotine-induced antinociception are uncertain. In this study, we focused on spinal cord and investigated the involvement of endogenous opioidergic neurons in nicotine-induced antinociception in mice. In the tail-pinch test, subcutaneously administered nicotine (5 mg/kg) produced maximal antinociception 0.5 h after nicotine administration; this was attenuated by mecamylamine (MEC, 3 mg/kg, s.c.) or naloxone (NLX, 1 mg/kg, s.c.) administration. Intrathecal nicotine (10 mug) produced maximal antinociception at 2 min and this was also attenuated by MEC (3 mg/kg, s.c.) or NLX (1 mg/kg, s.c.) administration. The preproenkephalin (ppENK) mRNA level in spinal cord, but not dorsal root ganglion, was significantly increased 2 h following nicotine administration and recovered to control level 4 h after nicotine (5 mg/kg, s.c.) administration. This increase in ppENK mRNA level was inhibited by MEC (3 mg/kg, s.c.). The mRNA levels of preprodynorphin and preproopiomelanocortin were not increased by nicotine (5 mg/kg, s.c.). In the dorsal horn of the lumbar spinal cord, methionine-enkephalin (Met-ENK)-like IR was remarkably reduced at 0.5 h following nicotine administration and recovered to control levels by 2 h after nicotine (3 mg/kg, s.c.) administration. These results suggest that nicotine has an antinociceptive effect by promoting the release of Met-ENK, but not dynorphins and endorphins, from activated opioidergic neurons in spinal cord.

Topics: Analgesics; Animals; Dose-Response Relationship, Drug; Down-Regulation; Dynorphins; Enkephalin, Methionine; Enkephalins; Male; Mecamylamine; Mice; Mice, Inbred ICR; Naloxone; Narcotic Antagonists; Nicotine; Nicotinic Agonists; Nicotinic Antagonists; Nociceptors; Pain; Pain Measurement; Pain Threshold; Posterior Horn Cells; Pro-Opiomelanocortin; Protein Precursors; RNA, Messenger

A visceral pain model incorporating use of cyclophosphamide (CP) to induce bladder inflammation has been described. CP treatment in rats produces changes in behavior (abnormal postures and eye closure) and respiration rate indicative of visceral pain. We characterized the dose-dependency and progression of CP-induced cystitis pain after intraperitoneal (i.p.) CP. The behavioral and respiration rate changes were ameliorated by systemic morphine and ABT-594 [(R)-5-(2-azetidinylmethoxy)-2-chloropyridine], a neuronal nicotinic acetylcholine receptor agonist, in a manner reversible by naloxone and mecamylamine, respectively. Sites of antinociceptive actions of morphine and ABT-594 were investigated using systemic, intrathecal (i.t.), or intracerebroventricular (i.c.v.) administration of blood-brain barrier impenetrant antagonists. Naloxone methiodide produced a complete antagonism of morphine antinociception after i.c.v. but not i.p. or i.t. administration. Chlorisondamine blocked ABT-594 antinociception after i.c.v. but not i.p. administration. Further pharmacological characterization of behavioral and respiration changes in CP-cystitis was performed using standard analgesics. The alpha(2)-adrenoceptor agonist clonidine produced a weak attenuation of CP-pain behavior. NSAIDs (ibuprofen, acetaminophen, and celecoxib) and anticonvulsants (gabapentin and lamotrigine) were without effect. These results demonstrate that morphine and ABT-594 produce antinociception in CP-cystitis by a predominantly supraspinal site of action, and that mechanisms producing robust centrally-mediated antinociception could be beneficial in cystitis pain.. In this article, potential antinociceptive effects of a variety of pharmacological agents were evaluated in a rat cystitis pain model. Morphine and a nicotinic acetylcholine receptor agonist ABT-594 were found to exert potent antinociception in this model. Findings presented here aid identification of agents to treat cystitis pain in the clinic.

Topics: Analgesics; Animals; Azetidines; Behavior, Animal; Brain; Chlorisondamine; Cyclophosphamide; Cystitis; Disease Models, Animal; Male; Mecamylamine; Morphine; Naloxone; Narcotic Antagonists; Nicotinic Antagonists; Pain; Pyridines; Quaternary Ammonium Compounds; Rats; Rats, Sprague-Dawley; Receptors, Nicotinic; Viscera

The role in nociception of nociceptin/orphanin FQ (N/OFQ) and its receptor, the opioid receptor-like 1 (NOP), remains unclear because this peptide has been implicated in both suppression and enhancement of nociception. The present work characterises the effects of N/OFQ and the NOP receptor antagonist, the pseudopeptide [Phe(1)Psi(CH(2)NH)Gly(2)]-nociceptin(1-13)-NH(2) (Phe(1)Psi), on thermonociception in the snail Helix aspersa using the hot plate assay. Additionally, the possible interaction of each of these compounds with morphine or dynorphin A(1-17) and naloxone was studied. Compounds were administered into the hemocoel cavity of H. aspersa and the latency to the aversive withdrawal behaviour recorded. Dose-response and time course curves were done. N/OFQ and naloxone produced a similar dose-dependent pronociceptive effect; however, N/OFQ reached its peak effect earlier and was 30 times more potent than naloxone. [Phe(1)Psi(CH(2)NH)Gly(2)]-nociceptin(1-13)-NH(2) and the opioid agonists, morphine and dynorphin A(1-17) produced antinociception with a similar efficacy, but [Phe(1)Psi(CH(2)NH)Gly(2)]-nociceptin(1-13)-NH(2) reached its peak effect more rapidly and lasted longer than that of dynorphin A(1-17) and morphine. [Phe(1)Psi(CH(2)NH)Gly(2)]-nociceptin(1-13)-NH(2) was 50 times less potent than dynorphin A(1-17), but 30 times more potent than morphine. N/OFQ significantly reduced morphine and dynorphin A(1-17)-induced antinociception. Combined administration of low doses of [Phe(1)Psi(CH(2)NH)Gly(2)]-nociceptin(1-13)-NH(2) and morphine or dynorphin A(1-17) produced a potent antinociceptive effect. Sub-effective doses of naloxone and N/OFQ also synergised to produce pronociception. Data suggest that these two opioid classes regulate nociception through parallel systems. The H. aspersa model appears as a valuable experimental preparation to continue the study of these opioid receptor systems.

Topics: Animals; Dose-Response Relationship, Drug; Drug Interactions; Dynorphins; Helix, Snails; Hot Temperature; Morphine; Motor Activity; Naloxone; Narcotic Antagonists; Nociceptin; Nociceptin Receptor; Opioid Peptides; Pain; Peptide Fragments; Reaction Time; Receptors, Opioid

The aim of the present study was to examine the effect of ultra-low-dose naloxone on pertussis toxin (PTX)-induced thermal hyperalgesia in rats and its underlying mechanisms. Male Wistar rats, implanted with an intrathecal catheter with or without a microdialysis probe, received a single intrathecal injection of PTX (1 microg in 5 microl saline). Four days after PTX injection, they were randomly given a different dose of naloxone (either 15 microg or 15 ng in 5 microl saline), followed by a morphine injection (10 microg in 5 microl saline) after 30 min. The results found that PTX injection induced thermal hyperalgesia and increasing excitatory amino acid (EAA; L-glutamate and L-aspartate) concentration in the spinal CSF dialysates. Ultra-low-dose naloxone not only preserved the antinociceptive effect of morphine but also suppressed the PTX-evoked EAA release as well. Moreover, ultra-low-dose naloxone plus morphine administration inhibited the downregulation of L-glutamate transporters (GTs) and the L-glutamate-metabolizing enzyme glutamine synthetase (GS), and, moreover, inhibited microglial activation and suppressed cytokine expression in PTX-treated rat spinal cords. These results show that ultra-low-dose naloxone preserves the antinociceptive effect of morphine in PTX-treated rats. The mechanisms include (a) inhibition of pro-inflammatory cytokine expression, (b) attenuation of PTX-evoked EAA release, and (c) reversion of the downregulation of GT expression.

Topics: Analgesics, Opioid; Animals; Anti-Inflammatory Agents, Non-Steroidal; Dose-Response Relationship, Drug; Drug Synergism; Male; Morphine; Naloxone; Pain; Pain Measurement; Pertussis Toxin; Rats; Rats, Wistar; Spinal Cord

Human hemokinin-1 (h HK-1) and its truncated form h HK-1(4-11) are mammalian tachykinin peptides encoded by the recently identified TAC4 gene in human, and the biological functions of these peptides have not been well investigated. In the present study, an attempt has been made to investigate the effects and mechanisms of action of h HK-1 and h HK-1(4-11) in pain modulation at the supraspinal level in mice using the tail immersion test. Intracerebroventricular (i.c.v.) administration of h HK-1 (0.3, 1, 3 and 6 nmol/mouse) produced a dose- and time-related antinociceptive effect. This effect was significantly antagonized by the NK(1) receptor antagonist SR140333, but not by the NK(2) receptor antagonist SR48968, indicating that the analgesic effect induced by i.c.v. h HK-1 is mediated through the activation of NK(1) receptors. Interestingly, naloxone, beta-funaltrexamine and naloxonazine, but not naltrindole and nor-binaltorphimine, could also block the analgesic effect markedly, suggesting that this effect is related to descending mu opioidergic neurons (primary mu(1) subtype). Human HK-1(4-11) could also induce a dose- and time-dependent analgesic effect after i.c.v. administration, however, the potency of analgesia was less than h HK-1. Surprisingly, SR140333 could not modify this analgesic effect, suggesting that this effect is not mediated through the NK(1) receptors like h HK-1. SR48968 could modestly enhance the analgesic effect induced by h HK-1(4-11), indicating that a small amount of h HK-1(4-11) may bind to NK(2) receptors. Furthermore, none of the opioid receptor (OR) antagonists could markedly block the analgesia of h HK-1(4-11), suggesting that the analgesic effect is not mediated through the descending opioidergic neurons. Blocking of delta ORs significantly enhanced the analgesia, indicating that delta OR is a negatively modulatory factor in the analgesic effect of h HK-1(4-11). It is striking that bicuculline (a competitive antagonist at GABA(A) receptors) effectively blocked the analgesia induced by h HK-1(4-11), suggesting that this analgesic effect is mediated through the descending inhibitory GABAergic neurons. The novel mechanism involved in the analgesic effect of h HK-1(4-11), which is different from that of h HK-1, may pave the way for a new strategy for the investigation and control of pain.

Topics: Analgesics; Animals; Benzamides; Bicuculline; Dose-Response Relationship, Drug; GABA Antagonists; Humans; Injections, Intraventricular; Male; Mice; Naloxone; Naltrexone; Narcotic Antagonists; Neurokinin-1 Receptor Antagonists; Pain; Pain Measurement; Peptide Fragments; Piperidines; Receptors, Neurokinin-2; Tachykinins; Tropanes

Tramadol is one of the most widely used centrally acting analgesics worldwide. Because of its multimodal analgesic mechanism (opioid plus nonopioid), the adverse effects profile of tramadol, similar to its analgesic profile, can be atypical compared with single-mechanism opioid analgesics. The comparison is often favorable (e.g., less respiratory depression or abuse), but it is sometimes cited as unfavorable in regard to seizure potential. As part of a broader study of this analgesic, we compared seizure induction in mice produced by administration of tramadol, the enantiomers and metabolites [M1 (O-desmethyl tramadol), M2 (N-desmethyl tramadol), M3 (N,N-didesmethyl tramadol), M4 (O,N,N-tridesmethyl tramadol), and M5 (O,N-didesmethyl tramadol)] of tramadol, and opioid and nonopioid reference compounds. We found that tramadol, its enantiomers, and M1 to M5 metabolites were of intermediate potency in this endpoint (on either a milligram per kilogram or millimole per kilogram basis). The SD50 (estimated dose required to induce seizures in 50% of test group) of tramadol to antinociceptive ED50 ratio was almost identical to that of codeine. The enantiomers of tramadol were about equipotent to tramadol on this endpoint. The M1 to M5 metabolites (and M1 enantiomers) of tramadol were less potent than tramadol. The relative potency of tramadol to opioids was not altered by quinidine (an inhibitor of CYP4502D6), noxious stimulus (48 degrees C hot-plate), multiple dosing, or in reserpinized mice. Tramadol seizures were increased by naloxone, principally at high tramadol doses and due to an effect on the (-)enantiomer that overcame the opposite effect on the (+)enantiomer. No synergistic effect on seizure induction was observed between concomitant tramadol and codeine or morphine.

Topics: Analgesics, Opioid; Animals; Codeine; Cytochrome P-450 CYP2D6 Inhibitors; Drug Interactions; Hot Temperature; Male; Mice; Mice, Inbred Strains; Morphine; Naloxone; Narcotic Antagonists; Oxycodone; Pain; Quinidine; Reserpine; Seizures; Stereoisomerism; Tramadol

Analgesics such as morphine cause many side effects including addiction, but kappa-opioid receptor agonist can produce antinociception without morphine-like side effects. With the aim of developing new and potent analgesics with lower abuse potential, we studied the antinociceptive and physical dependent properties of a derivate of ICI-199441, an analogue of (-)U50,488H, named (2-(3,4-dichloro)-phenyl)-N-methyl-N-[(1S)-1-(2-isopropyl)-2-(1-(3-pyrrolinyl))ethyl] acetamides (LPK-26). LPK-26 showed a high affinity to kappa-opioid receptor with the Ki value of 0.64 nM and the low affinities to micro-opioid receptor and delta-opioid receptor with the Ki values of 1170 nM and >10,000 nM, respectively. It stimulated [(35)S]GTPgammaS binding to G-proteins with an EC50 value of 0.0094 nM. In vivo, LPK-26 was more potent than (-)U50,488H and morphine in analgesia, with the ED50 values of 0.049 mg/kg and 0.0084 mg/kg in hot plat and acetic acid writhing tests, respectively. Moreover, LPK-26 failed to induce physical dependence, but it could suppress naloxone-precipitated jumping in mice when given simultaneously with morphine. Taken together, our results show that LPK-26 is a novel selective kappa-opioid receptor agonist with highly potent antinociception effects and low physical dependence potential. It may be valuable for the development of analgesic and drug that can be used to reduce morphine-induced physical dependence.

Topics: Acetic Acid; Analgesics, Opioid; Animals; Behavior, Animal; CHO Cells; Cricetinae; Cricetulus; Disease Models, Animal; Dose-Response Relationship, Drug; Guanosine 5'-O-(3-Thiotriphosphate); Hot Temperature; Humans; Male; Mice; Motor Activity; Naloxone; Narcotic Antagonists; Opioid-Related Disorders; Pain; Pain Measurement; Pain Threshold; Protein Binding; Pyrroles; Rats; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Time Factors; Transfection

ZC88 is a novel non-peptide N-type voltage-sensitive calcium channel blocker synthesized by our institute. In the present study, the oral analgesic activity of ZC88 in animal models of acute and neuropathic pain, and functional interactions between ZC88 and morphine in terms of analgesia, tolerance and dependence were investigated. In mice acetic acid writhing tests, ZC88 (10-80 mg/kg) administered by oral route showed significant antinociceptive effects in a dose-dependent manner. The ED50 values of ZC88 were 14.5 and 14.3 mg/kg in male and female mice, respectively. In sciatic nerve chronic constriction injury rats, mechanical allodynia was ameliorated by oral administration of ZC88 at doses of 14, 28 and 56 mg/kg, suggesting ZC88 relieved allodynic response of neuropathic pain. When concurrently administered with morphine, ZC88 (20-80 mg/kg) dose-dependently potentiated morphine analgesia and attenuated morphine analgesic tolerance in hot-plate tests. ZC88 also prevented chronic exposure to morphine-induced physical dependence and withdrawal, but not morphine-induced psychological dependence in conditioned place preference model. These results suggested that ZC88, a new non-peptide N-type calcium channel blocker, had notable oral analgesia and anti-allodynia for acute and neuropathic pain. ZC88 might be used in pain relief by either application alone or in combination with opioids because it enhanced morphine analgesia while prevented morphine-induced tolerance and physical dependence.

Topics: Acetic Acid; Analgesics; Analgesics, Opioid; Animals; Calcium Channel Blockers; Calcium Channels, N-Type; Conditioning, Operant; Drug Tolerance; Mice; Morphine; Morphine Dependence; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Peripheral Nervous System Diseases; Physical Stimulation; Piperidines; Rats; Rats, Sprague-Dawley; Reaction Time; Sciatic Neuropathy

This study was performed to determine the antinociceptive and anti-inflammatory activities of aqueous extract of Kaempferia galanga leaves using various animal models. The extract, in the doses of 30, 100, and 300 mg/kg, was prepared by soaking (1:10; w/v) the air-dried powdered leaves (40 g) in distilled water (dH(2)O) for 72 h and administered subcutaneously in mice/rats 30 min prior to the tests. The extract exhibited significant (P < 0.05) antinociceptive activity when assessed using the abdominal constriction, hot-plate and formalin tests, with activity observed in all tests occurring in a dose-dependent manner. Furthermore, the antinociceptive activity of K. galanga extract was significantly (P < 0.05) reversed when prechallenged with 10 mg/kg naloxone. The extract also produced a significantly (P < 0.05) dose-dependent anti-inflammatory activity when assessed using the carrageenan-induced paw-edema test. In conclusion, this study demonstrated that K. galanga leaves possessed antinociceptive and anti-inflammatory activities and thus supports the Malay's traditional uses of the plant for treatments of mouth ulcer, headache, sore throat, etc.

Topics: Analgesics, Non-Narcotic; Analysis of Variance; Animals; Anti-Inflammatory Agents, Non-Steroidal; Carrageenan; Disease Models, Animal; Dose-Response Relationship, Drug; Edema; Female; Mice; Mice, Inbred BALB C; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Phytotherapy; Plant Extracts; Plant Leaves; Rats; Rats, Sprague-Dawley; Zingiberaceae

N-Allylation (-CH(2)-CHCH(2)) of [Dmt(1)]endomorphins yielded the following: (i) [N-allyl-Dmt(1)]endomorphin-2 (Dmt=2',6'-dimethyl-l-tyrosine) (12) and [N-allyl-Dmt(1)]endomorphin-1 (15) (K(i)mu=0.45 and 0.26nM, respectively) became mu-antagonists (pA(2)=8.59 and 8.18, respectively) with weak delta-antagonism (pA(2)=6.32 and 7.32, respectively); (ii) intracerebroventricularly administered 12 inhibited morphine-induced CNS-mediated antinociception in mice [AD(50) (0.148ng/mouse) was 16-fold more potent than naloxone], but not spinal antinociception, and (iii) 15 reversed the alcohol-elevated frequency in spontaneous inhibitory post-synaptic currents (IPSC) in hippocampal CA1 pyramidal cells in rat brain slices (P=0.0055). Similarly, N-allylation of the potent mu-opioidmimetic agonists, 1,6-bis-[H-Dmt-NH]-hexane and 3,6-bis-[Dmt-NH-propyl]-2(1H)-pyrazinone, converted them into mu-antagonists (pA(2)=7.23 and 7.17 for the N-allyl-derivatives 17 and 19, respectively), and exhibited weak delta-antagonism. Thus, N-allylation of Dmt containing opioid peptides or opioidmimetics continues to provide a facile means to convert selective mu-opioid agonists into potent mu-opioid antagonists.

Topics: Alkylation; Analgesics, Opioid; Animals; Brain; Disease Models, Animal; Guinea Pigs; Male; Mice; Morphine; Pain; Rats; Receptors, Opioid, mu; Structure-Activity Relationship; Synaptosomes; Vas Deferens

Sickle cell anemia is a common genetic disorder in African Americans. Opioid analgesics are traditionally the treatment for the severe pain associated with this disease. Here we reveal that the opioid antagonist naloxone possesses potent analgesic activity in two transgenic mouse models of sickle cell anemia (NY1DD and hBERK1) and not in their respective controls (ICR-CD1 and C57BL/6J) when administered by three parenteral routes [intracerebroventricular (i.c.v.), intrathecal, and subcutaneous]. In the NY1DD mice, naloxone (i.c.v.) possessed approximately 300-fold greater potency than morphine (i.c.v.). Other opioid antagonists (naltrexone, norbinaltorphimine, and naltrindole) were substantially less effective in producing analgesia. Naloxone and morphine were synergistic in NY1DD mice, suggesting different receptor systems. Microarray analysis suggested naloxone-induced down-regulation of the CC chemokine receptor (CCR)5 in NY1DD mice but not in control mice. Pretreatment of control mice with CC chemokine ligand 5 [CCL5 (RANTES)] enabled naloxone to produce analgesia similar to that observed in NY1DD mice. Mu opioid receptor knockout mice treated similarly also displayed analgesia. That the effect of CCL5 was specifically related to CCR5 and/or CCR1 activation was demonstrated by antagonism of analgesia with the chemokine antagonist methionylated RANTES. Similar antagonism of naloxone-induced analgesia also was observed when NY1DD mice were pretreated with methionylated RANTES. These results indicate that CCR5/CCR1 receptors are directly or indirectly involved in analgesia produced by naloxone. The present study suggests that naloxone may be clinically useful in the treatment of pain associated with sickle cell disease and other disorders involving inflammation.

Topics: Analgesics; Analgesics, Opioid; Anemia, Sickle Cell; Animals; Chemokine CCL5; Disease Models, Animal; Dose-Response Relationship, Drug; Down-Regulation; Drug Synergism; Injections, Intraventricular; Injections, Spinal; Injections, Subcutaneous; Male; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; Mice, Knockout; Mice, Transgenic; Morphine; Naloxone; Pain; Pain Measurement; Receptors, CCR5

In this study, the effect of curcumin on the formalin-induced pain was investigated in rats. Interaction between curcumin and opioid system using morphine and naloxone was also examined. A biphasic pain response was induced after intraplantar injection of formalin (50 microL, 1%). Curcumin, morphin and naloxone had no effect on the early phase of pain. Late phase of pain was suppressed by curcumin at the doses of 100 and 200 mg kg(-1) body weigh. Morphine (1 mg kg(-1) BW) reduced, whereas naloxone (1 mg kg(-1) BW) did not affect the late phase of pain. Currcumin did not influence the morphine-induced antinociception, but reversed the effect of naloxone on pain. Present findings indicate that curcumin may produce antinociception by activation of both opioid and non opioid mechanisms of pain.

Topics: Analgesics, Opioid; Animals; Antineoplastic Agents; Curcumin; Male; Morphine; Naloxone; Pain; Pain Measurement; Rats; Rats, Wistar; Receptors, Opioid

Current therapy for inflammatory pain includes the peripheral application of opioid receptor agonists. Activation of opioid receptors modulates voltage-gated ion channels, but it is unclear whether opioids can also influence ligand-gated ion channels [e.g., the transient receptor potential vanilloid type 1 (TRPV1)]. TRPV1 channels are involved in the development of thermal hypersensitivity associated with tissue inflammation. In this study, we investigated mu-opioid receptor and TRPV1 expression in primary afferent neurons in the dorsal root ganglion (DRG) in complete Freund's adjuvant (CFA)-induced paw inflammation. In addition, the present study examined whether the activity of TRPV1 in DRG neurons can be inhibited by mu-opioid receptor (mu-receptor) ligands and whether this inhibition is increased after CFA inflammation. Immunohistochemistry demonstrated colocalization of TRPV1 and mu-receptors in DRG neurons. CFA-induced inflammation increased significantly the number of TRPV1- and mu-receptor-positive DRG neurons, as well as TRPV1 binding sites. In whole-cell patch clamp studies, opioids significantly decreased capsaicin-induced TRPV1 currents in a naloxone- and pertussis toxinsensitive manner. The inhibitory effect of morphine on TRPV1 was abolished by forskolin and 8-bromo-cAMP. During inflammation, an increase in TRPV1 is apparently rivaled by an increase of mu-receptors. However, in single dissociated DRG neurons, the inhibitory effects of morphine are not different between animals with and without CFA inflammation. In in vivo experiments, we found that locally applied morphine reduced capsaicin-induced thermal allodynia. In summary, our results indicate that mu-receptor activation can inhibit the activity of TRPV1 via G(i/o) proteins and the cAMP pathway. These observations demonstrate an important new mechanism underlying the analgesic efficacy of peripherally acting mu-receptor ligands in inflammatory pain.

Topics: Animals; Cyclic AMP; Disease Models, Animal; Ganglia, Spinal; GTP-Binding Proteins; Inflammation; Male; Naloxone; Neurons, Afferent; Pain; Pertussis Toxin; Rats; Rats, Wistar; Receptors, Opioid, mu; RNA, Messenger; TRPV Cation Channels

Antinociception achieved after peripheral administration of opioids has opened a new approach to the treatment of severe and chronic pain. Additionally, opioid analgesics with restricted access to the central nervous system could improve safety of opioid drugs used in clinical practice. In the present study, peripheral components of antinociceptive actions of 6-amino acid-substituted derivatives of 14-O-methyloxymorphone were investigated after local intraplantar (i.pl.) administration in rat models of inflammatory and neuropathic pain. Their antinociceptive activities were compared with those of morphine, the classical mu-opioid receptor agonist. Intraplantar administration of morphine and the 6-amino acid derivatives produced dose-dependent reduction of formalin-induced flinching of the inflamed paw, without significant effect on the paw edema. Local i.pl. administration of the new derivatives in rats with neuropathic pain induced by sciatic nerve ligation produced antiallodynic and antihyperalgesic effects; however, the antinociceptive activity was lower than that observed in inflammatory pain. In both models, the 6-amino acid derivatives and morphine at doses that produced analgesia after i.pl. administration were systemically (s.c.) much less active indicating that the antinociceptive action is due to a local effect. Moreover, the local opioid antinociceptive effects were significantly attenuated by naloxone methiodide, a peripherally acting opioid receptor antagonist, demonstrating that the effect was mediated by peripheral opioid receptors. The present data indicate that the peripherally restricted 6-amino acid conjugates of 14-O-methyloxymorphone elicit antinociception after local administration, being more potent in inflammatory than in neuropathic pain. Opioid drugs with peripheral site of action can be an important target for the treatment of long lasting pain.

Topics: Analgesics, Opioid; Animals; Dose-Response Relationship, Drug; Hyperalgesia; Inflammation; Male; Morphine; Naloxone; Neuralgia; Oxymorphone; Pain; Rats; Rats, Wistar; Structure-Activity Relationship

Pain due to peripheral nerve injury or disease is a dynamic process, such that the mechanism that underlies it alters over time. Tramadol has been reported to be analgesic in clinical neuropathic pain, with varying levels of efficacy due to a patient population that has had neuropathic pain for a wide range of time. In order to address and examine the issue, the antinociceptive efficacy of tramadol over time was tested in rats with a chronic constriction injury (CCI) of the left sciatic nerve. Rats developed a robust hind paw hypersensitivity to innocuous mechanical stimulation ipsilateral to CCI surgery. Subcutaneous injection of tramadol in rats two weeks after CCI surgery dose-dependently attenuated mechanical hypersensitivity, which was abolished with the mu-opioid receptor antagonist naloxone but not the alpha(2)-adrenoceptor antagonist yohimbine. Systemic tramadol also attenuated mechanical hypersensitivity four weeks after CCI surgery, but the efficacy significantly diminished at this time point. In addition, the effect of tramadol at this later time point could be reduced with yohimbine as well as naloxone. These data demonstrate that the efficacy of tramadol depends in part on the duration of nerve injury-evoked nociception, and that its antinociceptive mechanism changes over time. Alteration in antinociceptive mechanism over time may explain the inconsistency in efficacy of this and other analgesic drugs in chronic pain patients.

Topics: Adrenergic alpha-Antagonists; Analgesics, Opioid; Animals; Constriction, Pathologic; Dose-Response Relationship, Drug; Hyperalgesia; Male; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Peripheral Nervous System Diseases; Rats; Rats, Sprague-Dawley; Time Factors; Tramadol; Yohimbine

Earlier, we reported that morphine-nimodipine combination produces significantly higher antinociception after intrathecal but not after systemic administration in mice. Different doses of morphine and nimodipine (5 microg of morphine, 5 microg of nimodipine, 5 microg each of morphine and nimodipine, 10 microg of morphine, 10 microg of nimodipine, 10 microg morphine with 5 microg nimodipine and 5 microg of morphine with 10 microg of nimodipine) were now injected intrathecally in Wistar rats to further characterise this antinociceptive effect. The acute antinociceptive effect was measured by the tail-flick test between 15 min to 7 h. The onset of maximum antinociception (100% MPE) was earlier (by 15 min) in nimodipine (5 microg) than in morphine (5 microg) treated group (by 30 min). Though earlier in onset, 5 microg nimodipine produced transient antinociception, which was significantly higher than saline treated controls for the initial 30 min only. Morphine (5 microg) produced significantly higher antinociception between 15 min to 3:30 h in comparison to control animals. However, co-administration of both morphine and nimodipine led to significantly higher antinociception than morphine alone at 4:00 h and also between 5:00 to 6:30 h. Interestingly, the combined antinociceptive action of morphine and nimodipine was not significantly different from 10 microg of morphine, which indicated synergistic interaction. Naloxone (5 mg/kg) could reverse this antinociceptive effect of morphine-nimodipine combination though it failed to reverse nimodipine (5 microg)-mediated antinociception at 15 min. Increasing the dose of either morphine or nimodipine to 10 mug did not increase antinociception except between 6:30-7:00 h. No obvious side effect was noted after administration of either morphine or nimodipine or both.

Topics: Analgesics, Opioid; Animals; Calcium Channel Blockers; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Routes; Drug Synergism; Injections, Spinal; Male; Morphine; Motor Activity; Naloxone; Narcotic Antagonists; Nimodipine; Pain; Pain Measurement; Rats; Rats, Wistar; Receptors, Opioid, mu; Tail

The antagonism by Tyr-D-Pro-Trp-Gly-NH2 (D-Pro2-Tyr-W-MIF-1), a Tyr-Pro-Trp-Gly-NH2 (Tyr-W-MIF-1) analog, of the antinociception induced by the mu-opioid receptor agonists Tyr-W-MIF-1, [D-Ala2,NMePhe4,Gly(ol)5]-enkephalin (DAMGO), Tyr-Pro-Trp-Phe-NH2 (endomorphin-1), and Tyr-Pro-Phe-Phe-NH2 (endomorphin-2) was studied with the mouse tail-flick test. D-Pro2-Tyr-W-MIF-1 (0.5-3 nmol) given intracerebroventricularly (i.c.v.) had no effect on the thermal nociceptive threshold. High doses of D-Pro2-Tyr-W-MIF-1 (4-16 nmol) administered i.c.v. produced antinociception with a low intrinsic activity of about 30% of the maximal possible effect. D-Pro2-Tyr-W-MIF-1 (0.25-2 nmol) co-administered i.c.v. showed a dose-dependent attenuation of the antinociception induced by Tyr-W-MIF-1 or DAMGO without affecting endomorphin-2-induced antinociception. A 0.5 nmol dose of D-Pro2-Tyr-W-MIF-1 significantly attenuated Tyr-W-MIF-1-induced antinociception but not DAMGO- or endomorphin-1-induced antinociception. The highest dose (2 nmol) of D-Pro2-Tyr-W-MIF-1 almost completely attenuated Tyr-W-MIF-1-induced antinociception. However, that dose of D-Pro2-Tyr-W-MIF-1 significantly but not completely attenuated endomorphin-1 or DAMGO-induced antinociception, whereas the antinociception induced by endomorphin-2 was still not affected by D-Pro2-Tyr-W-MIF-1. Pretreatment i.c.v. with various doses of naloxonazine, a mu1-opioid receptor antagonist, attenuated the antinociception induced by Tyr-W-MIF-1, endomorphin-1, endomorphin-2, or DAMGO. Judging from the ID50 values for naloxonazine against the antinociception induced by the mu-opioid receptor agonists, the antinociceptive effect of Tyr-W-MIF-1 is extremely less sensitive to naloxonazine than that of endomorphin-1 or DAMGO. In contrast, endomorphin-2-induced antinociception is extremely sensitive to naloxonazine. The present results clearly suggest that D-Pro2-Tyr-W-MIF-1 is a selective antagonist for the mu2-opioid receptor in the mouse brain. D-Pro2-Tyr-W-MIF-1 may also discriminate between Tyr-W-MIF-1-induced antinociception and the antinociception induced by endomorphin-1 or DAMGO, which both show a preference for the mu2-opioid receptor in the brain.

Topics: Analgesics, Opioid; Animals; Brain; Disease Models, Animal; Dose-Response Relationship, Drug; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Hot Temperature; Injections, Intraventricular; Male; Mice; MSH Release-Inhibiting Hormone; Naloxone; Narcotic Antagonists; Oligopeptides; Pain; Pain Measurement; Pain Threshold; Reaction Time; Receptors, Opioid, mu; Somatostatin; Time Factors

While many preclinical models detect the analgesic activity of nonsteroidal antiinflammatory drugs (NSAIDs), the radiant heat tail-flick response has repeatedly been insensitive to this class of drugs. As the tail-flick test involves nociceptive processing at spinal circuits with supraspinal modulation, it seems reasonable to assume that the NSAIDs should not modify strong nociceptive stimuli, since the primary site of action of NSAIDs is likely to be in the periphery.. We injected 3-300 mug of diclofenac, dipyrone, ketorolac, lysine acetyl salicylate, and sodium salicylate intradermally into mice tails and evaluated the tail-flick response to radiant heat. These results were compared with intraperitoneally injected controls. We also evaluated the ability of naloxone to reverse the observed effects.. Intradermal injection of each NSAID produced a dose-dependent increase in tail-flick latency. Intraperitoneal NSAIDs injection produced no antinociceptive effects. Naloxone pretreatment had no effect on the antinociceptive effects of intradermal diclofenac, ketorolac, lysine acetyl salicylate, and sodium salicylate. Naloxone completely blocked the antinociceptive effects of intradermal dipyrone.. Local, but not systemic, administration of NSAIDs produced antinociception in the tail-flick thermal assay. The endogenous opioid system contributes to the peripheral antinociceptive effects of dipyrone, but not to that of diclofenac, ketorolac, lysine acetyl salicylate, or sodium salicylate, suggesting differences in the mechanisms of action among the NSAIDs.

Topics: Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Diclofenac; Dipyrone; Disease Models, Animal; Dose-Response Relationship, Drug; Hot Temperature; Injections, Intradermal; Injections, Intraperitoneal; Ketorolac; Lysine; Male; Mice; Mice, Inbred BALB C; Motor Activity; Naloxone; Narcotic Antagonists; Pain; Reaction Time; Sodium Salicylate; Tail; Time Factors

The compound LXM-10 (2,4-dimethyl-9-beta-phenylethyl-3-oxo-6, 9-diazaspiro [5.5]undecane chloride) is a new spirocyclopiperazinium salt compound. This is the first article to evaluate its antinociceptive effect in the abdominal constriction test induced by acetic acid and the hot-plate test. In the abdominal constriction test, LXM-10 had a significant dose-response effect, and the maximal inhibition ratio was 79.2%. In the hot-plate test, LXM-10 had significant dose-response and time-response effects. The antinociceptive effect began at 1.0 h, peaked at 2.0 h, and persisted 3.0 h after s.c. administration. The hot-plate latency was increased by 126.8% at the dose of 12.0 mg/kg. The antinociceptive effect of LXM-10 was blocked by mecamylamine (a central and peripheral neuronal nicotinic acetylcholine receptor antagonist, 0.25, 0.5, 1.0 mg/kg, i.p.), hexamethonium (a peripheral neuronal nicotinic acetylcholine receptor antagonist, 0.2, 1.0, 5.0 mg/kg, i.p.), atropine (a central and peripheral muscarinic acetylcholine receptor antagonist, 0.2, 1.0, 5.0 mg/kg, i.p.), and atropine methylnitrate (a peripheral muscarinic acetylcholine receptor antagonist, 0.2, 1.0, 5.0 mg/kg, i.p.) in a dose-dependent fashion. In contrast, the effect was not blocked by naloxone (a non-selective opioid receptor antagonist, 2.0 mg/kg, i.p.) or yohimbine (a alpha(2)-adrenergic receptor antagonist, 1.0, 2.5, 5.0 mg/kg, i.p.) in the hot-plate test. Therefore, the antinociceptive effects of LXM-10 involve the peripheral neuronal nicotinic and muscarinic acetylcholine receptors; they are not related to opioid receptors or alpha(2)-adrenergic receptors. LXM-10 did not affect motor coordination, spontaneous activity, or body temperature. These findings with LXM-10 suggest that spirocyclopiperazinium derivatives could provide insight on new analgesics.

Topics: Analgesics; Animals; Atropine; Atropine Derivatives; Body Temperature; Drug Evaluation, Preclinical; Female; Hexamethonium; Male; Mecamylamine; Mice; Mice, Inbred ICR; Motor Activity; Naloxone; Pain; Pain Measurement; Piperazines; Psychomotor Performance; Receptors, Adrenergic, alpha-2; Receptors, Muscarinic; Receptors, Nicotinic; Receptors, Opioid; Yohimbine

Tramadol (1RS, 2RS)-2-[(dimethylamino)-methyl]-1-(3-methoxyphenyl)-cyclohexanol) is an atypical centrally acting analgesic agent with weak opioid receptor affinity that, like some antidepressants, enhances the extraneuronal concentrations of the monoamine neurotransmitters, noradrenaline and serotonin, by interfering with their re-uptake and release mechanisms.. The present study was undertaken to evaluate the potential role of 5-HT(1A) receptors and opioids receptors in the analgesic effect of tramadol in neuropathic pain. With this aim, the effect of either a selective 5-HT(1A) receptor antagonist (WAY-100635, N-2-[4-(2-methoxyphenyl-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexane carboxamide) or a selective 5-HT(1A) receptor agonist (8-OH-DPAT, 8-hydroxy-2-(di-n-propylamine) tetralin hydrobromide) or an opioid receptor antagonist (naloxone; naloxone hydrochloride dihydrate) was investigated in combination with tramadol by means of the cold-plate test in the chronic constriction injury model in rats.. The results showed that WAY-100635 (0.8 mg/kg) significantly enhanced the antiallodynic effect of non-effective doses of tramadol (5-10 mg/kg). In contrast, 8-OH-DPAT (0.5 mg/kg) counteracted the antiallodynic effect of an effective dose of tramadol (22 mg/kg). Naloxone (0.5 mg/kg) partially counteracted the antiallodynic effect of tramadol (22 mg/kg).. These findings suggest the involvement of opioid and 5-HT(1A) receptors in the antinociceptive effect of tramadol and support the idea that the combination of tramadol with compounds having 5-HT(1A) antagonist properties could be a new strategy to improve tramadol-induced analgesia in neuropathic pain.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Analgesics, Opioid; Animals; Chronic Disease; Disease Models, Animal; Drug Interactions; Male; Naloxone; Narcotic Antagonists; Pain; Pain Threshold; Piperazines; Pyridines; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT1A; Receptors, Opioid; Sciatic Nerve; Sciatic Neuropathy; Serotonin 5-HT1 Receptor Agonists; Tramadol

The antinociceptive properties of Casearia sylvestris Sw. (Flacourtiaceae) were investigated in various models of pain-related behavior in mice. The hydroalcoholic crude extract of the plant (30-300mg/kg, per os) clearly inhibited nocifensive responses induced by ovalbumin (hindpaw licking) or acetic acid (writhes) in graded fashion. At 300mg/kg, the extract reduced nocifensive behaviors (from 71.1+/-13.3 to 14.8+/-9.3s; from 31.3+/-4.5 to 3.3+/-1.2 writhes, respectively) to similar extents as indomethacin (5mg/kg; 5.7+/-1.1s and 3.3+/-1.2 writhes, respectively). Significant antinociceptive effects in the hot plate test were only detected following administration of the highest extract dose, but this analgesic action appeared to be specific as the extract failed to change motor and exploratory activities. The antinociceptive effect of Casearia sylvestris extract in the acetic acid test was prevented by prior treatment with the non-selective opioid receptor antagonist naloxone (1mg/kg; 5.8+/-4.2 and 31.5+/-3.1 writhes in vehicle-treated and naloxone-treated groups, respectively), indicating that the endogenous opioid system is involved in its analgesic mechanism of action. Thus, our investigation suggests a potential therapeutic benefit of Casearia sylvestris Sw. in treating conditions associated with inflammatory pain.

Topics: Analgesics; Analgesics, Opioid; Animals; Casearia; Disease Models, Animal; Dose-Response Relationship, Drug; Lethal Dose 50; Male; Mice; Morphine; Naloxone; Narcotic Antagonists; Pain; Plant Extracts; Rats

The mechanisms of the analgesic action of carbamazepine and oxcarbazepine, in particular the role of opioid receptors, have not been established precisely. The systemic effects of naloxone, an opioid receptor antagonist, on the antihyperalgesic effects of carbamazepine and oxcarbazepine were examined in the model of inflammatory hyperalgesia induced by the intraplantar (i.pl.) administration of concanavaline A (Con A, 0.8 mg/paw) into the rat hind paw. Naloxone (3 mg/kg; i.p.) did not alter the antihyperalgesic effects of either carbamazepine or oxcarbazepine. These results indicate that the opioid system of pain modulation does not play a significant role in the antihyperalgesic effects of carbamazepine and oxcarbazepine.

Topics: Analgesics, Non-Narcotic; Animals; Anticonvulsants; Carbamazepine; Concanavalin A; Hyperalgesia; Male; Naloxone; Narcotic Antagonists; Oxcarbazepine; Pain; Rats; Rats, Wistar

We have previously demonstrated that (+)-morphine and (-)-morphine pretreated spinally for 45 min stereoselectively attenuates the tail-flick inhibition produced by (-)-morphine given spinally in the mouse. The present study is then undertaken to determine if the same phenomenon observed in the mouse spinal cord can also take place in the ventral periaqueductal gray of the rat. Pretreatment with (+)-morphine for 45 min at 0.3 to 3.3 fmol dose-dependently attenuated the tail-flick inhibition produced by (-)-morphine (9 nmol) given into the ventral periaqueductal gray. Likewise, pretreatment with (-)-morphine for 45 min at a higher dose (3-900 pmol), which given alone did not affect the baseline tail-flick latency, also dose-dependently attenuated the tail-flick inhibition produced by (-)-morphine. Thus, (+)-morphine is approximately 270,000-fold more potent than (-)-morphine in attenuating the (-)-morphine-produced tail-flick inhibition. The attenuation of the (-)-morphine-produced tail-flick inhibition induced by (+)-morphine or (-)-morphine was dose-dependently reversed by (+)-naloxone (27.5 to 110 pmol) pretreatment for 50 min given into the ventral periaqueductal gray. Pretreatment with the sigma receptor antagonist BD1047 (N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino)ethylamine dihydrobromide) (11-45 nmol) for 45 min given into the ventral periaqueductal gray also reversed dose-dependently the attenuation of the (-)-morphine-produced tail-flick inhibition induced by (+)-morphine or (-)-morphine, indicating that the effects are mediated by the activation of the sigma receptors. Since (+)-morphine, (-)-morphine and (+)-naloxone do not have any affinity for the naloxone-inaccessible sigma receptors, we therefore propose that (+)-morphine and (-)-morphine attenuate the (-)-morphine-produced tail-flick inhibition via the activation of the naloxone-sensitive sigma receptor originally proposed by Tsao and Su [Tsao, L.T., Su, T.P., 1997. Naloxone-sensitive, haloperidol-sensitive, [(3)H](+)-SKF-1047-binding protein partially purified from rat liver and rat brain membranes: an opioid/sigma receptor. Synapse 25, 117-124].

Topics: Analgesics, Opioid; Animals; Dose-Response Relationship, Drug; Ethylenediamines; Male; Microinjections; Models, Anatomic; Morphine; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Periaqueductal Gray; Rats; Receptors, sigma; Stereoisomerism; Tail; Time Factors

In the present study, we investigated whether the peripherally acting micro-opioid receptor agonist loperamide would inhibit allodynia in the non-inflamed dermatome of mice with herpetic pain. Subcutaneous (s.c.) injection of loperamide (1 and 3 mg/kg) inhibited allodynia. Local (intraplantar) injection of loperamide (1 and 5 microg/site) also produced an anti-allodynic effect. The peripheral opioid receptor antagonist naloxone methiodide (0.1 mg/kg, s.c.) and the micro-opioid receptor-selective antagonist beta-funaltrexamine (40 nmol/site, intraplantar and 20 mg /kg, s.c.) antagonized the anti-allodynic effects of systemic and local loperamide. Local injection of loperamide into the contralateral hind paw was without effect, suggesting that the effect is mediated through local action, not systemic action. Acute and subacute tolerance did not develop to the anti-allodynic effect of loperamide. In addition, there were no cross-tolerance between local opioids (morphine and loperamide) and systemic morphine. These results suggest that stimulation of peripheral micro-opioid receptors suppresses herpetic allodynia without tolerance development. The non-narcotic micro-opioid receptor agonist loperamide may relieve acute herpetic pain in patients with herpes zoster.

Topics: Analgesics, Opioid; Animals; Data Interpretation, Statistical; Dose-Response Relationship, Drug; Drug Tolerance; Female; Foot; Herpes Simplex; Herpesvirus 1, Human; Injections; Injections, Subcutaneous; Loperamide; Mice; Mice, Inbred C57BL; Morphine; Naloxone; Naltrexone; Narcotic Antagonists; Pain; Physical Stimulation

We have previously shown that microinjection of galanin into the arcuate nucleus of hypothalamus (ARC) produced antinociceptive effects in rats (Sun et al., 2003a). In this study, the neural pathway of galanin from ARC to midbrain periaqueductal gray (PAG) in nociceptive modulation was investigated. The hindpaw withdrawal latencies (HWLs) with noxious thermal and mechanical stimulation were assessed by the hotplate and the Randall Selitto tests. Intra-ARC administration of 0.1, 0.5, or 1 nmol of galanin induced significant increases in HWLs of rats. The galanin-induced increases in HWLs were inhibited by injection of 10 microg of the opioid receptor antagonist naloxone or 1 nmol of the mu-opioid receptor antagonist beta-funaltrexamine (beta-FNA) into PAG, suggesting that the antinociceptive effects induced by intra-ARC injection of galanin occur via the neural pathway from ARC to PAG. Furthermore, our results demonstrate that the galaninergic fibers directly innervated the beta-endorphinergic neurons in ARC by immunofluorescent methods. Taken together, our results suggest that galanin produces antinociceptive effects in the ARC of rats by activating the beta-endorphinergic pathway from ARC to PAG.

Topics: Animals; Arcuate Nucleus of Hypothalamus; beta-Endorphin; Fluorescent Antibody Technique; Galanin; Hindlimb; Hot Temperature; Injections, Intraventricular; Male; Naloxone; Naltrexone; Narcotic Antagonists; Neural Pathways; Neurons; Pain; Periaqueductal Gray; Physical Stimulation; Rats; Rats, Wistar

We have previously demonstrated that (+)-morphine and (-)-morphine given spinally stereoselectively attenuate the spinally-administered (-)-morphine-produced tail-flick inhibition in the mouse. The phenomenon has been defined as antianalgesia. Present studies were then undertaken to determine if the systemic administration of (+)-morphine and (-)-morphine also stereoselectively attenuates the systemic (-)-morphine-produced tail-flick inhibition and the effects of (+)-morphine and (-)-morphine are mediated by the naloxone-sensitive sigma receptor activation in male CD-1 mice. Pretreatment with (+)-morphine at a dose of 0.01-10 ng/kg given subcutaneously dose-dependently attenuated the tail-flick inhibition produced by subcutaneously-administered (-)-morphine (5 mg/kg). Pretreatment with (-)-morphine (0.01-1.0 mg/kg) given subcutaneously also attenuates the (-)-morphine-produced tail-flick inhibition. The ED50 values for (+)-morphine and (-)-morphine for inhibiting the (-)-morphine-produced tail-flick inhibition were estimated to be 30.6 pg/kg and 97.5 microg/kg, respectively. The attenuation of the (-)-morphine-produced tail-flick inhibition induced by (+)-morphine or (-)-morphine pretreatment was reversed by the pretreatment with (+)-naloxone or by the sigma receptor antagonist BD1047 (N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino)ethylamine dihydrobromide) given subcutaneously. Pretreatment with (+)-pentazocine, a selective sigma receptor agonist, (1-10 mg/kg) given subcutaneously also attenuates (-)-morphine-produced tail-flick inhibition, which was restored by (+)-naloxone (4 mg/kg) or BD1047 (10 mg/kg) pretreated subcutaneously. It is concluded that (+)-morphine exhibits extremely high stereoselective action over (-)-morphine given systemically in attenuating the systemic (-)-morphine-produced antinociception and the antianalgesic effect of (+)-morphine and (-)-morphine is mediated by activation of the naloxone-sensitive sigma receptor.

Topics: Analgesics, Opioid; Animals; Dose-Response Relationship, Drug; Ethylenediamines; Injections, Subcutaneous; Male; Mice; Morphine; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Pain Threshold; Pentazocine; Receptors, sigma; Stereoisomerism

Psalmotoxin 1, a peptide extracted from the South American tarantula Psalmopoeus cambridgei, has very potent analgesic properties against thermal, mechanical, chemical, inflammatory and neuropathic pain in rodents. It exerts its action by blocking acid-sensing ion channel 1a, and this blockade results in an activation of the endogenous enkephalin pathway. The analgesic properties of the peptide are suppressed by antagonists of the mu and delta-opioid receptors and are lost in Penk1-/- mice.

Topics: Acid Sensing Ion Channels; Analgesics; Animals; Area Under Curve; Behavior, Animal; Disease Models, Animal; Dose-Response Relationship, Drug; Enkephalins; Membrane Proteins; Mice; Mice, Knockout; Morphine; Naloxone; Naltrexone; Narcotic Antagonists; Nerve Tissue Proteins; Neurons; Pain; Pain Measurement; Peptides; Protein Precursors; Reaction Time; Sodium Channels; Spider Venoms; Spinal Cord; Time Factors

There is a major societal concern relating to the addictive properties of analgesic drugs such as morphine with regard to alleviating pain. Because of this, alternative methods of pain relief are, and have been, actively pursued. An extremely promising method for treatment of low to moderate levels of chronic pain in humans is transcutaneous electrical nerve stimulation (TENS).. All experiments utilized the invertebrate marine bivalve mollusc Mytilus edulis pedal ganglia. TENS was achieved using a stimulation apparatus developed by Professor Han of Peking University. TENS experiments employed 2 stimulation protocols: 1) low 2 Hz frequency at 5 mA current, 2) alternating low and high frequencies at 2 and 100 Hz, respectively at 5 mA current. Real-time measurements of nitric oxide (NO), using an amperometric probe, measured NO released into the tissue bath subsequent to TENS.. Pooled M. edulis pedal ganglia exposed to TENS demonstrate that stimulation at 2 Hz and 5 mA current promotes time-dependent release of NO. In another experiment, pooled ganglia were stimulated at alternating frequencies of 2 Hz and 100 Hz and 5 mA, which also released NO in a time-dependent manner. Unstimulated control ganglia did not release significant amounts of NO. NO release was antagonized by naloxone and L-NAME exposure, demonstrating that it was receptor and nitric oxide synthase mediated, respectively.. It would appear that TENS stimulates endogenous morphine release since NO release was blocked by naloxone and opioid peptides do not release NO. The present study is highly suggestive of the occurrence of this same mechanism in mammalian neural systems since all biochemical and signaling components are present. Furthermore, it would appear that this process has evolutionary survival value since it occurs in an animal that evolved 500 million years ago.

Topics: Animals; Calibration; Ganglia; Models, Biological; Morphine; Mytilus edulis; Naloxone; Nervous System; Neurons; NG-Nitroarginine Methyl Ester; Nitric Oxide; Opioid Peptides; Pain; Signal Transduction; Transcutaneous Electric Nerve Stimulation

Topics: Chronic Disease; Clinical Trials as Topic; Constipation; Delayed-Action Preparations; Drug Combinations; Humans; Naloxone; Narcotics; Oxycodone; Pain

Previous in vitro studies have shown that the degradation of [Met(5)]enkephalin-Arg(6)-Phe(7) during incubation with cerebral membrane preparations is largely prevented by a mixture of three peptidase inhibitors: amastatin, captopril, and phosphoramidon. The present in vivo study shows that the inhibitory effect of [Met(5)]enkephalin-Arg(6)-Phe(7) administered intra-third-ventricularly on the tail-flick response was increased more than 1000-fold by the intra-third-ventricular pretreatment with three peptidase inhibitors. The antinociceptive effect produced by the [Met(5)]enkephalin-Arg(6)-Phe(7) in rats pretreated with any combination of two peptidase inhibitors was significantly smaller than that in rats pretreated with three peptidase inhibitors, indicating that any residual single peptidase could inactivate significant amounts of the [Met(5)]enkephalin-Arg(6)-Phe(7). The present data, together with those obtained from previous studies, clearly show that amastatin-, captopril-, and phosphoramidon-sensitive enzymes play important roles in the inactivation of endogenous opioid peptides, such as [Met(5)]enkephalin, [Met(5)]enkephalin-Arg(6)-Phe(7), [Met(5)]enkephalin-Arg(6)-Gly(7)-Leu(8), and dynorphin A (1-8), administered intra-third-ventricularly to rats.

Topics: Analgesics; Animals; Captopril; Dose-Response Relationship, Drug; Drug Synergism; Enkephalin, Methionine; Glycopeptides; Injections, Intraventricular; Injections, Subcutaneous; Male; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Peptides; Protease Inhibitors; Rats; Rats, Wistar

We previously reported that mutations in the mu-opioid receptor (MOR), S196L or S196A, rendered MOR responsive to the opioid antagonist naloxone without altering the agonist phenotype. Subsequently, a mouse strain carrying the S196A mutation exhibited in vivo naloxone antinociceptive activity without the development of tolerance. In this study we investigated the possibility of combining the in vivo site-directed delivery of MORS196A and systemic naloxone administration as a paradigm for pain management. Double-stranded adenoassociated virus type 2 (dsAAV2) was used to deliver MORS196A-EGFP by injecting the virus into the spinal cord (S2/S3) dorsal horn region of ICR mice. MORS196A-EGFP fluorescence colocalized with some calcitonin gene-related peptide and neuron-specific protein immunoreactivity in the superficial layers of the dorsal horn 1 week after injection and lasted for at least 6 months. In mice injected with the mutant receptor, morphine induced similar antinociceptive responses and tolerance development or precipitated withdrawal symptoms and reward effects, similar to those in the control mice (saline injected into the spinal cord). Conversely, in the dsAAV2-injected mice, naloxone produced antinociceptive effects at the spinal level but not at the supraspinal level, whereas naloxone had no measurable effect on the control mice. Furthermore, the chronic administration of naloxone to mice injected with dsAAV2-MORS196A-EGFP did not induce tolerance, dependence, or reward responses. Thus, our current approach to activate a mutant receptor, but not the endogenous receptor, with an opioid antagonist represents an alternative to the use of traditional opioid agonists for pain management.

Topics: Animals; Dependovirus; Drug Tolerance; Gene Expression Regulation; Gene Transfer Techniques; Genes, Reporter; Male; Mice; Morphine; Mutation; Naloxone; Pain; Pain Measurement; Receptors, Opioid, mu; Serine; Spinal Cord; Time Factors

Topics: Analgesics, Opioid; Constipation; Delayed-Action Preparations; Dose-Response Relationship, Drug; Drug Combinations; Gastrointestinal Motility; Humans; Naloxone; Oxycodone; Pain; Palliative Care; Randomized Controlled Trials as Topic; Sleep

Topics: Analgesics, Opioid; Constipation; Delayed-Action Preparations; Dose-Response Relationship, Drug; Drug Combinations; Gastrointestinal Motility; Humans; Multicenter Studies as Topic; Naloxone; Oxycodone; Pain; Palliative Care; Patient Satisfaction; Quality of Life; Randomized Controlled Trials as Topic

Morphine and surgical cingulotomy, or transection of the anterior cingulate cortex (ACC), provides relief of chronic pain by selectively decreasing the affective dimension of the condition without altering sensory processing. Clinical reports suggest that morphine might be acting at the level of the ACC to alter the complex experience of pain. Therefore, the purpose of this experiment was to directly examine the functional role of the ACC in processing the aversive nature of pain induced by ligation of the L5 spinal nerve. Systemic administration of low dose morphine produced a selective attenuation of pain affect, as indicated by a decrease in the aversiveness of noxious cutaneous stimulation in nerve-damaged animals, with no alteration of mechanical paw withdrawal threshold. Supraspinally, microinjection of morphine into the ACC produced a selective naloxone reversible reduction in pain affect, as indicated by a decrease in the aversiveness of noxious cutaneous stimulation in nerve-damaged animals, with no alteration of response to mechanical stimulation. These data demonstrate the central role of the ACC opioid system in selectively processing the aversive quality of noxious mechanical stimulation in animals with a persistent pain condition.

Topics: Animals; Avoidance Learning; Cerebral Cortex; Endorphins; Escape Reaction; Gyrus Cinguli; Male; Microinjections; Morphine; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Peripheral Nervous System Diseases; Physical Stimulation; Rats; Rats, Sprague-Dawley; Receptors, Opioid

Echium amoenum Fisch & C.A. Mey. has been used in Iranian traditional medicine as demulcent and analgesic in common cold from long ago. In this investigation, the analgesic effect of the methanolic extract of the petals of this plant on male albino mice was evaluated by formalin and hot-plate test. The methanolic percolated extract with different doses 5, 10, 20 and 30 mg/kg were injected intraperitoneally to mice. The results showed that the dose of 10 mg/kg of extract had the highest analgesia in formalin (P<0.05) and hot-plate test (P<0.01) compared to the control group. The analgesic effect of extract was lower than morphine 2.5 mg/kg and ASA 300 mg/kg in the chronic phase of pain in formalin test (P<0.05) and in hot-plate test too (P<0.05). Pretreatment of animal with naloxone 4 mg/kg, s.c. 5 min before extract, decreased the analgesia induced by extract in hot-plate and acute phase of formalin tests; therefore, the opioid receptor may be involved at least partly in the analgesic effect of Echium amoenum extract. The results suggested that Echium amoenum extract has a suitable analgesic effect and further studies are required to evaluate these effects and the potential of the plant.

Topics: Analgesics; Animals; Dose-Response Relationship, Drug; Echium; Flowers; Formaldehyde; Hot Temperature; Injections, Intraperitoneal; Iran; Male; Medicine, Arabic; Mice; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Plant Extracts; Receptors, Opioid; Time Factors

Previous studies have indicated that interferon-alpha (IFN-alpha) can bind to opioid receptors and exerts an antinociceptive effect in both peripheral and central nervous systems. The current study investigated the antinociceptive effect of IFN-alpha unilaterally microinjected into the thalamic nucleus submedius (Sm) of rats on noxious thermal stimulus, and the roles of different subtypes of opioid receptors in mediating the Sm IFN-alpha-evoked antinociception. The results indicated that unilateral microinjection of IFN-alpha (4, 8, 16 pmol) into the Sm dose-dependently increased the hind paw withdrawal latency from the noxious heat stimulus, and this effect was reversed by pretreatment with non-selective opioid receptor antagonist naloxone (200 pmol) and specific mu-opioid receptor antagonist beta-FNA (1 nmol) into the same sites, whereas delta-opioid receptor antagonist ICI174,864 (1 nmol) and kappa-opioid receptor antagonist nor-BNI (1 nmol) failed to alter the effect of IFN-alpha. These results suggest that Sm is involved in IFN-alpha-evoked antinociception and mu- but not delta- and kappa-opioid receptor mediates the Sm IFN-alpha-evoked antinociception.

Topics: Animals; Escape Reaction; Interferon-alpha; Male; Mediodorsal Thalamic Nucleus; Microinjections; Naloxone; Naltrexone; Pain; Rats; Rats, Sprague-Dawley; Reaction Time; Receptors, Opioid, kappa; Receptors, Opioid, mu

The antinociceptive effect and the mechanism of bee venom acupuncture (BVA) on inflammatory pain, especially in the rat model of collagen-induced arthritis (CIA), have not yet been fully studied. This study was designed to investigate the antinociceptive effect and its mu-opioid and alpha2-adrenergic mechanism of BVA in the CIA rat model. To induce CIA, male Sprague-Dawley rats were immunized with bovine type II collagen emulsified in Freund's incomplete adjuvant followed by a booster injection 14 days later. The antinociceptive effect was evaluated by tail flick latency (TFL). After induction of arthritis, the inflammatory pain threshold decreased as time passed, and there was no big change of the pain threshold after 3 weeks. Three weeks after the first immunization, BVA (0.25 mg/kg) injected into the Zusanli acupoint (ST36) showed the antinociceptive effect. Furthermore, the antinociceptive effect of BVA was blocked by yohimbine (alpha2-adrenergic receptor antagonist, 2 mg/kg, i.p) pretreatment, but not by naloxone (mu-opioid receptor antagonist, 2 mg/kg, i.p.) pretreatment. These results suggest that BVA can relieve inflammatory pain in CIA and the antinociceptive effect of BVA can be mediated by alpha2-adrenergic receptor.

Topics: Acupuncture Points; Adrenergic alpha-Antagonists; Animals; Arthritis, Experimental; Bee Venoms; Behavior, Animal; Collagen; Disease Models, Animal; Drug Administration Routes; Drug Interactions; Male; Naloxone; Narcotic Antagonists; Pain; Pain Management; Pain Measurement; Rats; Rats, Sprague-Dawley; Reaction Time; Receptors, Adrenergic, alpha-2; Statistics, Nonparametric; Yohimbine

Previous studies have indicated that the ventrolateral orbital cortex (VLO) is involved in opioid-mediated antinociception in the tail flick test and formalin test. The aim of the current study was to examine the effect of opioids microinjected into the VLO on allodynia in the rat L5/L6 spinal nerve ligation (SNL) model of neuropathic pain and determine the roles of different subtypes of opioid receptors in this effect. The allodynia was assessed by both mechanical (von Frey filaments) and cold plate (4 degrees C) stimuli. Morphine (1.0, 2.5, and 5.0 microg) microinjected into the VLO contralateral to the nerve ligation dose-dependently depressed the mechanical and cold allodynia and these effects were reversed by nonselective opioid receptor antagonist naloxone (1.0 microg) administrated into the same site. Microinjection of endomorphin-1 (5.0 microg), a highly selective mu-opioid receptor agonist, and [D-Ala2, D-Leu5]-enkephalin (DADLE, 10 microg), a delta-/mu-opioid receptor agonist, also depressed the allodynia, and the effects of both drugs were blocked by selective mu-receptor antagonist beta-funaltrexamine (beta-FNA, 3.75 microg), but the effects of DADLE were not influenced by the selective delta-receptor antagonist naltrindole (5.0 microg). Microinjection of U-62066 (100 microg), a kappa-opioid receptor agonist, into the VLO had no effect on the allodynia. These results suggest that the VLO is involved in opioid-induced antiallodynia and mu- but not delta- and kappa-opioid receptor mediates these effects in the rat with neuropathic pain.

Topics: Analgesics, Opioid; Analysis of Variance; Animals; Behavior, Animal; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Male; Morphine; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Physical Stimulation; Prefrontal Cortex; Rats; Rats, Sprague-Dawley; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Spinal Cord Injuries; Time Factors

It is well known that there are three types of opioid receptors, mu- (MOR), delta- (DOR), and kappa-opioid receptor (KOR) in the central nervous system. The present study investigated the involvement of opioid receptors in morphine-induced antinociception in the nucleus accumbens (NAc) of rats. The hindpaw withdrawal latencies to thermal and mechanical stimulation increased markedly after intra-NAc administration of morphine. The antinociceptive effects induced by morphine were dose-dependently inhibited by intra-NAc administration of the non-selective opioid receptor antagonist naloxone. Furthermore, the morphine-induced antinociception was significantly attenuated by subsequent intra-NAc injection of the MOR antagonist beta-funaltrexamine or the KOR antagonist nor-binaltorphimine, but not the DOR antagonist naltrindole. The results indicate that MOR and KOR, but not DOR are involved in the morphine-induced antinociception in the NAc of rats.

Topics: Analgesics, Opioid; Animals; Male; Morphine; Naloxone; Naltrexone; Nucleus Accumbens; Pain; Physical Stimulation; Rats; Rats, Sprague-Dawley; Reaction Time; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu

1 The reversible fatty acid amide hydrolase (FAAH) inhibitor OL135 reverses mechanical allodynia in the spinal nerve ligation (SNL) and mild thermal injury (MTI) models in the rat. The purpose of this study was to investigate the role of the cannabinoid and opioid systems in mediating this analgesic effect. 2 Elevated brain concentrations of anandamide (350 pmol g(-1) of tissue vs 60 pmol g(-1) in vehicle-treated controls) were found in brains of rats given OL135 (20 mg kg(-1)) i.p. 15 min prior to 20 mg kg(-1) i.p. anandamide. 3 Predosing rats with OL135 (2-60 mg kg(-1) i.p.) 30 min before administration of an irreversible FAAH inhibitor (URB597: 0.3 mg kg(-1) intracardiac) was found to protect brain FAAH from irreversible inactivation. The level of enzyme protection was correlated with the OL135 concentrations in the same brains. 4 OL135 (100 mg kg(-1) i.p.) reduced by 50% of the maximum possible efficacy (MPE) mechanical allodynia induced by MTI in FAAH(+/+)mice (von Frey filament measurement) 30 min after dosing, but was without effect in FAAH(-/-) mice. 5 OL135 given i.p. resulted in a dose-responsive reversal of mechanical allodynia in both MTI and SNL models in the rat with an ED(50) between 6 and 9 mg kg(-1). The plasma concentration at the ED(50) in both models was 0.7 microM (240 ng ml(-1)). 6 In the rat SNL model, coadministration of the selective CB(2) receptor antagonist SR144528 (5 mg kg(-1) i.p.), with 20 mg kg(-1) OL135 blocked the OL135-induced reversal of mechanical allodynia, but the selective CB(1) antagonist SR141716A (5 mg kg(-1) i.p.) was without effect. 7 In the rat MTI model neither SR141716A or SR144528 (both at 5 mg kg(-1) i.p.), or a combination of both antagonists coadministered with OL135 (20 mg kg(-1)) blocked reversal of mechanical allodynia assessed 30 min after dosing. 8 In both the MTI model and SNL models in rats, naloxone (1 mg kg(-1), i.p. 30 min after OL135) reversed the analgesia (to 15% of control levels in the MTI model, to zero in the SNL) produced by OL135.

Topics: Amidohydrolases; Analgesics; Animals; Arachidonic Acids; Brain; Dose-Response Relationship, Drug; Endocannabinoids; Enzyme Inhibitors; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Models, Animal; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Polyunsaturated Alkamides; Pyridines; Rats; Rats, Sprague-Dawley; Spinal Cord

Nociceptive signals are transmitted to the spinal dorsal horn via primary afferent fibers, and the signals induce withdrawal reflexes by activating spinal motoneurons in the ventral horn. Therefore, nociceptive stimuli increase motoneuronal firing and ventral root discharges. This study was aimed to develop a method for the study of pain mechanisms and analgesics by recording ventral root discharges. Spinalized rats were laminectomized in the lumbo-sacral region. The fifth lumbar ventral root was sectioned and placed on a pair of wire electrodes. Multi unit efferent discharges from the ventral root were increased by mechanical stimulation using a von Frey hair applied to the plantar surface of the hindpaw. The low-intensity mechanical stimuli increased the discharges during stimulation (during-discharges) without increasing the discharges after cessation of stimulation (after-discharges), and the high-intensity mechanical stimuli increased both during- and after-discharges. Pretreatment with resiniferatoxin, an ultrapotent analogue of capsaicin, halved during-discharges and eliminated after-discharges, suggesting that after-discharges are generated by heat- and mechanosensitive polymodal nociceptors. Ezlopitant, a neurokinin-1 (NK-1) receptor antagonist, but not its inactive enantiomer, selectively reduced the after-discharges. Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, preferentially reduced the after-discharges, demonstrating that NK-1 and NMDA receptors mediate the after-discharges. Morphine reduced the after-discharges without affecting during-discharges. By contrast, mephenesin, a centrally acting muscle relaxant, reduced both during- and after-discharges. There results suggest that simultaneous recordings of during- and after-discharges are useful to study pain mechanisms and analgesics as well as to discriminate the analgesic effects from the side effects such as muscle relaxant effects.

Topics: Action Potentials; Analysis of Variance; Animals; Benzylamines; Bridged Bicyclo Compounds, Heterocyclic; Diterpenes; Dose-Response Relationship, Drug; Dose-Response Relationship, Radiation; Excitatory Amino Acid Antagonists; Ketamine; Male; Mephenesin; Morphine; Naloxone; Narcotic Antagonists; Narcotics; Neurotoxins; Pain; Pain Measurement; Physical Stimulation; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Receptors, Neurokinin-1; Spinal Nerve Roots; Time Factors

Opioids are commonly used in the treatment of moderate to severe pain. However, their chronic use is limited by analgesic tolerance and physical dependence. Few studies have examined how chronic pain affects the development of tolerance or dependence, and essentially no studies have looked at the role of both genetics and pain together. For these studies we used 12 strains of inbred mice. Groups of mice from each strain were tested at baseline for morphine analgesic sensitivity, mechanical nociceptive threshold, and thermal nociceptive threshold. Mice were then given morphine in a 4-day escalating morphine administration paradigm followed by reassessment of the morphine dose-response relationship. Finally, physical dependence was measured by administering naloxone. Parallel groups of mice underwent hind paw injection of complete Freund's adjuvant (CFA) to induce chronic hind paw inflammation 7 days prior to the beginning of testing. The data showed that CFA treatment tended to lower baseline ED(50) values for morphine and enhanced the degree of analgesic tolerance observed after 4 days of morphine treatment. In addition, the degree of jumping behavior indicative of physical dependence was often altered if mice had been treated with CFA. The influence of background strain was substantial for all traits measured. In silico haplotypic mapping of the tolerance and physical dependence data demonstrated that CFA pretreatment altered the pattern of the predicted associations and greatly reduced their statistical significance. We conclude that chronic inflammatory pain and genetics interact to modulate the analgesic potency of morphine, tolerance, and physical dependence.

Topics: Analgesics, Opioid; Animals; Chronic Disease; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Tolerance; Freund's Adjuvant; Genetic Predisposition to Disease; Genotype; Inflammation Mediators; Male; Mice; Mice, Inbred AKR; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Inbred MRL lpr; Morphine; Naloxone; Narcotic Antagonists; Opioid-Related Disorders; Pain; Pain Threshold; Species Specificity

The role of medullary and spinal 5-HT(1A) receptors in endogenous regulation of neuropathic hypersensitivity was studied. When administered in the rostroventromedial medulla or subcutaneously, WAY-100635, a 5-HT(1A) receptor antagonist, attenuated mechanical hypersensitivity in rats with a spinal nerve injury. Thermal or mechanical nociception outside of the injured area was not influenced by medial medullary or subcutaneous administration of WAY-100635. Intrathecal administration of WAY-100635 had no significant effect on pain-related behavior. Suppression of mechanical hypersensitivity induced by medial medullary administration of WAY-100635 was reversed by intrathecal administration of WAY-100635 or atipamezole, an alpha2-adrenoceptor antagonist, but not by naloxone, an opioid receptor antagonist. The results indicate that endogenous release of 5-HT, via action on medial medullary 5-HT(1A) receptors, tonically suppresses descending inhibition in neuropathic animals. Following medial medullary administration of a 5-HT(1A) receptor antagonist, descending pain regulatory pathways are disinhibited. This leads to selective attenuation of neuropathic hypersensitivity, due to action on spinal 5-HT(1A) receptors and alpha2-adrenoceptors.

Topics: Adrenergic alpha-Antagonists; Animals; Dose-Response Relationship, Drug; Hot Temperature; Hyperalgesia; Imidazoles; Injections, Intraventricular; Injections, Spinal; Injections, Subcutaneous; Male; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Pain Threshold; Piperazines; Pyridines; Rats; Rats, Wistar; Receptor, Serotonin, 5-HT1A; Serotonin 5-HT1 Receptor Antagonists; Serotonin Antagonists; Spinal Nerves

Clinical and experimental studies have been reported that antidepressant drugs can be used as co-analgesics in the management of neuropathic pain. However, the mechanism through which they alleviate pain still remains unclear. The aim of the present study was to investigate the possible mechanism of action of fluoxetine-induced antinociceptive effect in streptozotocin-induced diabetic mice, especially the involvement of non-serotonergic neurotransmitters and their receptors. Diabetes was induced in male Laka mice with a single intraperitoneal injection of streptozotocin (200 mg/kg). Four weeks after streptozotocin, diabetic mice were tested for pain responses in the tail-immersion and hot-plate assays. Diabetic mice exhibited significant hyperalgesia as compared with control mice. Fluoxetine (10 and 20 mg/kg, i.p) injected into diabetic mice produced an antinociceptive effect in both tail-immersion and hot-plate assays. The antinociceptive effect of fluoxetine in diabetic mice was significantly lower as compared with that in control mice. Pretreatment with a muscarinic receptor antagonist, atropine (2 and 5 mg/kg, i.p) and an opioid receptor antagonist, naloxone (2 and 5 mg/kg, i.p), but not the alpha(2)-adrenoreceptor antagonist, yohimbine (2 and 5 mg/kg, i.p) reversed the antinociceptive effect of fluoxetine (20 mg/kg). These results suggest that apart from serotonin pathway, muscarinic and opioid receptors also participate in fluoxetine-induced antinociception in diabetic neuropathic pain.

Topics: Analgesics; Animals; Atropine; Diabetes Mellitus, Experimental; Dose-Response Relationship, Drug; Fluoxetine; Male; Mice; Muscarinic Antagonists; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Pain Threshold; Receptors, Muscarinic; Receptors, Opioid; Secologanin Tryptamine Alkaloids; Serotonin Antagonists

The purpose of this report is to explore the mechanisms of hypercapnia-induced antinociception. We carried out three experiments, the first to confirm whether moderate hypercapnia induces anesthetic effects, the second to determine whether naloxone reverses the anesthetic effects, and the third to evaluate whether beta-endorphin is related to the anesthetic effects. In a pre-test, we determined the optimal CO(2) concentration in a chamber which would cause moderate hypercapnia in rats. Eighteen rats were divided into control, hypercapnia, and hypercapnia plus naloxone groups in experiment 1. The naloxone group rats were injected with naloxone (10 mg/kg) intraperitoneally before gas inhalation. After 60 min gas inhalation, 10% formalin was injected into the left rear paw of all rats, and nociceptive behaviors were observed for 1 h. In experiment 2, 11 rats were divided into control and hypercapnia groups. The brain was removed and fixed under pentobarbital anesthesia. Sections were immunostained for c-Fos and beta-endorphin (ACTH) with the ABC method. All neurons double-labeled for c-Fos and beta-endorphin (ACTH) in the arcuate nucleus were counted by blinded investigators. Moderate hypercapnia (PaCO(2) 83+/-7 mmHg) reduced nociceptive behavior in the formalin test and naloxone pre-treatment attenuated this phenomenon. However, beta-endorphin-producing neurons were not activated by CO(2) inhalation. Endogenous opioids are related to moderate, hypercapnia-induced anesthetic effects, but, beta-endorphin-producing neurons in the hypothalamus were not activated by the CO(2) inhalation stress.

Topics: Anesthetics, Inhalation; Animals; beta-Endorphin; Carbon Dioxide; Hypothalamus; Male; Naloxone; Narcotic Antagonists; Neurons; Pain; Pain Measurement; Pain Threshold; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Receptors, Opioid

Topics: Adult; Aged; Aged, 80 and over; Analgesics, Opioid; Chronic Disease; Clinical Trials as Topic; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Naloxone; Narcotic Antagonists; Pain; Tilidine; Time Factors

Oxytocin has been implicated in the modulation of somatosensory transmission such as nociception and pain. The present study investigates the effect of oxytocin on formalin-induced pain response, a model of tonic continuous pain. The animals were injected with 0.1 ml of 1% formalin in the right hindpaw and the left hindpaw was injected with an equal volume of normal saline. The time spent by the animals licking or biting the injected paw during 0-5 min (early phase) and 20-25 min (late phase) was recorded separately. Oxytocin (25, 50, 100 microg/kg, i.p.) dose dependently decreased the licking/biting response, both in the early as well as the late phases. The antinociceptive effect of oxytocin (100 microg/kg, i.p.) was significantly attenuated in both the phases by a higher dose of the non-selective opioid receptor antagonist naloxone (5 mg/kg, i.p.), MR 2266 (0.1 mg/kg, i.p.), a selective kappa-opioid receptor antagonist and naltrindole (0.5 mg/kg, i.p.), a selective delta-opioid receptor antagonist but not by a lower dose of naloxone (1 mg/kg, i.p.) or beta-funaltrexamine (2.5 microg/mouse, i.c.v.), a selective mu-opioid receptor antagonist. Nimodipine, a calcium channel blocker (1 and 5 mg/kg, i.p.) produced a dose-dependent analgesic effect. The antinociceptive effect of oxytocin was significantly enhanced by the lower dose of nimodipine (1 mg/kg, i.p.) in both the phases. Chronic treatment with oxytocin (100 microg/kg/day, i.p. daily for 7 days) did not produce tolerance in both the phases of formalin-induced pain response. The results thus indicate that oxytocin displays an important analgesic response in formalin test; both kappa- and delta-opioid receptors as well as voltage-gated calcium channels seem to be involved in the oxytocin-induced antinociception.

Topics: Analgesics; Animals; Behavior; Calcium Channel Blockers; Dose-Response Relationship, Drug; Formaldehyde; Mice; Motor Activity; Naloxone; Naltrexone; Narcotic Antagonists; Nimodipine; Oxytocin; Pain; Random Allocation; Receptors, Opioid, delta; Receptors, Opioid, kappa

In Morocco, Thymus broussonetii is widely used in folk medicine for the treatment of a variety of diseases including gastroenteric and bronchopulmonary disorders and to relieve dolorous process. The antinociceptive effect of the aqueous, butanolic and ethyl acetate extracts of this species was examined in rats and mice using chemical and thermal models. The results obtained showed that aqueous and butanolic extracts exerted an antinociceptive activity in the two phases of formalin (50-300 mg/kg), tail immersion and writhing tests. Whereas, the ethyl acetate extract reduced the nociceptive response only in the second phase of formalin (100-300 mg/kg) and writhing tests. The aqueous extract, which is the most effective, contains active analgesic principles acting both centrally and peripherally. Furthermore, this antinociceptive effect has been avoided by naloxone at a dose of 1mg/kg in the first phase of formalin and hot plate tests indicating that this extract acts partly through an opioid-mediated mechanism. The present results demonstrated that Thymus broussonetii contains active constituents which possess antinociceptive activity justifying its popular use to relieve some pains.

Topics: Acetic Acid; Analgesics; Animals; Dose-Response Relationship, Drug; Formaldehyde; Male; Mice; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Pain Threshold; Plant Bark; Plant Extracts; Plant Leaves; Rats; Rats, Sprague-Dawley; Thymus Plant

The effect of aminoguanidine, an inducible nitric oxide synthase (iNOS) inhibitor, on morphine-induced tolerance and dependence in mice was investigated in this study. Acute administration of aminoguanidine (20 mg/kg, p.o.) did not affect the antinociceptive effect of morphine (10 mg/kg, s.c.) as measured by the hot plate test. Repeated administration of aminoguanidine along with morphine attenuated the development of tolerance to the antinociceptive effect of morphine. Also, the development of morphine dependence as assessed by naloxone-precipitated withdrawal manifestations was reduced by co-administration of aminoguanidine. The effect of aminoguanidine on naloxone-precipitated withdrawal was enhanced by concurrent administration of the non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist, dizocilpine (0.25 mg/kg, i.p.) or the non-specific nitric oxide synthase (NOS) inhibitor, l-N(G)-nitroarginine methyl ester (l-NAME; 5 mg/kg, i.p.) and antagonized by concurrent administration of the nitric oxide (NO) precursor, l-arginine (50 mg/kg, p.o.). Concomitantly, the progressive increase in NO production, but not in brain glutamate level, induced by morphine was inhibited by repeated administration of aminoguanidine along with morphine. Similarly, co-administration of aminoguanidine inhibited naloxone-induced NO overproduction, but it did not inhibit naloxone-induced elevation of brain glutamate level in morphine-dependent mice. The effect of aminoguanidine on naloxone-induced NO overproduction was potentiated by concurrent administration of dizocilpine or l-NAME and antagonized by concurrent administration of l-arginine. These results provide evidence that blockade of NO overproduction, the consequence of NMDA receptor activation, by aminoguanidine, via inhibition of iNOS, can attenuate the development of morphine tolerance and dependence.

Topics: Analgesics; Analgesics, Opioid; Animals; Arginine; Behavior, Animal; Brain; Dizocilpine Maleate; Drug Tolerance; Enzyme Inhibitors; Glutamates; Guanidines; Male; Mice; Morphine; Morphine Dependence; Naloxone; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Nitrites; Pain; Pain Measurement; Time Factors

This study examined the effects of intracerebroventricular (i.c.v.), intraperitoneal (i.p.) or intraplantar (i.pl.) administration of ghrelin, the endogenous ligand of the growth hormone secretagogue receptor, in the development of hyperalgesia and edema induced by intraplantar injection of carrageenan in rats. Central ghrelin (4 ng to 4 microg/rat) given 5 min before carrageenan produced a dose-related reversal of carrageenan-induced mechanical hyperalgesia measured by Randall-Selitto test with an ED50 of 81.7 ng/rat. Ghrelin at the dose of 4 microg/rat i.c.v. was also effective in inhibiting edema. When ghrelin (4 microg/rat i.c.v.) was administered 150 min after carrageenan, it failed to modify either hyperalgesia or the paw volume. Given i.p., 30 min before carrageenan, ghrelin (20-160 microg/kg) induced a significant dose-dependent inhibition of hyperalgesia with an ED50 of 77 microg/kg and a slight reduction of edema. Intraplantar ghrelin (40 ng to 12 microg/rat) did not significantly modify both the hyperalgesic and edematous activities of carrageenan. The anti-hyperalgesic and anti-edematous effects of ghrelin (4 microg/rat i.c.v.) were reversed by naloxone (10 microg/rat i.c.v.). Systemic administration of the peripheral selective opioid antagonist, naloxone methiodide (3 mg/kg s.c.), did not antagonize antinociception elicited by i.p. ghrelin. Overall these data indicate that ghrelin exerts an inhibitory role on inflammatory pain through an interaction with the central opioid system.

Topics: Analysis of Variance; Animals; Behavior, Animal; Carrageenan; Cytokines; Dose-Response Relationship, Drug; Drug Administration Routes; Drug Interactions; Edema; Gene Expression Regulation; Ghrelin; Male; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Pain Threshold; Peptide Hormones; Pro-Opiomelanocortin; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Time Factors

[Dmt1]Endomorphin-1 is a novel analogue of the potent mu-opioid agonist endomorphin-1. Given the physiological role of endomorphin-1 in vivo, this compound was investigated to determine if the antinociception occurred through systemic, supraspinal or in a combination of both neuronal pathways. This compound exhibited a potent dose-dependent effect intracerebroventricularly in both spinal and supraspinal regions, and was blocked by opioid antagonist naloxone, which verified the involvement of opioid receptors. Specific opioid antagonists characterized the apparent receptor type: beta-funaltrexamine (mu1/mu2-irreversible antagonist) equally inhibited spinal- and central-mediated antinociception; on the other hand, naloxonazine (mu1-subtype) was ineffective in both neural pathways and naltrindole (delta-selective antagonist) partially (26%), though not significantly, blocked only the spinal-mediated antinociception. Therefore, spinal antinociception was primarily triggered by mu2-subtypes without involvement of mu1-opioid receptors; however, although a slight enhancement of antinociception by delta-receptors cannot be completely ruled out since functional bioactivity indicated mixed mu-agonism/delta-antagonism. In terms of the CNS action, [Dmt1]endomorphin-1 appears to act through mu2-opioid receptor subtypes.

Topics: Analgesia; Animals; Brain; Guinea Pigs; Ileum; Injections, Intraventricular; Male; Mice; Naloxone; Naltrexone; Oligopeptides; Pain; Pain Measurement; Receptors, Opioid, delta; Receptors, Opioid, mu; Spinal Cord; Tail; Vas Deferens

Aiming to clarify the effect of interactive interconnections between the endogenous opioid peptides-neural links and GABAergic pathways on panic-like responses, in the present work, the effect of the peripheral and central administration of morphine or the non-specific opioid receptors antagonist naloxone was evaluated on the fear-induced responses (defensive attention, defensive immobility and escape behavior) elicited by electric and chemical stimulation of the inferior colliculus. Central microinjections of opioid drugs in the inferior colliculus were also performed followed by local administration of the GABA(A)-receptor antagonist bicuculline. The defensive behavior elicited by the blockade of GABAergic receptors in the inferior colliculus had been quantitatively analyzed, recording the number of crossing, jump, rotation and rearing, in each minute, during 30 min, in the open-field test. The opioid receptors stimulation with morphine decreased the defensive attention, the defensive immobility and escape behavior thresholds, and the non-specific opioid receptors blockade caused opposite effects, enhancing the defensive behavior thresholds. These effects were corroborated by either the stimulation or the inhibition of opioid receptors followed by the GABA(A) receptor blockade with bicuculline, microinjected into the inferior colliculus. There was a significant increase in the diverse fear-induced responses caused by bicuculline with the pretreatment of the inferior colliculus with morphine, and the opposite effect was recorded after the pretreatment of the inferior colliculus nuclei with naloxone followed by bicuculline local administration. These findings suggest an interaction between endogenous opioid-peptides-containing connections and GABA(A)-receptor-mediated system with direct influence on the organization of the panic-like or fear-induced responses elaborated in the inferior colliculus during critical emotional states.

Topics: Analysis of Variance; Animals; Behavior, Animal; Bicuculline; Drug Interactions; Electric Stimulation; Freezing Reaction, Cataleptic; GABA Antagonists; Inferior Colliculi; Male; Morphine; Naloxone; Narcotic Antagonists; Neural Pathways; Opioid Peptides; Pain; Rats; Rats, Wistar; Receptors, GABA-A; Stimulation, Chemical

The study was designed to determine whether the protein kinase C (PKC) is involved in nociceptive c-Fos expression and the concomitant signaling processes of endogenous opioid-like substances (OLS) that modulate c-Fos expression in the spinal dorsal horn following formalin injection into the unilateral hindpaw in rats by using immunocytochemical techniques. In the first part of experiments in which rats were pretreated with intrathecal (i.t.) chelerythrine (Chel), an inhibitor of PKC, the nociceptive c-Fos-like immunoreactive (Fos-LI) neurons in the lumbar dorsal horn ipsilateral to the formalin injection were significantly suppressed with a reduction rate of 60.3% (p < .001) as compared to that in the control group with i.t. saline. In the second part of experiments in which rats were pretreated with i.t. naloxone (Nal), the nociceptive Fos-LI neurons were significantly increased by 53.2% (p < .01) as compared to that in the control group; however, when rats were pretreated with combined i.t. Nal + Chel, the nociceptive Fos-LI neurons exhibited a percentage reduction similar to that in group with i.t. Chel alone, although the real number of Fos-LI neurons in group with i.t. Nal + Chel still significantly surpassed that in group with i.t. Chen only. These results suggest that: (1) PKC may play an important role in the induction of nociceptive c-Fos expression; (2) nociceptive c-Fos expression is subject to the modulation of endogenous OLS that suppress the nociceptive responses of the dorsal horn neurons; and (3) PKC may not be involved in the signaling processes by which the endogenous OLS modulate the nociceptive c-Fos expression in the spinal level.

Topics: Alkaloids; Animals; Behavior, Animal; Benzophenanthridines; Enzyme Inhibitors; Formaldehyde; Functional Laterality; Gene Expression; Immunohistochemistry; Male; Naloxone; Narcotic Antagonists; Nociceptors; Pain; Phenanthridines; Posterior Horn Cells; Protein Kinase C; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Spinal Cord

We examined the properties of the drug interaction between morphine and 5-HT(3) receptor antagonist at the spinal level. The nociceptive state was induced by subcutaneously injecting formalin solution (5%, 50 microl) into the hindpaw of the rats. Intrathecal morphine and m-CPBG (5-HT(3) receptor agonist) dose-dependently decreased the flinching response during phase 1 and phase 2 in the formalin test. Intrathecal 5-HT(3) receptor antagonists (LY-278,584 and ondansetron) did not reverse the antinociceptive effect of intrathecal morphine. Intrathecal naloxone had little effect on attenuation of the antinociception of intrathecal m-CPBG. Taken together, no reciprocal interaction was noted between 5-HT(3) receptor and opioid receptors at the spinal level. Thus, the 5-HT(3) receptor antagonist may be useful to manage opioid-induced emesis at the spinal level.

Topics: Analgesia; Analgesics, Opioid; Animals; Biguanides; Dose-Response Relationship, Drug; Formaldehyde; Hindlimb; Indazoles; Injections, Spinal; Male; Morphine; Motor Activity; Muscle Tonus; Naloxone; Narcotic Antagonists; Ondansetron; Pain; Pain Measurement; Rats; Rats, Sprague-Dawley; Receptors, Opioid; Receptors, Serotonin, 5-HT3; Serotonin 5-HT3 Receptor Antagonists; Serotonin Receptor Agonists; Spinal Cord; Tropanes

The anti-inflammatory pentacyclic triterpene, oleanolic acid (OA) was examined on acute nociception induced by intraplantar injection of capsaicin in mice. OA administered orally to mice at 10, 30 and 100 mgkg(-1), significantly attenuated the paw-licking response to capsaicin (1.6 microg/paw) by 53%, 68.5% and 36.6%, respectively. Ruthenium red (3 mgkg(-1), s.c.), a non-competitive vanilloid receptor (V1, TRPV1)-antagonist also suppressed the capsaicin nociception by 38.6%. The maximal antinociception produced by 30 mgkg(-1) OA was significantly blocked in animals pre-treated with naloxone (2 mgkg(-1), i.p.), the opioid antagonist; l-arginine (600 mgkg(-1), i.p.), the substrate for nitric oxide synthase; or glibenclamide (2 mgkg(-1), i.p.), the K(ATP)-channel blocker, but was unaffected by yohimbine (2 mgkg(-1), i.p.), an alpha(2)-adrenoceptor antagonist. In open-field and rota-rod tests that detect motor deficits, mice received 30 mgkg(-1) OA did not manifest any effect per se, indicating that the observed antinociception is not a consequence of motor abnormality. These data suggest that OA inhibits capsaicin-evoked acute nociception due to mechanisms possibly involving endogenous opioids, nitric oxide, and K(ATP)-channel opening.

Topics: Adrenergic alpha-Antagonists; Analgesics, Opioid; Animals; Capsaicin; Coloring Agents; Enzyme Inhibitors; Glyburide; Hypoglycemic Agents; KATP Channels; Lamiaceae; Male; Mice; Morphine; Motor Activity; Naloxone; Narcotic Antagonists; NG-Nitroarginine Methyl Ester; Oleanolic Acid; Pain; Pain Measurement; Postural Balance; Potassium Channels, Inwardly Rectifying; Ruthenium Red; Yohimbine

The combined administration of low doses of opiates with non-steroidal anti-inflammatory drugs can produce additive or supra-additive analgesic effects while reducing unwanted side effects. We have recently reported that co-administration of morphine with dipyrone (metamizol) produces analgesic potentiation both in naïve and in morphine-tolerant rats. The purpose of this work was to determine the role of opioids on the acute potentiation observed between morphine and dipyrone i.v. in the rat tail flick test. To do this, two experiments were done. In the first one, naloxone was administered 10 min before morphine (3.1 mg/kg), dipyrone (600 mg/kg) or their combination at the same doses. Control animals received saline instead of naloxone. In the second experiment, naloxone (or saline) was given 2 min after reaching the maximal peak effect with each individual analgesic treatment. When naloxone was i.v. administered prior to analgesics, it completely blocked morphine effects, partially prevented morphine/dipyrone antinociception and delayed dipyrone-induced nociception. At 3.1 mg/kg, naloxone produced an increased nociception. When naloxone was given after analgesics, it dose-dependently blocked the effects of morphine alone and in combination with dipyrone but with different potency in each case. As to dipyrone, naloxone delayed the time to antinociceptive peak effect. Taken together, these results support the notion that endogenous opioids are involved in the analgesic potentiation observed with the combination of morphine plus dipyrone.

Topics: Analgesics, Opioid; Animals; Anti-Inflammatory Agents, Non-Steroidal; Dipyrone; Dose-Response Relationship, Drug; Drug Synergism; Male; Morphine; Naloxone; Narcotic Antagonists; Opioid Peptides; Pain; Pain Measurement; Pain Threshold; Rats; Rats, Wistar; Time Factors

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Analgesics, Opioid; Constipation; Drug Combinations; Humans; Middle Aged; Naloxone; Narcotic Antagonists; Oxycodone; Pain; Quality of Life; Surveys and Questionnaires; Time Factors

Glial stimulation by intrathecal injection of lipopolysaccharide (LPS) attenuated the tail-flick inhibition produced by morphine given intrathecally in the spinal cord of the male CD-1 mice. The phenomenon has been defined as antianalgesia. The effects of dextro-naloxone or levo-naloxone on the attenuation of morphine-produced tail-flick inhibition induced by LPS were then studied. Pretreatment with dextro-naloxone or levo-naloxone reversed the attenuation of the morphine-produced tail-flick inhibition induced by LPS. Pretreatment with dextro-naloxone or levo-naloxone alone did not affect the morphine-produced tail-flick inhibition. It is concluded that dextro-naloxone and levo-naloxone block the LPS-induced antianalgesia against morphine antinociception via a non-opioid mechanism.

Topics: Analgesics, Opioid; Animals; Injections, Spinal; Lipopolysaccharides; Male; Mice; Morphine; Naloxone; Narcotic Antagonists; Neuroglia; Pain; Spinal Cord; Stereoisomerism

Pain, not responsive to opioid analgesics, remains a problem for patients with chronic and cancer pain as well as their families, and clinicians. Opioid antagonists have various uses in pain and palliative care. Their use in the reversal of tolerance and hyperalgesia remains at the basic science level and has limited clinical exposure.. To improve symptom control and quality of life in patients with pain not responsive to opioid analgesics.. Present three cases in which patients have undergone administration of opioid antagonists for the purpose of analgesia.. Patients on opioids analgesics received parenteral opioid antagonist, naloxone. Complete withdrawal under a sedative or conscious sedation was allowed and then the opioid at smaller doses was restarted and analgesia was observed.. All patients had improved analgesia on a significantly lower dose of opioid analgesics.. Only three patients who have received this procedure were presented yet all have responded positively to this procedure. Further research is needed to elucidate the mechanism and clinical relevance in the acute use of opioid antagonists.

Topics: Adolescent; Adult; Analgesia; Humans; Inpatients; Male; Middle Aged; Naloxone; Narcotic Antagonists; Pain; Treatment Outcome; United States

We have previously verified that niga-ichigoside F(1) (NI), a triterpene isolated from Rubus imperialis, exhibits significant and potent antinociceptive action when evaluated in some pharmacological models of pain in mice. This effect was confirmed in other experimental models and also the mechanism of action has been evaluated. The antinociception caused by NI (60 mg kg(-1)) in both phases of the formalin test was significantly attenuated by intraperitoneal injection of mice with haloperidol (a dopaminergic antagonist, 0.20 mg kg(-1)) and L-arginine (precursor of nitric oxide, 600 mg kg(-1)). Regarding the cholinergic system, atropine (a cholinergic antagonist 60 mg kg(-1)) reverted only the second phase. The effect of NI was not affected by treatment of mice with yohimbine (an alpha2-adrenoceptor antagonist, 0.15 mg kg(-1)). The same pharmacological profile was observed for the administration of naloxone (an opioid receptor antagonist, 1 mg kg(-1)). On the other hand, intraperitoneal injection caused dose-related and significant effects against glutamate- and capsaicin-induced pain, respectively. In conclusion, the marked antinociception of NI appears to be related to the dopaminergic, cholinergic, glutamatergic, tachykininergic and oxinitrergic systems, supporting the ethnomedical use of Rubus imperialis (Rosaceae).

Topics: Analgesics; Animals; Apomorphine; Atropine; Capsaicin; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Glutamic Acid; Haloperidol; Injections, Intraperitoneal; Male; Mice; Molecular Structure; Morphine; Naloxone; Nitroarginine; Pain; Pain Measurement; Plant Extracts; Rosaceae; Saponins; Yohimbine

The activation of the delta-opioid receptors in the nucleus accumbens is known to induce a large and rapid increase of accumbal dopamine efflux. (+/-)-TAN-67 (2-methyl-4a(alpha)-(3-hydroxyphenyl)-1,2,3,4,4a,5,12,12a(alpha)-octahydro-quinolino[2,3,3,-g]isoquinoline) is a centrally acting non-peptidic delta opioid receptor agent which has recently become available. Interestingly, the (+) enantiomer of TAN-67 induces hyperalgesia in contrast to the (-) enantiomer of TAN-67 that produces profound antinociceptive effects in mice; the latter effects are mediated through delta-1 receptor stimulation. Using the microdialysis technique, the ability of the enantiomers of TAN-67 to alter the release of accumbal dopamine in vivo was analyzed. Like the 25-min infusion of the selective delta-1 opioid receptor agonist (D-[Pen2,5]-enkephalin) DPDPE (50 nM) and the delta-2 opioid receptor agonist deltorphin II (50 nM), the 25-min infusion of both (-)-TAN-67 (25 and 50 nM) and (+)-TAN-67 (25 and 50 nM) into the nucleus accumbens produced a similar transient dose-dependent increase in the accumbal extracellular dopamine level. Naloxone (1 mg/kg i.p., given 25 min prior to the drugs), namely a treatment that is known to inhibit the increase of dopamine induced by DPDPE and deltorphin II, did not affect the transient increase in the accumbal dopamine level produced by infusion of the enantiomers of TAN-67. The DPDPE and deltorphin II-induced increase in accumbal dopamine level, but not that of (-)-TAN-67 and (+)-TAN-67, was eliminated by subsequently perfused tetrodotoxin (2 microM) into the nucleus accumbens. The increase in accumbal dopamine level produced by an infusion of (-)-TAN-67 and (+)-TAN-67 was not altered by a Ca2+-free Ringer's solution. The (-)-TAN-67 and (+)-TAN-67-induced accumbal dopamine efflux was strongly prevented by reserpine (5 mg/kg i.p., given 24 h earlier) or alpha-methyl-para-tyrosine (250 mg/kg i.p., given 2 h earlier). The effects of the enantiomers of TAN-67 on the accumbal dopamine were nullified by combined treatment with reserpine and alpha-methyl-para-tyrosine. The (-)-TAN-induced dopamine efflux was significantly reduced by the N-methyl-D-aspartate (NMDA) receptor antagonists ifenprodil (20 mg/kg i.p., 20 min before) and MK-801 (0.5 mg/kg i.p., 20 min before), respectively. The effects of (-)-TAN-67 on the dopamine efflux were also inhibited by the free radical scavenger N-2-mercaptopropionyl glycine (100 mg/kg i.p., 20 min before). These re

Topics: Adrenergic Uptake Inhibitors; alpha-Methyltyrosine; Animals; Dopamine; Enkephalin, D-Penicillamine (2,5)-; Enzyme Inhibitors; Extracellular Space; Free Radicals; Glutamic Acid; Male; Microdialysis; Naloxone; Narcotic Antagonists; Nucleus Accumbens; Oligopeptides; Pain; Quinolines; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Receptors, Opioid, delta; Reserpine

The enhanced organizational emphasis on the management of pain in hospitalized patients mandated by the Joint Commission for Accreditation of Health Care Organizations (JCAHO) pain initiative precipitated a number of changes by the perioperative services at our facility. In October 2002, a numeric pain scale became mandatory in our postanesthesia care unit (PACU). Response to analgesia in the PACU was recorded using this scale. In addition, an acceptable pain score was required for discharge from the PACU. We evaluated the effects of these changes in the pain management of 1082 patients undergoing general, orthopedic, neurosurgical, urologic, and gynecologic surgeries. We detected an overall increase in the average consumption of opiates (morphine equivalents) in 2002 compared with 2000 (46.6 +/- 20.4 mg versus 40.4 +/- 13.2 mg, P <0.001). This increase was most significant in the PACU (10.5 +/- 10.4 mg versus 6.5 +/- 7.3 mg, P <0.001 between the 2 periods, respectively). This increase in opiate use was not associated with an increased length of stay, an increase in the requirement for naloxone, or an increase in treatment for postoperative nausea and vomiting. We conclude that the increase in opiate use, which could be explained by compliance with the JCAHO pain initiative, was not associated with additional opiate-induced morbidity in the immediate postoperative period.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Analgesics, Opioid; Antiemetics; Drug Utilization; Female; Guidelines as Topic; Humans; Intraoperative Care; Joint Commission on Accreditation of Healthcare Organizations; Length of Stay; Male; Middle Aged; Morphine; Naloxone; Narcotic Antagonists; Pain; Pain Management; Pain Measurement; Postoperative Nausea and Vomiting; Recovery Room; Respiratory Insufficiency; United States

Topics: Humans; Naloxone; Narcotic Antagonists; Pain; Placebo Effect; Placebos

Endogenous hemorphins, derived from degradation of the beta-chain of hemoglobin, lower arterial blood pressure and exert an antinociceptive action in experimental models of nociception. Hemopressin, derived from the alpha-chain of hemoglobin, also decreases blood pressure, but its effects on pain have not been studied. In this work, we examined the influence of hemopressin on inflammatory pain. Hemopressin reverted the hyperalgesia induced by either carrageenin or bradykinin when injected concomitantly or 2.5 h after the phlogistic agents. Hemopressin administered systemically also reverted the hyperalgesia induced by carrageenin. Naloxone did not prevent the antinociceptive action of this peptide. These data suggest that hemopressin inhibits peripheral hyperalgesic responses by mechanisms independent of opioid receptor activation.

Topics: Analgesics; Animals; Blood Pressure; Bradykinin; Carrageenan; Disease Models, Animal; Endorphins; Hemoglobins; Hyperalgesia; Inflammation; Male; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Peptide Fragments; Peptides; Rats; Rats, Wistar; Receptors, Opioid; Time Factors

We have recently observed that a single exposure of mice to a magnetically shielded environment can attenuate opioid induced analgesia. Here, we report the effect of repeated exposures to the same magnetically shielded environment. Adult male Swiss CD-1 mice were placed in a Mu-metal lined box or an opaque Plexiglas box (sham condition) for 1 h per day for 10 consecutive days. Nociception was measured as the latency time to a foot lift/lick in response to an aversive thermal stimulus (hotplate analgesiometer, 50 +/- 1 degrees C) before and immediately after exposure. Multiple experiments were conducted in which thermal latency was tested on each of the 10 days or on days 1, 5, and 10, with some utilizing post-exposure testing only. It was shown that mice can detect and will respond to the repeated absence of the ambient magnetic field, with a maximum analgesic response occurring over days 4-6 of exposure and returning to baseline thereafter. The effect was robust, independent of pre-exposure and intermittent testing, and seems to be opioid related, since the results obtained on day 5 were similar to those from a 5 mg/kg dose of morphine and were abolished with the opioid antagonist, naloxone.

Topics: Analgesia; Animals; Background Radiation; Body Burden; Dose-Response Relationship, Radiation; Electromagnetic Fields; Environment, Controlled; Male; Mice; Naloxone; Pain; Pain Measurement; Radiation Dosage; Radiation Protection; Radiation Tolerance; Thermosensing

Nerve ligation injury may produce a tactile allodynia. Intrathecal adenosine receptor agonists or morphine have an antiallodynic effect. In this study, we examined the effect of intrathecal morphine on the antiallodynic state induced by the adenosine A1 receptor agonist, N(6)-(2-phenylisopropyl)-adenosine R-(-)isomer (R-PIA), in a rat model of nerve ligation injury. Rats were prepared with ligation of left L5-6 spinal nerves and intrathecal catheter implantation. Tactile allodynia was measured by applying von Frey filaments to the lesioned hindpaw. Thresholds for withdrawal response were assessed. Morphine and R-PIA were administered to obtain the dose-response curve and the 50% effective dose (ED(50)). Fractions of ED(50)s were administered concurrently to establish the ED(50) of the drug combination. The drug interaction was analyzed using the isobolographic method. Intrathecal 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), an A1 receptor antagonist, and naloxone were administered to examine the reversal of the antiallodynic effect. Side effects were also observed. Intrathecal morphine and R-PIA and their combination produced a dose-dependent antagonism without severe side effects. Intrathecal morphine synergistically enhanced the antiallodynic effect of R-PIA when coadministered. Intrathecal naloxone and DPCPX reversed the maximal antiallodynic effect in the combination group. These results suggest that activation of mu-opioid and A1 receptors at the spinal level is required for the synergistic interaction on tactile allodynia.

Topics: Adenosine A1 Receptor Agonists; Analgesics, Opioid; Animals; Circadian Rhythm; Dose-Response Relationship, Drug; Drug Synergism; Injections, Spinal; Ligation; Male; Morphine; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Peripheral Nervous System Diseases; Phenylisopropyladenosine; Rats; Rats, Sprague-Dawley; Xanthines

The potent opioid [Dmt1]endomorphin-2 (Dmt-Pro-Phe-Phe-NH2) differentiated between the opioid receptor subtypes responsible for the antinociception elicited by endomorphin-2 in mice. Antinociception, induced by the intracerebroventricular administration of [Dmt1]endomorphin-2 and inhibited by various opioid receptor antagonists [naloxone, naltrindole, beta-funaltrexamine, naloxonazine], was determined by the tail-flick (spinal effect) and hot-plate (supraspinal effect) tests. The opioid receptor subtypes involved in [Dmt1]endomorphin-2-induced antinociception differed between these in vivo model paradigms: naloxone (non-specific opioid receptor antagonist) and beta-funaltrexamine (irreversible mu1/mu2-opioid receptor antagonist) blocked antinociception in both tests, although stronger inhibition occurred in the hot-plate than the tail-flick test suggesting involvement of other opioid receptors. Consequently, we applied naloxonazine (mu1-opioid receptor antagonist) that significantly blocked the effect in the hot-plate test and naltrindole (delta-opioid receptor antagonist), which was only effective in the tail-flick test. The data indicated that [Dmt1]endomorphin-2-induced spinal antinociception was primarily mediated by both mu2- and delta-opioid receptors, while a supraspinal mechanism involved only mu1/mu2-subtypes.

Topics: Analgesia; Animals; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Hot Temperature; Injections, Intraventricular; Injections, Subcutaneous; Male; Mice; Naloxone; Naltrexone; Nociceptors; Oligopeptides; Pain; Pain Measurement; Receptors, Opioid, delta; Receptors, Opioid, mu; Tail; Time Factors

ABT-594 ((R)-5-(2-azetidinylmethoxy)-2-chloropyridine) represents a novel class of broad-spectrum analgesics whose primary mechanism of action is activation of the neuronal nicotinic acetylcholine receptors. The present study characterized the effects of ABT-594 in a rat chemotherapy-induced neuropathic pain model, where it attenuated mechanical allodynia with an ED50 = 40 nmol/kg (i.p.). This anti-allodynic effect was not blocked by systemic (i.p.) pretreatment with naloxone but was blocked completely with mecamylamine. Pretreatment with chlorisondamine (0.2-5 micromol/kg, i.p.) only partially blocked the effects of ABT-594 at the higher doses tested. In contrast, central (i.c.v.) pretreatment with chlorisondamine completely blocked ABT-594's anti-allodynic effect. Taken together, the data demonstrate that ABT-594 has a potent anti-allodynic effect in the rat vincristine model and that, in addition to its strong central site of action, ABT-594's effects are partially mediated by peripheral nicotinic acetylcholine receptors in this animal model of chemotherapy-induced neuropathic pain.

Topics: Acetylcholine; Analgesia; Animals; Azetidines; Chlorisondamine; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Routes; Drug Administration Schedule; Drug Evaluation, Preclinical; Drug Therapy, Combination; Humans; Mecamylamine; Naloxone; Nicotinic Agonists; Pain; Pyridines; Rats; Rats, Sprague-Dawley; Time Factors; Vincristine

Functional magnetic resonance imaging (fMRI) in rats can non-invasively identify brain regions activated by physiological stimuli and the effects of pharmacological intervention on these responses.. This study was conducted to investigate the effects of systemic administration of the mu-opioid receptor agonist morphine on whole brain functional signal intensity in anaesthetised rats; to investigate whether pre-treatment with the opioid receptor antagonist naloxone blocks the effects of morphine; to determine whether pre-treatment with morphine attenuates noxious-evoked changes in whole brain functional signal intensity.. Continuous whole brain fMRI scanning was used to study brain signal intensity prior to, and following, systemic administration of morphine (5 mg/kg, n=7), systemic administration of naloxone (1 mg/kg) and morphine (n=8). Effects of pre-treatment with saline (n=5) or morphine (5 mg/kg, n=5) on formalin (5%, intraplantar)-evoked changes in signal intensity were determined. Data were processed using SMP99 with fixed-effects analysis (p<0.05).. Morphine produced significant positive bilateral increases in signal intensity in the cingulate cortex, amygdala, thalamus, hypothalamus and PAG (p<0.05), and these effects were blocked by naloxone. Intraplantar injection of formalin produced a significant positive increase in signal intensity in the cingulate cortex, somatosensory cortex, amygdala, thalamus, hypothalamus and PAG (p<0.05). Morphine attenuated formalin-evoked increases in signal intensity in the PAG, amygdala, hypothalamus and cingulate cortex.. Our data demonstrate that morphine modulates noxious-evoked changes in signal intensity in discrete brain regions. fMRI studies in rats are able to identify specific brain regions involved in the pharmacological modification of physiologically evoked changes in regional brain activation.

Topics: Analgesics, Opioid; Analysis of Variance; Animals; Brain; Brain Mapping; Drug Interactions; Formaldehyde; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Morphine; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Rats; Rats, Sprague-Dawley; Reaction Time; Receptors, Opioid

Previous studies have shown that jaw reflexes and activity patterns of the jaw muscles were modulated in the presence of jaw muscle pain. However, there is no study comparing the modulatory effects on the jaw reflexes induced by noxious stimulation to the jaw muscle. To clarify this, effects of the application of mustard oil (MO), an inflammatory irritant, into the temporalis (jaw-closing) muscle on (1) jaw-opening reflex evoked by tooth pulp stimulation (TP-evoked JOR) as a nociceptive reflex, (2) jaw-opening reflex evoked by inferior alveolar nerve stimulation as a non-nociceptive reflex and (3) jaw-closing reflex evoked by trigeminal mesencephalic nucleus stimulation as a proprioceptive reflex were investigated in anesthetized rats. The MO application induced suppression of all reflexes, and the effect on the TP-evoked JOR was more prominent than on the other reflexes. To elucidate the involvement of endogenous opioid system for the suppressive effect, a systemic administration of naloxone following the MO application was conducted. The MO-induced suppressive effect on the TP-evoked JOR was reversed by the naloxone administration. The results suggest that noxious stimulation to the jaw muscle modulate jaw reflexes particularly for the nociceptive jaw-opening reflex, and the modulatory effect includes both facilitatory and inhibitory aspects. The results also suggest that pain modulatory systems such as the endogenous opioid system play a crucial role in the suppression of the nociceptive transmissions related to nociceptive reflexes, and in some pathological states, defense reflexes may not be evoked properly.

Topics: Analysis of Variance; Animals; Conditioning, Psychological; Dental Pulp; Electric Stimulation; Electromyography; Inflammation; Jaw; Male; Naloxone; Narcotic Antagonists; Neural Pathways; Nociceptors; Pain; Rats; Rats, Wistar; Reaction Time; Reflex; Temporal Muscle

Topics: Analgesia; Glucose; Humans; Infant, Newborn; Naloxone; Narcotic Antagonists; Pain; Receptors, Opioid

Chronic opioid-induced drug dependence and withdrawal syndrome after opioid cessation remain a severe obstacle in clinical treatment of chronic pain and opioid drug addiction. One of the key symptoms during opioid withdrawal is a state of sensitized pain. The most significant molecular adaptation induced by chronic opioids in the brain is upregulation of the cAMP-signaling pathway. Although the cAMP system is known to have multiple effects on central neuron functions, how its upregulation mediates behavioral opioid dependence and withdrawal-induced pain in vivo remains unclear. In this study, we demonstrate that withdrawal from chronic morphine significantly upregulates the mRNA level of adenylyl cyclase (AC) VI and VIII isoforms and immunoreactivity of ACV/VI in the nucleus raphe magnus (NRM), a brainstem site critically involved in opioid modulation of pain. In cellular studies of NRM neurons containing mu-opioid receptors, we show that morphine withdrawal significantly increases glutamate synaptic transmission via a presynaptic mechanism mediated by an upregulated cAMP pathway. Morphine withdrawal also enhances the hyperpolarization-activated current in these neurons by increased intracellular cAMP. Both of the withdrawal-induced cAMP actions increase the excitability of these mu-receptor-containing neurons, which are thought to facilitate spinal pain transmission. Furthermore, in morphine-dependent rats in vivo, blocking the cAMP pathway significantly reduces withdrawal-induced pain sensitization. These results illustrate neurobiological mechanisms for the cAMP-mediated withdrawal pain and provide potential therapeutic targets for the treatment of opioid dependence and withdrawal-related problems.

Topics: 2-Amino-5-phosphonovalerate; 6-Cyano-7-nitroquinoxaline-2,3-dione; 8-Bromo Cyclic Adenosine Monophosphate; Adenylyl Cyclases; Animals; Animals, Newborn; Behavior, Animal; Blotting, Western; Colforsin; Cyclic AMP; Dose-Response Relationship, Radiation; Drug Administration Schedule; Drug Interactions; Electric Stimulation; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Excitatory Postsynaptic Potentials; Gene Expression Regulation; Imines; In Vitro Techniques; Isoquinolines; Male; Membrane Potentials; Microinjections; Morphine; Naloxone; Narcotic Antagonists; Narcotics; Opioid-Related Disorders; Oxidoreductases; Pain; Pain Measurement; Patch-Clamp Techniques; Pyrimidines; Raphe Nuclei; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sulfonamides

Acupuncture and acupressure points correlate well with sites on the body that have low transcutaneous electrical resistance (TER). Using lightly sedated, adult Sprague-Dawley rats, we identified an acupoint (i.e. site with low TER) located on the hind limb of the rat and compared the effects of acupressure at this site on the nociceptive threshold to an adjacent, non-acupoint site (i.e. site with high TER). Focal pressure (55.42 +/- 2.2 g) was applied to the site for 10 minutes and the tail flick response (TFR) was determined by draping the distal portion of the tail over a heated wire (75 +/- 5 degrees C). Three trials were performed during each of three randomized conditions (i.e. acupoint, placebo and control) and the trials were averaged. All rats tested (5/5) showed a statistically significant increase in TFR following 10 minutes of acupressure at the acupoint compared to placebo or control trials (p = 0.007). Acupressure at the placebo point resulted in a TFR that was not statistically different from the control. Systemic administration of naloxone completely abolished the tail-flick inhibition induced by acupressure at the acupoint. These data suggest that acupressure elicits an antinociceptive effect in rats that is mediated by the endogenous release of opioids.

Topics: Acupressure; Acupuncture Analgesia; Animals; Disease Models, Animal; Female; Male; Naloxone; Narcotic Antagonists; Nociceptors; Opioid Peptides; Pain; Pain Management; Rats; Rats, Sprague-Dawley

This paper investigates the possible antinociceptive effect of systemically administered ciprofloxacin and gentamicin and its influence on intrathecal morphine-induced antinociception. Using thermal nociceptive tests (hot-plate test and tail-flick test) and a motor function test (catalepsy test) in male Sprague-Dawley rats (n=5-9/dose), the following observations were made: ciprofloxacin administered intraperitoneally in the dose range 4-64 mg/kg demonstrated a modest antinociceptive effect in both nociceptive tests. Solvent of ciprofloxacin (intraperitoneally) and saline (intraperitoneally), given as a control, showed no effect. Gentamicin, administered at a dose of 0.1-4 mg/kg intraperitoneally, demonstrated a significant (P<0.05) antinociceptive effect in the tail-flick test but not in the hot-plate test. However, opioid antagonists caused no significant change in the antibiotics. Furthermore, ciprofloxacin intraperitoneally produced a significant left-shift in the hot-plate test (ED50 saline-morphine=2.86 [CI 95%: 2.2, 4.32]microg; ED50 ciprofloxacin-morphine=0.87 (CI 95% 0.68, 1.21) microg, P<0.05) and in the tail-flick test (ED50 saline-morphine=1.98 (CI 95%: 1.21, 2.84) microg; ED50 ciprofloxacin-morphine=0.37 (CI 95%: 0.23, 0.44) microg; P<0.05) for intrathecal morphine-induced antinociception. From a comparison of these data with the predicted ciprofloxacin-morphine value (hot-plate test: 1.61 (CI 95%: 1.18, 2.51]microg; tail-flick test: 0.82 (CI 95%: 0.52, 1.92) microg) we estimate that ciprofloxacin and morphine produce at least additive effects (P>0.05). This was reversed with intraperitoneal naloxone (P<0.05). Gentamicin intraperitoneally did not influence the antinociception achieved with intrathecal administration of morphine (hot-plate test: ED50 gentamicin-morphine=2.71 (CI 95%: 2.35; 3.2) microg; tail-flick test: ED50 gentamicin-morphine=2.43 (CI 95%: 1.58; 5.22]microg; P>0.05). These data show that intraperitoneal administration of ciprofloxacin and gentamicin produces a modest antinociceptive effect in the hot-plate test and tail-flick test. Ciprofloxacin, but not gentamicin, can interact at least additively to increased naloxone-reversible morphine intrathecal antinociception. Differences in the ability to penetrate the blood-brain barrier between the two antibiotics could explain the lack of effect from gentamicin in the hot plate and on morphine-induced antinociception.

Topics: Analgesics; Animals; Behavior, Animal; Ciprofloxacin; Drug Synergism; Female; Gentamicins; Injections, Intraperitoneal; Injections, Spinal; Morphine; Motor Activity; Naloxone; Pain; Pain Measurement; Rats; Rats, Sprague-Dawley

The possible participation of the nitric oxide (NO)-cyclic GMP-K(+) channel pathway, serotonergic or opioidergic system on lumiracoxib-induced local or intrathecal antinociception was assessed in the formalin test. Local or intrathecal administration of lumiracoxib dose-dependently produced antinociception in the second phase of the test. Moreover, local or intrathecal pretreatment with N(G)-L-nitro-arginine methyl ester (L-NAME, NO synthesis inhibitor), 1H-(1,2,4)-oxadiazolo(4,2-a)quinoxalin-1-one (ODQ, guanylyl cyclase inhibitor), glibenclamide (ATP-sensitive K(+) channel blocker), charybdotoxin and apamin (large- and small-conductance Ca(2+)-activated-K(+) channel blockers, respectively) or margatoxin (voltage-dependent K(+) channel blocker), but not N(G)-D-nitro-arginine methyl ester (D-NAME) or vehicle, significantly prevented lumiracoxib-induced antinociception. The intrathecal injection of methiothepin (serotonin receptor antagonist) reduced lumiracoxib-induced intrathecal antinociception. Local peripheral or intrathecal naloxone did not modify either local or intrathecal lumiracoxib-induced antinociception. Results suggest that lumiracoxib activates the NO-cyclic GMP-K(+) channels to produce local and intrathecal antinociception. Data also suggest that lumiracoxib activates the intrathecal serotonergic system, but not opioid receptors either at peripheral or spinal sites.

Topics: Analgesics; Animals; Apamin; Behavior, Animal; Charybdotoxin; Diclofenac; Dose-Response Relationship, Drug; Enzyme Inhibitors; Female; Formaldehyde; Glyburide; Guanylate Cyclase; Hindlimb; Injections, Spinal; Injections, Subcutaneous; Methiothepin; Naloxone; Neurotoxins; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Organic Chemicals; Oxadiazoles; Pain; Pain Measurement; Quinoxalines; Rats; Rats, Wistar; Scorpion Venoms

The aim of this study was to evaluate the analgesic effect of the low level laser therapy (LLLT) with a He-Ne laser on acute inflammatory pain, verifying the contribution of the peripheral opioid receptors and the action of LLLT on the hyperalgesia produced by the release of hyperalgesic mediators of inflammation.. All analgesic drugs have undesired effects. Because of that, other therapies are being investigated for treatment of the inflammatory pain. Among those, LLLT seems to be very promising.. Male Wistar rats were used. Three complementary experiments were done. (1) The inflammatory reaction was induced by the injection of carrageenin into one of the hind paws. Pain threshold and volume increase of the edema were measured by a pressure gauge and plethysmography, respectively. (2) The involvement of peripheral opioid receptors on the analgesic effect of the laser was evaluated by simultaneous injection of carrageenin and naloxone into one hind paw. (3) Hyperalgesia was induced by injecting PGE2 for the study of the effect of the laser on the sensitization increase of nociceptors. A He-Ne laser (632.8 nm) of 2.5 J/cm2 was used for irradiation.. We found that He-Ne stimulation increased the pain threshold by a factor between 68% and 95% depending on the injected drug. We also observed a 54% reduction on the volume increase of the edema when it was irradiated.. He-Ne LLLT inhibits the sensitization increase of nociceptors on the inflammatory process. The analgesic effect seems to involve hyperalgesic mediators instead of peripheral opioid receptors.

Topics: Animals; Carrageenan; Dinoprostone; Edema; Hyperalgesia; Inflammation; Injections; Low-Level Light Therapy; Male; Naloxone; Narcotic Antagonists; Nociceptors; Pain; Pain Threshold; Rats; Rats, Wistar

Zolpidem and zopiclone are two of a newer hypno-sedative class of drugs, the "Z compounds". Their use for the treatment of short-term insomnia has been expanding constantly during the last two decades. The "Z compounds" are considered to cause less significant rebound insomnia or tolerance than the conventional hypnotic benzodiazepines. Their possible antinociceptive effect and interaction with the opioid system has not been studied yet. Our results demonstrate a significant difference between the antinociceptive properties of zopiclone and zolpidem when injected s.c. in the hotplate analgesic assay in mice. Zopiclone induced a weak, dose-dependent antinociceptive effect, antagonized only by the alpha2-adrenergic receptor antagonist yohimbine. Zolpidem induced a weak, biphasic dose-dependent antinociceptive effect, antagonized primarily by the non-selective opioid antagonist naloxone and by yohimbine. The weak antinociceptive effect of both drugs, evident only at very high doses (far beyond those used clinically to induce sleep), implies no clinical use for zopiclone or zolpidem in the management of pain. However, the possible interaction of zolpidem with the opioid system should be further investigated (in behavioral models, which do not overlap with the acute-pain antinociception model we used), both for possible side effects in special populations (i.e. elderly) and for possible drug-drug interactions, in order to minimize possible hazards and maximize clinical beneficial effects of its use for sleep.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Adrenergic Agonists; Adrenergic Antagonists; Analgesics; Animals; Azabicyclo Compounds; Behavior, Animal; Benzamides; Clonidine; Dose-Response Relationship, Drug; Hypnotics and Sedatives; Male; Mice; Mice, Inbred ICR; Morphine; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Piperazines; Pyridines; Receptors, Opioid; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Zolpidem

Microinjection of dipyrone (metamizol) into the periaqueductal gray matter (PAG) in rats causes antinociception. This is mediated by endogenous opioidergic circuits located in the PAG itself, in the nucleus raphe magnus and adjacent structures, and in the spinal cord. The clinical relevance of these findings, however, is unclear. Therefore, in the present study, dipyrone was administered intravenously, and the involvement of endogenous opioidergic circuits in the so-induced antinociception was investigated. In rats, responses of dorsal spinal wide-dynamic range neurons to mechanical noxious stimulation of a hindpaw were strongly inhibited by intravenous dipyrone (200 mg/kg). This effect was abolished by microinjection of naloxone (0.5 microg/0.5 microl) into the ventrolateral and lateral PAG or into the nucleus raphe magnus or by direct application of naloxone (50 microg/50 microl) onto the spinal cord surface above the recorded neuron. These results show that dipyrone, a non-opioid analgesic with widespread use in Europe and Latin America, when administered in a clinically relevant fashion causes antinociception by activating endogenous opioidergic circuits along the descending pain control system.

Topics: Action Potentials; Analysis of Variance; Animals; Anti-Inflammatory Agents, Non-Steroidal; Dipyrone; Drug Interactions; Injections, Intraventricular; Lower Extremity; Male; Microinjections; Naloxone; Pain; Pain Measurement; Periaqueductal Gray; Physical Stimulation; Posterior Horn Cells; Raphe Nuclei; Rats; Rats, Sprague-Dawley

P2X3/P2X2/3 receptors have emerged as important components of nociception. However, there is limited information regarding the neurochemical systems that are affected by antagonism of the P2X3/P2X2/3 receptor and that ultimately contribute to the ensuing antinociception. In order to determine if the endogenous opioid system is involved in this antinociception, naloxone was administered just prior to the injection of a selective P2X3/P2X2/3 receptor antagonist, A-317491, in rat models of neuropathic, chemogenic, and inflammatory pain. Naloxone (1-10 mg kg(-1), i.p.), dose-dependently reduced the antinociceptive effects of A-317491 (1-300 micromol kg(-1), s.c.) in the CFA model of thermal hyperalgesia and the formalin model of chemogenic pain (2nd phase), but not in the L5-L6 spinal nerve ligation model of neuropathic allodynia. In comparison experiments, the same doses of naloxone blocked or attenuated the actions of morphine (2 or 8 mg kg(-1), s.c.) in each of these behavioral models. Injection of a peripheral opioid antagonist, naloxone methiodide (10 mg kg(-1), i.p.), did not affect A-317491-induced antinociception in the CFA and formalin assays, suggesting that the opioid component of this antinociception occurred within the CNS. Furthermore, this utilization of the central opioid system could be initiated by antagonism of spinal P2X3/P2X2/3 receptors since the antinociceptive actions of intrathecally delivered A-317491 (30 nmol) in the formalin model were reduced by both intrathecally (10-50 nmol) and systemically (10 mg kg(-1), i.p.) administered naloxone. This utilization of the opioid system was not specific to A-317491 since suramin-, a nonselective P2X receptor antagonist, induced antinociception was also attenuated by naloxone. In in vitro studies, A-317491 (3-100 microM) did not produce any agonist response at delta opioid receptors expressed in NG108-15 cells. A-317491 had been previously shown to be inactive at the kappa and mu opioid receptors. Furthermore, naloxone, at concentrations up to 1 mM, did not compete for [3H] A-317491 binding in 1321N1 cells expressing human P2X3 receptors. Taken together, these results indicate that antagonism of spinal P2X3/P2X2/3 receptors results in an indirect activation of the opioid system to alleviate inflammatory hyperalgesia and chemogenic nociception.

Topics: Analgesia; Animals; Arthritis, Experimental; Dose-Response Relationship, Drug; Endorphins; Formaldehyde; Freund's Adjuvant; Inflammation; Injections, Spinal; Ligation; Male; Naloxone; Narcotic Antagonists; Pain; Peripheral Nervous System Diseases; Phenols; Polycyclic Compounds; Rats; Rats, Sprague-Dawley; Receptors, Purinergic P2; Receptors, Purinergic P2X2; Receptors, Purinergic P2X3; Suramin

It has been shown that acupuncture relieves symptoms of abdominal pain and bloating in patients with irritable bowel syndrome (IBS). However, the mechanism of beneficial effects of acupuncture still remains unproven. The aim of the present study was to investigate the mechanisms of the antinociceptive effects of acupuncture in conscious dogs. We evaluated the increase in mean arterial blood pressure (MAP) caused by rectal distension as an index of visceral pain. Electroacupuncture (EA; 10 Hz) at ST-36 (lower leg), but not at BL-21 (back), significantly reduced the increase in MAP in response to rectal distension (30 and 40 cm3). The antinociceptive effect of EA at ST-36 was abolished by pretreatment with naloxone (a central and peripheral opioid receptor antagonist) but not by naloxone methiodide (a peripheral opioid receptor antagonist). These results suggest that EA at ST-36 may reduce visceral pain via central opioid pathway. Acupuncture may be useful to treat visceral hypersensitivity in IBS patients.

Topics: Animals; Back; Blood Pressure; Catheterization; Dogs; Electroacupuncture; Female; Hindlimb; Male; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Quaternary Ammonium Compounds; Rectal Diseases; Viscera

Formalin-induced pain is reduced in sigma-1 (sigma1) receptor knockout mice; therefore, we hypothesized that haloperidol and its metabolites I and II, which have affinity for sigma1 receptors, may modulate formalin-induced pain.. Intraplantar administration of formalin (2.5%) to CD-1 mice produced a biphasic period of pain. Haloperidol (0.03-1 mg/kg, s.c.) and reduced haloperidol (metabolite II, 0.25-8 mg/kg, s.c.) dose-dependently inhibited both phases of formalin-induced pain. Haloperidol metabolite I (4-128 mg/kg, s.c.) also produced dose-dependent antinociception in the second phase of the formalin test, but was less potent and effective against first-phase pain. Haloperidol metabolite III (16 and 128 mg/kg) and (-)sulpiride (200 mg/kg), which have no affinity for sigma1 receptors, did not produce significant antinociception in either phase of the formalin test. The order of potency of the drugs to produce their antinociceptive effect [haloperidol>metabolite II>metabolite I>>metabolite III= (-)sulpiride=inactive] correlated with their affinity for sigma1 receptors, but not with their affinity for sigma2 or dopamine D2 receptors. Naloxone (1 mg/kg, s.c.) did not antagonize the antinociception induced by haloperidol and its metabolites. None of the antinociceptive drugs in the formalin test produced any antinociception in the tail flick test.. These results suggest that the antinociceptive effect of haloperidol and its metabolites in the formalin test is not due to unspecific/generalised inhibition of nociception or modulation of opioid receptors, and that it may be related, at least partially, to the ability of these drugs to interact with sigma1 receptors.

Topics: Analgesics; Analysis of Variance; Animals; Behavior, Animal; Dose-Response Relationship, Drug; Drug Interactions; Female; Formaldehyde; Haloperidol; Mice; Morphine; Naloxone; Narcotic Antagonists; Narcotics; Pain; Pain Measurement; Time Factors

Rat/mouse hemokinin 1 (r/m HK-1) is a novel tachykinin peptide whose biological functions are not fully understood. This work was designed to observe the effects of r/m HK-1 in pain modulation at supraspinal level in mice using tail-flick test. Intracerebroventricular (i.c.v.) administration of r/m HK-1 (0.1, 0.3, 1, 3 nmol/mouse) dose-dependently induced potent analgesic effect (ED(50) = 0.2877 nmol/mouse). When r/m HK-1 co-injected (i.c.v.) with SR140333 (a selective NK(1) receptor antagonist), SR140333 could fully antagonize the analgesic effect of r/m HK-1. The maximal analgesic effect of r/m HK-1 (3 nmol/mouse) could also be reversed by naloxone (i.p., 2 mg/kg). However, i.c.v. low dose administration of r/m HK-1 (10, 3, 1 pmol/mouse) induced hyperalgesia with a "U" shape curve, which means that the maximal hyperalgesic effect appeared at 3 pmol/mouse, and this effect of r/m HK-1 could also be fully blocked by SR140333. Interestingly, [Nphe(1)]NC(1-13)NH(2), a selective opioid receptor like-1 (ORL-1) receptor antagonist, could fully reverse the maximal hyperalgesic effect of r/m HK-1 (3 pmol/mouse). In addition, when r/m HK-1 co-injected (i.c.v.) with SR48968 (a selective NK(2) receptor antagonist), SR48968 could hardly affect the nociceptive effects of r/m HK-1 either at nanomole concentration or at picomole concentration. These findings suggested that r/m HK-1 might play an important role in pain modulation at supraspinal level in mice and these effects were first elicited through the activation of NK(1) receptor, subsequently, whether activation of the classical opioid receptor or the ORL1 receptor depending on the dose of i.c.v. administration of r/m HK-1.

Topics: Analysis of Variance; Animals; Behavior, Animal; Benzamides; Dose-Response Relationship, Drug; Drug Administration Routes; GPI-Linked Proteins; Hemochromatosis; Hemochromatosis Protein; Injections, Spinal; Male; Membrane Proteins; Mice; Mice, Inbred Strains; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Piperidines; Quinuclidines; Rats; Somatostatin; Time Factors

Although the serine/threonine protein kinases involved in the pharmacological action of morphine are well recognized, the critical contribution of serine/threonine protein phosphatase (PP) has been appreciated on to a slight degree. We examined the involvement of subtypes of serine/threonine protein phosphatase (PP) in the antinociceptive effect of morphine in mice. The antinociceptive effect of subcutaneously administered morphine was attenuated by simultaneously intracerebroventricular (i.c.v.) or intrathecal (i.t.) injection of okadaic acid (OA), a PP inhibitor. To reveal which subtypes of PPs participated in the antinociceptive effect of morphine, mice received i.c.v. or i.t. injections of antisense oligodeoxynucleotide (AS-ODN) directed against either the PP 2 A or PP5 subtypes of PPs before assessment of morphine-induced antinociception. Pretreatment with AS-ODN against PP 2 A or PP5 via each route weakened the antinociceptive effect of morphine, accompanied by reduction of expression levels of PP in the periaqueductal gray (PAG) and the spinal cord. Subcutaneously administered morphine increased activity of OA-sensitive PPs in the PAG and the spinal cord in a dose-dependent manner; this was prevented by concurrent administration of naloxone. These results suggest that PP 2 A and PP5 are involved in the antinociceptive effect of morphine in mice.

Topics: Animals; Area Under Curve; Blotting, Western; Brain; Dose-Response Relationship, Drug; Drug Administration Routes; Drug Interactions; Enzyme Activation; Enzyme Inhibitors; Male; Mice; Mice, Inbred ICR; Morphine; Naloxone; Narcotics; Nuclear Proteins; Okadaic Acid; Pain; Phosphoprotein Phosphatases; Phosphorylation; Serine; Threonine; Time Factors

In this study, we investigated single-unit responses of the primary sensorimotor cortex (SmI) and anterior cingulate cortex (ACC) to noxious stimulation of the tail of the rat. The influences of morphine on these nociceptive responses were also compared. Multiple single-unit activities were recorded from two eight-channel microwire arrays chronically implanted in the tail region of the SmI and ACC, respectively. CO2 laser-heat irradiation of the middle part of the tail at an intensity slightly higher than that causing a maximal tail flick response was used as a specific noxious stimulus. Examined individually, ACC neurons were less responsive than SmI neurons to laser-heat stimulus, in that only 51% of the ACC units (n = 125) responded compared with 88% of the SmI units (n = 74). Among these responsive ACC units, many had a very long latency and long-lasting excitatory type of response that was seldom found in the SmI. When ensemble activities were examined, laser heat evoked both short- (60 approximately 150 ms) and long-latency (151 approximately 600 ms) responses in the SmI and ACC. Latencies of both responses were longer in the ACC. Furthermore, a single dose of 2.5-10 mg/kg morphine intraperitoneally suppressed only the long latency response in the SmI, but significantly attenuated both responses in the ACC. These effects of morphine were completely blocked by prior treatment with the opiate receptor blocker, naloxone. These results provide further evidence suggesting that the SmI and ACC may play different roles in processing noxious information.

Topics: Action Potentials; Animals; Consciousness; Dose-Response Relationship, Drug; Drug Interactions; Electric Stimulation; Electromyography; Female; Gyrus Cinguli; Lasers; Morphine; Naloxone; Narcotic Antagonists; Narcotics; Neurons; Pain; Pain Measurement; Rats; Rats, Long-Evans; Reaction Time; Somatosensory Cortex

A series of preliminary studies was carried out to evaluate the antinociceptive (pain relief) activity of the aqueous extract of Corchorus olitorius L. leaves (COAE) and to determine the influence of temperature and opioid receptors on COAE activity using the abdominal constriction and hot plate tests in mice. COAE, at concentrations of 10, 25, 50, 75, and 100%, showed both peripheral and central antinociception that are non-concentration- and concentration-dependent respectively. The peripheral activity was clearly observed at a concentration of 25% and diminished at a concentration of 100%, while the central activity was observed at all the concentrations of COAE used. Furthermore, the insignificant results obtained indicated that this peripheral activity (at concentrations of 25 and 50%) was comparable to that of morphine (0.8 mg/kg). Pre-heating COAE at a temperature of 80 degrees C and 100 degrees C, or 60 degrees C and 80 degrees C was found to enhance its peripheral and central antinociception respectively. Pre-treatment with naloxone (10 mg/kg), a general opioid receptor antagonist, for 5 min, followed by COAE, was found to completely block its peripheral, but not central, antinociceptive activity. Based on this observation, we conclude that the antinociceptive activity exhibited by C. olitorius is enhanced by the increase in temperature and may be mediated peripherally, but not centrally, at least in part, via an opioid receptor.

Topics: Acetic Acid; Analgesics; Analgesics, Opioid; Animals; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Colic; Corchorus; Dose-Response Relationship, Drug; Male; Mice; Mice, Inbred ICR; Morphine; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Pain Threshold; Plant Extracts; Plant Leaves; Temperature

Tail flick test in rats and acetic acid induced writhing in mice were employed to study the antinociceptive activity of ethanolic leaf extract of Vitex-negundo (VN) (100, 250 and 500 mg/kg, p.o). The effect was compared with meperidine (40 mg/kg, sc) in tail flick method and aspirin (50 mg/kg, p.o) in writhing test as a standard control respectively. An interaction with naloxone hydrochloride was also studied in tail flick method for its mechanism of central analgesic action. The test drug showed significant analgesic activity in dose dependant manner in both the experimental models. In comparison to standard drug (meperidine), more than ten times dose of VN extract was required to produce comparable significant antinociceptive activity. The sub-effective dose (5 mg/kg, po) of VN potentiated the analgesic activity of meperidine (4 mg/kg, sc) and aspirin (25 mg/kg, po). Naloxone (1 mg/kg, sc) did not reverse the analgesic effect of VN extract. Our observations suggest that VN possesses both central and peripheral analgesic activity. The central analgesic action does not seem to be mediated through opioid receptors. It, may prove to be a useful adjuvant therapy along with standard analgesic drug.

Topics: Acetic Acid; Analgesics, Non-Narcotic; Animals; Aspirin; Dose-Response Relationship, Drug; Drug Interactions; Female; Male; Meperidine; Mice; Naloxone; Pain; Phytotherapy; Plant Extracts; Plant Leaves; Rats; Rats, Wistar; Vitex

To determine the effects of low-intensity exercise on chronic muscle pain and potential activation of the endogenous opioid system.. Randomized placebo-controlled trial.. Animal laboratory.. Sixty-three male Sprague-Dawley rats.. Rats performed a low-intensity exercise protocol for 5 consecutive days after the induction of chronic muscle pain. In a separate experiment, naloxone or saline was administered systemically before 5 low-intensity exercise sessions.. Mechanical hyperalgesia was measured using von Frey filaments to determine the mechanical withdrawal threshold.. Low-intensity exercise increased mechanical withdrawal threshold in the chronic muscle pain model. Naloxone attenuated the antihyperalgesic effects of low-intensity exercise.. Low-intensity exercise reversed mechanical hyperalgesia in the chronic muscle pain model through activation of the endogenous opioid system.

Topics: Analysis of Variance; Animals; Area Under Curve; Disease Models, Animal; Male; Muscular Diseases; Naloxone; Pain; Pain Measurement; Physical Conditioning, Animal; Probability; Random Allocation; Rats; Rats, Sprague-Dawley; Sensitivity and Specificity

The present study investigated the role of galanin in the transmission of nociceptive information in the spinal cord of rats with inflammation. Bilateral decreases in hindpaw withdrawal latencies (HWLs) to thermal and mechanical stimulation were observed after acute inflammation induced by injection of carrageenan into the plantar region of the rat left hindpaw. Intrathecal injection of galanin induced significant increases in the HWLs to thermal and mechanical stimulation in rats with inflammation. The galanin-induced antinociceptive effect was more pronounced in rats with inflammation than that in intact rats. The antinociceptive effect of galanin was partly inhibited by intrathecal injection of naloxone. Furthermore, intrathecal administration of galantide, an antagonist of galanin receptor, could attenuate the antinociceptive effect induced by intraperitoneal injection of morphine, suggesting an involvement of opioid systems in the galanin-induced antinociception. The results indicate that galanin plays an important role in the transmission of nociceptive information in the spinal cord of rats with inflammation, and opioid systems are involved in the galanin-induced antinociception.

Topics: Animals; Calcitonin; Carrageenan; Galanin; Inflammation; Injections, Spinal; Injections, Subcutaneous; Male; Naloxone; Narcotic Antagonists; Nociceptors; Pain; Pain Measurement; Rats; Rats, Sprague-Dawley; Receptors, Galanin; Receptors, Opioid; Spinal Cord

Topics: Analgesics, Opioid; Anti-Inflammatory Agents, Non-Steroidal; Drug Therapy, Combination; Humans; Middle Aged; Naloxone; Narcotic Antagonists; Pain; Patient Satisfaction; Surveys and Questionnaires; Tilidine; Time Factors

Stressful stimuli can activate the hypothalamo-pituitary-adrenal-axis and the endogenous opioid system. In addition, corticosterone and opioid release might cause analgesia. This rat study used adrenalectomy for corticosterone withdrawal and naloxone administration for opioid antagonism in order to study pain behavior and hypophyseal hormone release in the plasma after a formalin test. Twelve days before the formalin testing, male Sprague Dawley rats underwent adrenalectomy or sham-adrenalectomy, and non-operated rats were used as reference. The number of flinches and the duration of licking or biting behavior were measured during the early and late phase. In reference and sham-operated rats, injection of formalin 5% resulted in a marked pain behavior in the early and late phase with significant increases in ACTH and corticosterone plasma levels. In adrenalectomized rats, pain behavior was decreased during both phases. Naloxone, administered before the late phase, did not alter pain behavior in sham or reference rats, whereas in adrenalectomized rats pain reactivity returned to those levels observed in reference rats. Beta-endorphin plasma levels above the detection limit were more frequently found in adrenalectomized rats. Thyrotropin and prolactin levels were not different between studied groups. We speculate that the observed reduced pain behavior in adrenalectomized rats after formalin, is the result of an increased production of pro-opiomelanocortin, the pro-drug of both adrenocorticotrophic hormone and beta-endorphin.

Topics: Adrenalectomy; Animals; Behavior, Animal; beta-Endorphin; Corticosterone; Formaldehyde; Injections, Intraperitoneal; Male; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Pituitary Hormones; Prolactin; Rats; Rats, Sprague-Dawley; Thyrotropin

Nociceptin (NC), administered microiontophoretically at different concentrations, significantly reduced the spontaneous and stimulus-evoked activity on WDR neuron in rats with chronic constriction of one sciatic nerve and showing signs of neuropathic pain. The effect was not antagonized by Naloxone. The same concentrations of NC were ineffective on the noxious stimulus evoked responses of WDR neurons in sham and intact rats. This result indicates a facilitated inhibitory action of NC on nociceptive transmission in this pain model.

Topics: Animals; Constriction, Pathologic; Electrophysiology; Male; Naloxone; Narcotic Antagonists; Neurons; Nociceptin; Opioid Peptides; Pain; Rats; Rats, Sprague-Dawley; Sciatic Nerve; Vasodilator Agents

Topics: Analgesics, Opioid; Humans; Naloxone; Narcotic Antagonists; Neoplasms; Pain; Respiratory Insufficiency

Intrathecal (i.t.) pretreatment with a low dose (0.3 nmol) of morphine causes an attenuation of i.t. morphine-produced analgesia; the phenomenon has been defined as morphine-induced antianalgesia. The opioid-produced analgesia was measured with the tail-flick (TF) test in male CD-1 mice. Intrathecal pretreatment with low dose (0.3 nmol) of morphine time dependently attenuated i.t. morphine-produced (3.0 nmol) TF inhibition and reached a maximal effect at 45 min. Intrathecal pretreatment with morphine (0.009-0.3 nmol) for 45 min also dose dependently attenuated morphine-produced TF inhibition. The i.t. morphine-induced antianalgesia was dose dependently blocked by the nonselective mu-opioid receptor antagonist (-)-naloxone and by its nonopioid enantiomer (+)-naloxone, but not by endomorphin-2-sensitive mu-opioid receptor antagonist 3-methoxynaltrexone. Blockade of delta-opioid receptors, kappa-opioid receptors, and N-methyl-D-aspartate (NMDA) receptors by i.t. pretreatment with naltrindole, nor-binaltorphimine, and (-)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801), respectively, did not affect the i.t. morphine-induced antianalgesia. Intrathecal pretreatment with antiserum against dynorphin A(1-17), [Leu]-enkephalin, [Met]-enkephalin, beta-endorphin, cholecystokinin, or substance P also did not affect the i.t. morphine-induced antianalgesia. The i.t. morphine pretreatment also attenuated the TF inhibition produced by opioid muagonist [D-Ala2, N-Me-Phe4,Gly-ol5]-enkephalin, delta-agonist deltorphin II, and kappa-agonist U50,488H. It is concluded that low doses (0.009-0.3 nmol) of morphine given i.t. activate an antianalgesic system to attenuate opioid mu-, delta-, and kappa-agonist-produced analgesia. The morphine-induced antianalgesia is not mediated by the stimulation of opioid mu-, delta-, or kappa-receptors or NMDA receptors. Neuropeptides such as dynorphin A(1-17), [Leu]-enkephalin, [Met]-enkephalin, beta-endorphin, cholecystokinin, and substance P are not involved in this low-dose morphine-induced antianalgesia.

Topics: Analgesia; Animals; beta-Endorphin; Dizocilpine Maleate; Drug Interactions; Drug Tolerance; Dynorphins; Enkephalins; Male; Mice; Morphine; Naloxone; Naltrexone; Oligopeptides; Pain; Pain Measurement; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Spinal Cord; Substance P

Lactoferrin (LF) is a ubiquitous protein which exists in milk, plasma, synovial fluids, cerebrospinal fluid and other biological fluids. LF is also well known as a natural immunomodulator. Recently, we found that bovine milk-derived LF (BLF) produced micro-opioid receptor-mediated analgesia. In this study, we examined whether oral administration of BLF causes anti-nociceptive and anti-inflammatory effects, and also whether it modulates LPS-induced TNF-alpha and IL-10 production in rat model of rheumatoid arthritis (RA), rat adjuvant arthritis. BLF was administrated once daily, starting 3 hr before (preventive experiment) or 19 days after (therapeutic experiment) adjuvant injection. In both experiments, BLF suppressed the development of arthritis and the hyperalgesia in the adjuvant-injected paw. The single-administered BLF produced a dose-dependent analgesia, which was reversed by naloxone, in the adjuvant arthritis rats. Both repeated and single administration of BLF suppressed TNF-alpha production and increased IL-10 production in the LPS-stimulated adjuvant arthritis rats. These results suggest that orally administered BLF has both preventive and therapeutic effects on the development of adjuvant-induced inflammation and pain. Moreover, the immunomodulatory properties of BLF, such as down-regulation of TNF-alpha and up-regulation of IL-10, could be beneficial in the treatment of RA. Thus, we concluded that LF can be safely used as a natural drug for RA patients suffering from joint pain.

Topics: Administration, Oral; Analysis of Variance; Animals; Arthritis, Experimental; Disease Models, Animal; Inflammation; Interleukin-10; Lactoferrin; Male; Naloxone; Pain; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha

The clinical practice of spinal morphine administration for pain relief is based on observations in animals that opioid receptors exist in the spinal cord and intrathecal injections of opioids in those species (mostly rats) lead to antinociceptive effects. Clinicians are well aware that administration of spinal opioids is associated with side-effects, such as nausea and respiratory depression, that indicate supraspinal spread of the drug administered. Those observations call into question how much of the observed pain relief is due to action of the drug in the brain. This study investigated the spinal cord actions of morphine given intrathecally to rats in a model that allows investigation of drug-receptor interaction at the spinal cord level. Experiments were performed on male Wistar rats with chronically implanted lumbar subarachnoid catheters.. Nociceptive thresholds were measured in rats given morphine intrathecally alone and in combination with intrathecal injections of selective opioid receptor antagonists: beta-funaltrexamine (mu), naltrindole (delta) and nor-binaltorphimine (kappa).. Intrathecal morphine caused dose-related antinociceptive effects that were reversed totally by naloxone. Intrathecal beta-funaltrexamine and naltrindole did not reverse the effects of intrathecal morphine. However, intrathecal nor-binaltorphimine did reverse the electrical current threshold effects of morphine but not tail flick latency.. Antinociception following intrathecal morphine involves spinal and supraspinal opioid receptors. The tail flick effect described in rat experiments involves actions at opioid receptors in the brain that override any action that may be caused by combination of morphine with mu-opioid receptors in the spinal cord.

Topics: Analgesics, Opioid; Animals; Dose-Response Relationship, Drug; Injections, Spinal; Male; Models, Animal; Morphine; Naloxone; Naltrexone; Narcotic Antagonists; Nociceptors; Pain; Pain Threshold; Random Allocation; Rats; Rats, Wistar; Reaction Time; Receptors, Opioid; Spinal Cord; Tail

Mice lacking the mu-opioid receptor gene have been used to characterize the role of mu-opioid receptors in nociception and the analgesic actions of opioid agonists. In this study, the authors determined the role of mu-opioid receptors in neuropathic pain behaviors and the effectiveness of mu- and kappa-opioid receptor agonists on this behavior in mice.. The authors studied the behavioral responses of mu-opioid receptor knockout and wild-type mice to thermal and mechanical stimuli before and after neuropathic pain induced by unilateral ligation and section of the L5 spinal nerve. Response to mechanical stimuli was evaluated by determining the frequency of hind paw withdrawal to repetitive stimulation using a series of von Frey monofilaments. Thermal hyperalgesia was assessed by determining the paw withdrawal latencies to radiant heat and frequency of hind paw withdrawal to cooling stimuli. The effects of systemic morphine, the kappa-opioid agonist U50488H, and naloxone on responses to mechanical and thermal stimuli were also studied in spinal nerve-injured mice.. After spinal nerve injury, wild-type mice developed increased responsiveness to mechanical, heat, and cooling stimuli ipsilateral to nerve injury. mu-Opioid receptor knockout mice not only had more prominent mechanical allodynia in the nerve-injured paw, but also expressed contralateral allodynia to mechanical stimuli. Hyperalgesia to thermal stimuli was similar between mu-opioid knockout and wild-type animals. Morphine decreased mechanical allodynia dose dependently (3-30 mg/kg subcutaneous) in wild-type mice--an effect that was attenuated in the heterozygous mice and absent in the homozygous mu-opioid knockout mice. The kappa-opioid agonist U50488H (3-10 mg/kg subcutaneous) attenuated mechanical allodynia in wild-type, heterozygous, and homozygous mu-opioid mice. Naloxone in wild-type mice resulted in enhanced ipsilateral and contralateral allodynia to mechanical stimuli that resembled the pain behavior observed in mu-opioid receptor knockout mice.. The authors' observations indicate that (1) unilateral nerve injury induces a bilateral tonic activation of endogenous mu-opioid receptor-mediated inhibition that attenuates mechanical allodynia but not thermal hyperalgesia, (2) both mu- and kappa-opioid agonists attenuate neuropathic pain in mice, and (3) the antihyperalgesic actions of morphine are mediated primarily via mu-opioid receptors.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Disease Models, Animal; Mice; Morphine; Naloxone; Pain; Reaction Time; Receptors, Opioid, mu; Spinal Nerves

Domperidone, a prokinetic drug with minimal extrapyramidal side-effects was investigated for its antinociceptive response in mice using formalin assay procedure. Two parameters namely the pain score and the time spent by the animal in licking/biting the formalin injected paw were considered. Domperidone (1, 2.5 or 5 mg/kg; ip) injected 15 min prior to formalin effectively reduced the pain score bringing it to zero at the 15th minute and was also effective till 30 min but to a lesser degree. This effect of domperidone (2.5 mg/kg) was significantly attenuated in naloxone pretreated mice indicating a partial role for opioid pathways. In the other parameter i.e. time spent in licking/biting, domperidone in all the doses employed failed to modify significantly the same by the animal in the early phase. In contrast, a dose related inhibition of the time spent was recorded in the late phase. Besides, a trend towards the enhancement of the inhibitory effect of domperidone (2.5 mg/kg) in the late phase was noticed in naloxone pretreated mice. Possibly, the peripheral analgesic mechanisms may play a role in this response since the late phase was considered akin to inflammation. The results confirm the antinociceptive effect of domperidone and suggest that caution be exercised while selecting the parameters when formalin assay is employed.

Topics: Analgesics; Animals; Disinfectants; Domperidone; Dopamine Antagonists; Drug Combinations; Formaldehyde; Male; Mice; Naloxone; Narcotic Antagonists; Nociceptors; Pain; Pain Measurement; Time Factors

Buprenorphine is a relatively nonselective opioid receptor partial agonist that is used in the management of both pain and addiction. To improve understanding of the opioid receptor subtypes important for buprenorphine effects, we now report the results of our investigation on the roles of mu-, delta-, and kappa-opioid receptors in antinociceptive responses and place preferences induced by buprenorphine. Buprenorphine antinociception, assessed by hot-plate and tail-flick tests, was significantly reduced in heterozygous mu-opioid receptor knockout (MOR-KO) mice and abolished in homozygous MOR-KO mice. In contrast, buprenorphine retained its ability to establish a conditioned place preference (CPP) in homozygous MOR-KO, although the magnitude of place preference was reduced as the number of copies of wild-type mu-opioid receptor genes was reduced. The remaining CPP of buprenorphine was abolished by pretreatment with the nonselective opioid antagonist naloxone, but only partially blocked by pretreatment with either the delta-selective opioid antagonist naltrindole or the kappa-selective opioid antagonist norbinaltorphimine. These data, and biochemical confirmation of buprenorphine actions as a partial delta-, mu-, and kappa-agonist, support the ideas that mu-opioid receptors mediate most of analgesic properties of buprenorphine, but that mu- and delta- and/or kappa-opioid receptors are each involved in the rewarding effects of this drug.

Topics: Analgesics, Opioid; Animals; Buprenorphine; CHO Cells; Conditioning, Operant; Cricetinae; Cyclic AMP; DNA, Complementary; Hot Temperature; Humans; Mice; Mice, Knockout; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Radioligand Assay; Reaction Time; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Reward

Topics: Administration, Cutaneous; Analgesics, Opioid; Drug Interactions; Drug Therapy, Combination; Fentanyl; Humans; Male; Middle Aged; Naloxone; Narcotic Antagonists; Pain; Pruritus; Substance Withdrawal Syndrome; Uremia; Withholding Treatment

Two potent endogenous opioid peptides, endomorphin-1 (EM-1) and -2 (EM-2), which are selective micro-opioid agonists, have been identified from bovine and human brain. These endomorphins were demonstrated to produce a potent anti-allodynic effect at spinal level. In the present study, we further investigated their supraspinal anti-allodynic effects and rewarding effects. In a neuropathic pain model (sciatic nerve crush in rats), EM-1 and -2 (15 microg, i.c.v.) both showed significant suppressive effects in the cold-water allodynia test, but EM-1 showed a longer duration than EM-2. Naltrexone (NTX; 15 microg) and naloxonazine (NLZ; 15 microg) were both able to completely block the anti-allodynic effects of EM-1 and -2. In the tests of conditioned place preference (CPP), only EM-2 at the dose of 30 microg showed significant positive rewarding effect, whereas both endomorphins did not induce any reward at the dose of 15 microg. Due to the low solubility and the undesired effect (barrel rotation of the body trunk), EM-1 was not tested for the dose of 30 microg in the CPP tests. It was also found that acute EM-2 (30 microg) administration increased dopamine turnover in the shell of nucleus accumbens in the microdialysis experiments. From these results, it may suggest that EM-1 and -2 could be better supraspinal anti-allodynic agents compared with the other opioid drugs, although they may also induce rewarding.

Topics: Analgesics, Opioid; Animals; Male; Naloxone; Naltrexone; Narcotic Antagonists; Nerve Compression Syndromes; Oligopeptides; Pain; Pain Management; Pain Measurement; Rats; Rats, Sprague-Dawley

Our study addressed the hypothesis that spinal release of endogenous opioids underlies Delta9-tetrahydrocannabinol (Delta9-THC)-induced antinociception in Freund's adjuvant-induced arthritic and nonarthritic rats. The paw-pressure test was used to assess the antinociceptive effects of Delta9-THC versus those of morphine, and opioid and cannabinoid receptor-selective antagonists were used to characterize the involved receptors. Cerebrospinal fluid was collected after Delta9-THC injection (i.p.) for the measurement of endogenous opioid peptides. Our results indicate that morphine or Delta9-THC is equally potent and efficacious in both nonarthritic and arthritic rats. Delta9-THC-induced antinociception is attenuated by the kappa opioid receptor antagonist, nor-binaltorphimine, in arthritic rats only. Delta9-THC induces increased immunoreactive dynorphin A (idyn A) levels in nonarthritic rats while decreasing idyn A in arthritic rats. We hypothesize that the elevated idyn A level in arthritic rats contributes to hyperalgesia by interaction with N-methyl-D-aspartate receptors, and that Delta9-THC induces antinociception by decreasing idyn A release.

Topics: Animals; Arthritis, Experimental; Cannabinoid Receptor Antagonists; Dose-Response Relationship, Drug; Dronabinol; Dynorphins; Enkephalin, Leucine; Enkephalin, Methionine; Freund's Adjuvant; Injections, Intradermal; Injections, Intraperitoneal; Male; Morphine; Mycobacterium; Naloxone; Naltrexone; Narcotic Antagonists; Pain; Pain Measurement; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Receptors, Opioid; Rimonabant

Recent imaging reports demonstrate the activation of the orbitofrontal cortical (OFC) area during acute and chronic pain. The aim of this study was to compare the effects of chronic perfusion of this area with morphine on nociception in control rats and in rats subjected to mononeuropathy. Chronic perfusion of morphine, using miniosmotic pumps, produced significant and naloxone-reversible depression of tactile and cold allodynias and thermal hyperalgesia, observed in neuropathic rats, while it produced significant elevation and naloxone insensitive increase of acute nociceptive thresholds in control rats. The observed results support the idea that this area is a component of a flexible cerebral network involved in pain processing and perception.

Topics: Analgesics, Opioid; Animals; Behavior, Animal; Disease Models, Animal; Drug Administration Routes; Drug Administration Schedule; Frontal Lobe; Hyperalgesia; Mononeuropathies; Morphine; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Pain Threshold; Rats; Rats, Sprague-Dawley; Reaction Time; Time Factors

Nociceptin/orphanin FQ (noci/OFQ), the endogenous ligand for the orphan ORL1 (opioid receptor-like1), has been shown to be anti- or pronociceptive and modify morphine analgesia in rats after central administration. We comparatively examined the effect of noci/OFQ on hyperalgesia and morphine analgesia in two experimental models of neuropathic pain: diabetic (D) and mononeuropathic (MN) rats. Noci/OFQ, when intrathecally (i.t.) injected (0.1, 0.3, or 1, to 10 microg/rat) was ineffective in normal rats, but reduced and suppressed mechanical hyperalgesia (paw-pressure test) in D and MN rats, respectively. This spinal inhibitory effect was suppressed by naloxone (10 microg/rat, i.t.) in both models. Combinations of systemic morphine with spinal noci/OFQ resulted in a strong potentiation of analgesia in D rats. In MN rats, an isobolographic analysis showed that the morphine+noci/OFQ association (i.t.) suppressed mechanical hyperalgesia in a superadditive manner. In summary, the present findings reveal that spinal noci/OFQ produces a differential antinociception in diabetic and traumatic neuropathic pain according to the etiology of neuropathy, an effect possibly mediated by opioid receptors. Moreover, noci/OFQ combined with morphine produces antinociceptive synergy in experimental neuropathy, opening new opportunities in the treatment of neuropathic pain.

Topics: Animals; Behavior, Animal; Body Weight; Diabetes Mellitus, Experimental; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Hyperalgesia; Male; Mononeuropathies; Morphine; Naloxone; Narcotic Antagonists; Nociceptin; Nociceptin Receptor; Opioid Peptides; Pain; Pain Measurement; Rats; Rats, Sprague-Dawley; Receptors, Opioid; Sciatic Nerve; Streptozocin; Time Factors; Vocalization, Animal

Upon withdrawal from opioids many patients experience a heightened sensitivity to stimuli and an exaggerated pain response. We present evidence that neonatal rats exhibit allodynia and hyperalgesia on acute opiate withdrawal. Postnatal 7 and 21 day rats were used to approximately model a full term human infant and a human child, respectively. The opiate antagonist naloxone was used to precipitate withdrawal at 30 or 120 min after a single acute administration of morphine. Alternatively, rats were allowed to undergo spontaneous withdrawal. Behavioral manifestations of withdrawal syndrome were not observed when naloxone was administered at 30 min post-morphine, but were present when withdrawal was precipitated at 120 min. Spontaneous and precipitated withdrawal from a single acute administration of morphine produced mechanical allodynia and thermal hyperalgesia in postnatal day 7 rats and mechanical allodynia in postnatal day 21 rats. A higher dose of morphine was required to produce mechanical allodynia in postnatal day 21 versus 7 rats but this increase was independent of the analgesic efficacy of morphine at these two ages. The present work illustrates the need to examine the phenomenon of hypersensitivity upon opioid withdrawal in the human pediatric population.

Topics: Age Factors; Animals; Animals, Newborn; Behavior, Animal; Dose-Response Relationship, Drug; Drug Interactions; Hyperalgesia; Hyperesthesia; Morphine; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Rats; Rats, Sprague-Dawley; Sensory Thresholds; Substance Withdrawal Syndrome; Time Factors

On withdrawal from opioids many patients experience a heightened sensitivity to stimuli and an exaggerated pain response. The phenomenon has been little studied in infants. We present evidence that in postnatal day 7 rats an exaggerated nociceptive ventral root response of spinal cords in vitro and withdrawal-associated thermal hyperalgesia in vivo are dependent on protein kinase C (PKC), and we document the roles of PKC and gamma isozymes. In vitro, the slow ventral root potential (sVRP) is a nociceptive-related response in spinal cord that is depressed by morphine and recovers to levels significantly above control on administration of naloxone. A broad-spectrum PKC antagonist, GF109213X, blocked withdrawal hyperresponsiveness of the sVRP whereas an antagonist specific to Ca(++)-dependent isozymes, Go69076, did not. Consistent with this finding, a specific peptide inhibitor of calcium-independent PKC, but not an inhibitor of calcium-dependent PKC gamma, blocked withdrawal hyperresponsiveness of the sVRP. Similarly, in vivo in 7-day-old rat pups, inhibition of PKC, but not PKC gamma, prevented thermal hyperalgesia precipitated by naloxone at 30 min post-morphine. In contrast, thermal hyperalgesia during spontaneous withdrawal was inhibited by both PKC and gamma inhibitors. The consistency between the in vivo and in vitro findings with respect to naloxone-precipitated withdrawal provides further evidence that the sVRP reflects nociceptive neurotransmission. In addition the difference between naloxone-precipitated and spontaneous withdrawal in vivo suggests that in postnatal day 7 rats, morphine exposure produces an early phase of primary afferent sensitization dependent upon PKC translocation, followed by a later phase involving spinal sensitization mediated by PKC gamma.

Topics: Analysis of Variance; Animals; Animals, Newborn; Behavior, Animal; Drug Interactions; Enzyme Inhibitors; Female; Hyperalgesia; In Vitro Techniques; Indoles; Male; Maleimides; Membrane Potentials; Morphine; Naloxone; Narcotic Antagonists; Narcotics; Neurons; Pain; Peptides; Protein Kinase C; Protein Kinase C-epsilon; Rats; Rats, Sprague-Dawley; Reaction Time; Spinal Nerve Roots; Substance Withdrawal Syndrome

The present study was aimed to examine if protein kinase C (PKC) activation is necessarily involved in both the c-fos protein expression in the nocuously-activated c-fos protein-like immunoreactive (Fos-LI) neurons and the concomitant opioid receptor-mediated modulation in the dorsal horn circuitry of the spinal cord. Formalin was injected into a hindpaw of rats 5 min after the rats were pretreated with intrathecal (i.t.) administration of chelerythrine (Chel), an inhibitor of PKC, naloxone (Nal), combined administration of these two (Chel + Nal), or vehicle (n=5 in each group),respectively. By using immunocytochemical techniques, the formalin-induced Fos-LI neurons in the lumbar dorsal horn were calculated 1 h after formalin injection. The results showed that: (1) i.t. Chel significantly reduced the number of Fos-LI neurons in the dorsal horn of the spinal cord on the side ipsilateral to the formalin injection, showing a decrease by 60.3% (P<0.001) as compared to that observed in the i.t.vehicle group; (2) i.t. Nal significantly increased the number of Fos-LI neurons in the ipsilateral dorsal horn, with an increase of 46.0% (P<0.01) as compared to that in the i.t.vehicle group, the highest percentage increase being found in the deeper laminae of the dorsal horn; and (3) i.t. Chel + Nal also exhibited a significant decrease in Fos-LI neurons in the ipsilateral dorsal horn as compared to i.t. Nal group, showing a reduction of 53.2%, a value similar to that in the i.t. Chel group. These results suggest that: (1) PKC plays a role in the c-fos protein expression only in nearly one half of the Fos-LI neurons in the dorsal horn; and (2) PKC is possibly not involved in the concomitant modulation on the nociception mediated by micro- (and also partly delta-) opioid receptors in the spinal cord.

Topics: Animals; Formaldehyde; Immunohistochemistry; Male; Naloxone; Narcotic Antagonists; Nociceptors; Pain; Posterior Horn Cells; Protein Kinase C; Proto-Oncogene Proteins c-fos; Random Allocation; Rats; Rats, Sprague-Dawley; Receptors, Opioid, delta; Spinal Cord

The effects of bovine adrenal medulla 22 (BAM22), a cleaved product of proenkephalin A, were investigated on the noxious stimulus-evoked expressions of spinal c-fos-like immunoreactivity (FLI). Heat (51 degrees C) applied to the tail evoked FLI predominantly in laminae I-II of the sacral spinal cord. Intrathecal (i.t.) BAM22 at a dose of 7 nmol decreased the expressions of the heat-evoked FLI by 68%, 64% and 56% in laminae I-II, III-IV and V-VI, respectively, and the decrease pattern was comparable to that induced by i.t. morphine (10 mug). Naloxone (1 mg/kg, i.p.) significantly enhanced the heat-evoked FLI in laminae III-VI, prevented the morphine-induced inhibition, and decreased the potencies of BAM22 in laminae I-II and V-VI by 23-40%. Higher dose of naloxone (10 mg/kg, i.p.) also partially reduced the BAM22-induced suppression. Following intraplantar injection of formalin (2.5%), FLI neurons were preferentially distributed not only in laminae I-II but also in laminae III-IV and V-VI of segments L4-L5. Pretreatment with BAM22 (7 nmol, i.t.) reduced the formalin-evoked FLI neurons by 72%, 61% and 58%, in laminae I-II, III-IV and V-VI, respectively. Naloxone (1 mg/kg. i.p.) enhanced the formalin-evoked expressions of FLI in laminae III-VI and decreased the potencies of BAM22 by 22-38% in laminae I-II and V-VI. The present study provided evidence at a cellular level showing that opioid and non-opioid effects of BAM22 on nociceptive processing in acute and persistent pain models were associated with modulation of noxious stimulus-evoked activity of the spinal dorsal horn neurons.

Topics: Animals; Cattle; Cell Count; Drug Interactions; Enkephalin, Methionine; Enkephalins; Formaldehyde; Gene Expression Regulation; Hot Temperature; Immunohistochemistry; Male; Morphine; Naloxone; Narcotic Antagonists; Narcotics; Neurons; Pain; Pain Measurement; Physical Stimulation; Protein Precursors; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Spinal Cord

A 2003 study suggested that there are age differences in diffuse noxious inhibitory controls (DNIC), a form of endogenous pain inhibition. The present report describes a followup study employing a pharmacological blockade of endogenous opioids, i.e., using naloxone, in a small subset (n=6) of healthy young volunteers to characterize the opioid-dependence of DNIC, as well as DNIC's association with cardiovascular reactivity. Findings suggested that, while opioid blockade enhanced cardiovascular reactivity to cold pain, DNIC was not affected by administering naloxone. Interestingly, greater cardiovascular responses to noxious cold were associated with enhanced DNIC in this small sample. This relationship, which did not appear opioid-dependent, supports previous models integrating cardiovascular activity with the functioning of pain-modulatory systems.

Topics: Adult; Blood Pressure; Cold Temperature; Female; Humans; Male; Naloxone; Narcotic Antagonists; Narcotics; Nociceptors; Pain

Opioid-containing leukocytes can counteract inflammatory hyperalgesia. Under stress or after local injection of corticotropin releasing factor (CRF), opioid peptides are released from leukocytes, bind to opioid receptors on peripheral sensory neurons and mediate antinociception. Since polymorphonuclear cells (PMN) are the predominant opioid-containing leukocyte subpopulation in early inflammation, we hypothesized that PMN and their recruitment by chemokines are important for peripheral opioid-mediated antinociception at this stage. Rats were intraplantarly injected with complete Freund's adjuvant (CFA). Using flow cytometry, immunohistochemistry, and ELISA, leukocyte subpopulations, chemokine receptor (CXCR2) expression on opioid-containing leukocytes and the CXCR2 ligands keratinocyte-derived chemokine (KC), macrophage inflammatory protein-2 (MIP-2) and cytokine-induced neutrophil chemoattractant-2 (CINC-2) were quantified. Paw pressure threshold (PPT) was determined before and after intraplantar and subcutaneous injection of CRF with or without naloxone. PMN depletion was achieved by intravenous injection of an antiserum. Chemokines were blocked by intraplantar injection of anti-MIP-2 and/or anti-KC antiserum. We found that at 2 h post CFA (i) intraplantar but not subcutaneous injection of CRF produced dose-dependent and naloxone-reversible antinociception (P<0.05, ANOVA). (ii) Opioid-containing leukocytes in the paw and CRF-induced antinociception were reduced after PMN depletion (P<0.05, t-test). (iii) Opioid-containing leukocytes mostly expressed CXCR2. MIP-2 and KC, but not CINC-2 were detectable in inflamed but not in noninflamed tissue (P<0.05, ANOVA). (iv) Combined but not single blockade of MIP-2 and KC reduced the number of opioid-containing leukocytes and peripheral opioid-mediated antinociception (P<0.05, t-test; P>0.05, ANOVA). In summary, in early inflammation peripheral opioid-mediated antinociception is critically dependent on PMN and their recruitment by CXCR2 chemokines.

Topics: Analysis of Variance; Animals; Antibodies; Cell Count; Cell Movement; Chemokine CXCL2; Chemokines; Chemokines, CXC; Corticotropin-Releasing Hormone; Dose-Response Relationship, Drug; Drug Administration Routes; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Freund's Adjuvant; Gene Expression Regulation; Immunohistochemistry; Intercellular Signaling Peptides and Proteins; Male; Naloxone; Narcotics; Neurogenic Inflammation; Neutrophils; Pain; Pain Management; Pain Measurement; Pain Threshold; Rats; Rats, Wistar; Receptors, Interleukin-8B

The antinociceptive effect of the ethanolic extract of Melastoma malabathricum (MME) was investigated using acetic acid-induced abdominal writhing test and hot-plate test in mice. It was demonstrated that the extract (30-300 mg/kg, i.p.) strongly and dose-dependently inhibited the acetic acid-induced writhing with an ED(50) of 100 (78-160) mg/kg i.p. It also significantly increased the response latency period to thermal stimuli. Furthermore, the nonselective opioid receptor antagonist, naloxone blocked the antinociceptive effect of the extract in both tests, suggesting that M. malabathricum may act both at peripheral and central levels.

Topics: Acetic Acid; Analgesics; Animals; Dose-Response Relationship, Drug; Hot Temperature; Male; Melastomataceae; Mice; Mice, Inbred BALB C; Naloxone; Pain; Pain Measurement; Phytotherapy; Plant Bark; Plant Extracts; Plant Leaves

Several neurotransmitter mechanisms have been proposed as playing a role in the development of morphine tolerance. We provide evidence for the first time that endothelin antagonists can restore morphine analgesia in morphine-tolerant rats and prevent the development of tolerance to morphine. Studies were carried out in rats and mice treated with implanted placebo or implanted morphine pellet. The maximal tail-flick latency in morphine pellet + vehicle-treated rats (7.54 seconds) was significantly lower when compared with placebo pellet + vehicle-treated rats (10 seconds), indicating that tolerance developed to the analgesic effect of morphine. BQ123 potentiated tail-flick latency by 30.0% in placebo-tolerant rats and 94.5% in morphine-tolerant rats compared with respective controls. BMS182874 potentiated tail-flick latency by 30.2% in placebo-tolerant rats and 66.7% in morphine-tolerant rats. The enhanced analgesic effect of morphine after treatment with endothelin antagonists could be blocked by naloxone, indicating an opiate-mediated effect; but naloxone binding to brain membranes was not affected by BQ123. Guanosine triphosphate binding was stimulated by morphine and endothelin-1 in non-tolerant mice and not in morphine-tolerant mice; however, guanosine triphosphate binding was stimulated by BQ123 in morphine-tolerant mice and was unaffected in non-tolerant mice. These results suggest that uncoupling of G-protein occurs in morphine tolerance and endothelin antagonist restores the coupling of G-protein to its receptors. A combination use of endothelin antagonist and opiates could provide a novel approach in improving analgesia and eliminating tolerance.

Topics: Analgesics, Non-Narcotic; Analgesics, Opioid; Animals; Dansyl Compounds; Disease Models, Animal; Drug Therapy, Combination; Drug Tolerance; Endothelin A Receptor Antagonists; Guanosine 5'-O-(3-Thiotriphosphate); Injections, Intraventricular; Male; Mice; Morphine; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Pain Threshold; Peptides, Cyclic; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptors, Opioid, mu; Sulfur Radioisotopes; Time Factors

Objectives were to investigate the effect of nonselective nitric oxide synthase (NOS) inhibitor, L-NAME on codeine-induced analgesia and to see the role of NO in its antinociceptive effect. Also, to see if L-NAME can potentiate the antinociceptive response of sub-effective dose of codeine and to explore if opioid receptors have some role to play in L-NAME effects. Mice were injected with selected doses of codeine or other selected agents intraperitoneally and the latency to hot plate was recorded at zero, 15, 30, and 60 min of the treatments. The antinociceptive response of codeine (10 mg/kg, i.p.) was studied in comparison to those of the NOS inhibitor, L-NAME, and of nitric oxide donor, sodium nitroprusside (SNP). Assessment of nitrates and nitrites (NOx) in the sera of treated mice were also made. Codeine (20 mg/kg dose), induced analgesia significantly and dose dependently only after 15 min. L-NAME at 20, 40, and 80 mg/kg dose levels significantly changed the nonanalgesic effect of codeine (10 mg/kg) to highly significant analgesia. The effect of L-NAME 40 mg/kg was significantly higher than the other two doses and was almost equal to that of the higher dose of codeine. Naloxone itself did not show any intrinsic effect but almost abolished the L-NAME-codeine induced analgesia. Similarly, SNP (1 mg/kg) reversed the decrease in reaction time by L-NAME-codeine to its control values, significantly. Pretreatment with L-NAME rendered the nonanalgesic dose of codeine significantly analgesic almost in an equal potency to the high dose of codeine alone and indicate that the NO modulatory effect on the opioid analgesic codeine is probably, at least in part, through opioid receptors.

Topics: Analgesia; Analgesics; Analgesics, Opioid; Animals; Codeine; Dose-Response Relationship, Drug; Drug Synergism; Enzyme Inhibitors; Male; Mice; Naloxone; Narcotic Antagonists; NG-Nitroarginine Methyl Ester; Nitrates; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase; Nitrites; Nitroprusside; Pain; Time Factors

The dermorphin-derived tetrapeptide Tyr-D-Arg(2)-Phe-Sar(4) (TAPS) was tested for its ability to induce tolerance, cross-tolerance, withdrawal and its substitution properties in rats subjected to chronic intracerebroventricular (i.c.v.) infusions of mu-opiate receptor agonists. Tolerance and cross-tolerance were assessed by quantification of the thermally induced tail-flick response. Chronic intracerebroventricular infusion of TAPS resulted in antinociception at almost 1000-fold lower doses compared to morphine sulphate and [D-Ala(2), MePhe(4)Gly(ol)(5)]enkephalin (DAMGO). Tolerance to the antinociceptive effect of TAPS developed similar to DAMGO and morphine sulphate. Cross-tolerance to intracerebroventricular bolus injections of DAMGO, but not of TAPS, was evident in rats rendered tolerant to morphine sulphate and TAPS. Naloxone-induced withdrawal was equally pronounced in animals treated with morphine sulphate, DAMGO or TAPS. TAPS substituted for morphine sulphate and vice versa regarding the withdrawal syndrome in a cross-over experimental design. In contrast to DAMGO, TAPS retains its antinociceptive effect following bolus administration in rats rendered tolerant to mu-opioid receptor agonists.

Topics: Analgesics, Opioid; Animals; Dose-Response Relationship, Drug; Drug Tolerance; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; In Vitro Techniques; Infusion Pumps; Injections, Intraventricular; Male; Morphine; Naloxone; Oligopeptides; Pain; Rats; Rats, Sprague-Dawley; Substance Withdrawal Syndrome; Substance-Related Disorders; Time Factors

It is a well-known phenomenon that cerebral blood flow is coupled to neural activation induced by non-noxious somatosensory stimulation. However, basic questions related to pain-induced cerebral blood flow changes remain unanswered. In the present study, the sciatic nerve of anesthetized rats was subjected to electric stimulation with noxious and non-noxious parameters. Changes in local cerebral blood flow and neuronal activity were determined simultaneously in the sensory cortex and in the thalamus by laser-Doppler flowmetry and c-fos immunohistochemistry, respectively. The role of different vasoregulatory mechanisms and the pain-induced increase in mean arterial blood pressure (MABP) were examined with specific blocking agents and by means of rapid intra-arterial transfusion. Noxious stimulation resulted in significant enhancement of neuronal activity both in the thalamus and in the somatosensory cortex indicated by marked c-fos expression in these areas. Cortical and thalamic blood flow (cBF and tBF) increased by 47+/-4 and 44+/-3% during the stimulation while the MABP elevated by 35+/-2%. Similar changes in MABP induced by intra-arterial transfusion had no effect on tBF, while cBF increased only by 18+/-5%. Blockade of ATP sensitive potassium channels (K(+)(ATP)) and sympathetic beta-receptors significantly attenuated the pain-induced blood flow increases in both investigated areas, while inhibition of nitric oxide synthase was effective only in the thalamus. The blockade of the sympathetic alpha-receptors, opiate receptors, and the cyclooxygenase enzyme had no effect on the pain-induced cerebral blood flow elevations. These findings demonstrate that during noxious stimulation, cerebral blood flow is adjusted to the increased neural activity by the interaction of vasoconstrictor autoregulatory and specific vasodilator mechanisms, involving the activation of sympathetic beta-receptors, K(+)(ATP)-channels and the release of nitric oxide.

Topics: Animals; ATP-Binding Cassette Transporters; Blood Gas Analysis; Blood Pressure; Cerebrovascular Circulation; Endorphins; Enzyme Inhibitors; Genes, fos; Immunohistochemistry; KATP Channels; Male; Naloxone; Narcotic Antagonists; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Pain; Physical Stimulation; Potassium Channel Blockers; Potassium Channels; Potassium Channels, Inwardly Rectifying; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Wistar; Receptors, Adrenergic, alpha; Receptors, Adrenergic, beta; Sciatic Nerve; Somatosensory Cortex; Stereotaxic Techniques; Thalamus

Rapid development of tolerance and dependence limits the usefulness of morphine in long-term treatment. We examined the effects of clonidine (alpha(2)-adrenoceptor agonist) and prazosin (alpha(1)-adrenoceptor antagonist) on morphine analgesia, tolerance and withdrawal. Morphine tolerance was induced using a 3-day cumulative twice-daily dosing regimen with s.c. doses up to 120 mg/kg. Tolerance was assessed on day 4, as loss of the antinociceptive effect of a test dose of morphine (5 mg/kg). After 10 h, morphine withdrawal was precipitated with naloxone (1 mg/kg). Prazosin had no analgesic effect alone but dose-dependently potentiated morphine analgesia in morphine-naive mice. Another alpha(1)-adrenoceptor antagonist, corynanthine, had similar effects. Prazosin also increased the analgesic potency of the morphine test dose in morphine-tolerant mice. Naloxone-precipitated vertical jumping was not affected, but weight loss was reduced by prazosin. Acutely administered clonidine potentiated morphine analgesia and alleviated opioid withdrawal signs, as expected. We conclude that in addition to the already established involvement of alpha(2)-adrenoceptors in opioid actions, also alpha(1)-adrenoceptors have significant modulatory role in opioid analgesia and withdrawal.

Topics: Adrenergic alpha-Agonists; Adrenergic alpha-Antagonists; Analgesics, Opioid; Animals; Behavior, Animal; Clonidine; Dose-Response Relationship, Drug; Drug Synergism; Drug Tolerance; Male; Mice; Mice, Inbred C57BL; Morphine; Naloxone; Pain; Prazosin; Substance Withdrawal Syndrome; Weight Loss

Various evidence has demonstrated a role of the nitric oxide (NO)/cGMP signaling pathway in the processing of nociception. The exact role of phosphodiesterase-5 (PDE-5) via the NO/cGMP pathway is not fully understood in pain response. The aim of the present study was to investigate the possible peripheral interaction between a PDE-5 inhibitor (sildenafil) and morphine. Carrageenan-induced hyperalgesia in rats and the acetic-acid-induced writhing test in mice were used as animal models. Local administration of sildenafil (50-200 microg/paw, i.pl.) exhibited a dose-dependent antinociceptive effect against the paw pressure test. Sildenafil also demonstrated an antinociceptive effect (1-10 mg/kg, i.p.) against in the writhing test. Co-administration of sildenafil (100 microg/paw, i.pl. and 2 mg/kg, i.p.) significantly enhanced the antinociceptive effect of morphine (2 microg/ paw, i.pl. and 2 mg/kg, i.p respectively). The antinociception produced by the drugs alone or combined was due to a local action, as its administration in the contralateral paws was ineffective. Pretreatment with N(G)-nitro-L-arginine methyl ester (an NO synthesis inhibitor), methylene blue (gunalyl cyclase inhibitor) or naloxone (opioid receptor antagonist) blocked the effect of a sildenafil-morphine combination in both tests. The results suggest that opioid receptor (NO and cGMP) mechanisms are involved in the combined antinociceptive effect. Further, sildenafil produced antinociception per se and increased the response of morphine, probably through the inhibition of cGMP degradation.

Topics: Analgesics; Animals; Dose-Response Relationship, Drug; Drug Interactions; Enzyme Inhibitors; Female; Hyperalgesia; Male; Methylene Blue; Mice; Morphine; Naloxone; Narcotic Antagonists; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Pain; Pain Measurement; Phosphodiesterase Inhibitors; Piperazines; Purines; Rats; Sildenafil Citrate; Sulfones; Time Factors

This study set out to examine the vasomotor effects of the opioid-like peptide nociceptin on knee joint capsular blood flow in urethane-anaesthetized rats. Topical application of nociceptin (10(-15)-10(-8) mol) caused a progressive fall in joint perfusion that was significantly inhibited by the specific nociceptin receptor antagonist [Phe(1)-(CH(2)-NH)-Gly(2)] Nociceptin(1-13)-NH(2) as well as the nonspecific opioid antagonist naloxone. To test whether this constrictor response was sympathetically mediated, we administered nociceptin in animals treated with guanethidine to produce sympathetic blockade or in the presence of the alpha-adrenoceptor antagonist phentolamine. Both guanethidine treatment and phentolamine coadministration attenuated the constrictor response to nociceptin. Inhibition of nociceptin-mediated vasoconstriction revealed a supplementary hyperemic response that persisted in animals whose knee joints were treated with 1% capsaicin to destroy the articular unmyelinated nerve supply. These results show that, in the rat knee, peripheral administration of nociceptin primarily causes a sympathetically mediated vasoconstriction. In addition, high-dose nociceptin produces a vasodilatatory response that is likely due to the direct action of nociceptin on vascular smooth muscle and not by a neurogenic mechanism.

Topics: Adrenergic Fibers; Afferent Pathways; Animals; Capsaicin; Dose-Response Relationship, Drug; Efferent Pathways; Electric Stimulation; Guanethidine; Hindlimb; Male; Naloxone; Nociceptin; Opioid Peptides; Pain; Rats; Rats, Wistar; Regional Blood Flow; Sympathetic Nervous System; Synovial Membrane; Vasoconstriction

The efficacy of spinally versus supraspinally administered morphine was studied in rats with a spinal nerve ligation-induced neuropathy. Behavioural assessment indicated that the effect of intrathecally administered morphine on pain-related responses was attenuated when compared with unoperated controls. The decreased efficacy of spinal morphine was associated with neuropathic symptoms, since sham ligation or nerve ligation without accompanying tactile allodynia did not lead to spinal inefficacy of morphine. In contrast, the pain attenuating effect of morphine in the periaqueductal gray (PAG) was enhanced in neuropathic animals. The effect of systemically administered morphine on pain-related behavior of neuropathic rats was in the same range as in controls or decreased, depending on the test. Coadministration of lidocaine or MK-801, a N-methyl-D-aspartate (NMDA) receptor antagonist, into the rostroventromedial medulla enhanced the tactile antiallodynic but not the thermal antinociceptive effect of intrathecally administered morphine in neuropathic animals. Supraspinal administration of MK-801 or lidocaine did not influence efficacy of spinal morphine in sham-operated animals. Electrophysiological recordings of nociceptive wide-dynamic range (WDR) neurons in the deep spinal dorsal horn of pentobarbitone-anesthetized animals corresponded to a large extent with behavioral results. The inhibitory effect of spinally and systemically administered morphine on WDR neuron responses was attenuated whereas that induced by morphine in the PAG was enhanced in neuropathic animals. The results indicate that in spinal nerve ligation-induced neuropathy the efficacy of spinal morphine is decreased whereas that of supraspinal morphine is increased. Descending influence from brainstem-spinal pathways, involving NMDA receptors in the rostroventromedial medulla, may contribute to the selective reduction in tactile antiallodynic efficacy of spinal morphine.

Topics: Analgesics, Opioid; Anesthetics, Local; Animals; Behavior, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Interactions; Electrophysiology; Excitatory Amino Acid Antagonists; Hyperalgesia; Injections, Spinal; Lidocaine; Ligation; Male; Medulla Oblongata; Morphine; Naloxone; Narcotic Antagonists; Neurons; Pain; Pain Measurement; Periaqueductal Gray; Physical Stimulation; Rats; Rats, Wistar; Reaction Time; Spinal Cord; Spinal Nerves; Time Factors

To explore the facilitation of nociceptive response by dynorphin (Dyn ) A in a model of formalin test in rats, the effects of single intrathecal injection (i.t.) of normal saline (NS), MK-801 (antagonist of NMDA receptor), naloxone (antagonist of opioid receptor), or Dyn A (1-17) were observed, and the effects of i.t. MK-801 or naloxone followed by i.t. Dyn A (1-17) were observed as well. The nociceptive licking and biting induced by injection of formalin exhibited two phases. The first phase lasted for a relatively short period of 3-9 min, and the second phase lasted for a relatively longer period after a 3 to 6- min quietness. The results showed that there were no differences in the first phase in all groups; however, there were differences in the second phase as follows: (1) the duration of nociceptive response was significantly increased in Dyn A (1-17) group (489.5+/-22.5 s) as compared to that of NS group (344.7+/-12.9 s), MK-801 group (331.4+/-20.7 s) or naloxone group (352.5+/-18.4 s) (P<0.01 in three cases); (2) the duration of nociceptive response was significantly shortened in MK-801 plus Dyn A (1-17) group (285.7+/-19.4 s) as compared to that of Dyn A (1-17) group (P<0.01), but there were no significant differences as compared to that of MK-801 group; and (3) there was no significant difference in the second phase between naloxone plus Dyn A (1-17) group (473.8+/-17.8 s) and Dyn A (1-17) group, but the duration of nociceptive response was longer than that of NS group or naloxone group (P<0.01 in both). The results obtained suggest: (1) at the spinal cord, Dyn A (1-17) facilitates nociceptive responses; (2) NMDA receptors, but not opioid receptors, are possibly involved in the nociception by Dyn A (1-17).

Topics: Animals; Dizocilpine Maleate; Dynorphins; Formaldehyde; Injections, Spinal; Naloxone; Nociceptors; Pain; Rats; Receptors, N-Methyl-D-Aspartate

N-Acyloctahydropyrido[3,2,1-ij][1,6]naphthyridines were synthesized as derivatives of matrine-type alkaloids, and the structure-activity relations were examined by the acetic acid-induced abdominal contraction test. The antinociceptive potencies of N-acyloctahydropyrido[3,2,1-ij][1,6]naphthyridines were significantly lower than those of (+)-matrine. The antinociceptive effects of N-benzyloctahydropyrido[3,2,1-ij][1,6]naphthyridines are approximately 5.6 to 6.5 times less than those of N-benzoyloctahydropyrido[3,2,1-ij][1,6]naphthyridine. These findings suggest that the amide group of matrine-type alkaloids is an essential functional group that influences antinociceptive potency. The antinociceptive effect of 4c was markedly antagonized by pretreatment with Naloxone, and that of 3c partially so.

Topics: Alkaloids; Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Heterocyclic Compounds; Matrines; Mice; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Quinolizines; Reflex, Abdominal; Structure-Activity Relationship

We examined the pharmacologic characteristics of herpes simplex virus (HSV) vector-mediated expression of proenkephalin in the dorsal root ganglion in a rodent model of neuropathic pain. We found that: (i). vector-mediated enkephalin produced an antiallodynic effect that was reversed by naloxone; (ii). vector-mediated enkephalin production in animals with spinal nerve ligation prevented the induction of c-fos expression in second order sensory neurons in the dorsal horn of spinal cord; (iii). the effect of vector-mediated enkephalin enhanced the effect of morphine, reducing the ED(50) of morphine 10-fold; (iv). animals did not develop tolerance to the continued production of vector-mediated enkephalin over a period of several weeks; and, (v). vector transduction continued to provide an analgesic effect despite the induction of tolerance to morphine. This is the first demonstration of gene transfer to provide an analgesic effect in neuropathic pain. The pharmacologic analysis demonstrates that transgene-mediated expression and local release of opioid peptides produce some effects that are distinct from peptide analogues delivered pharmacologically.

Topics: Animals; Area Under Curve; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Tolerance; Enkephalins; Ganglia, Spinal; Genetic Vectors; Immunohistochemistry; Ligation; Male; Morphine; Naloxone; Narcotic Antagonists; Oncogene Proteins v-fos; Pain; Pain Measurement; Pain Threshold; Protein Precursors; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; Simplexvirus; Spinal Cord Diseases; Time Factors; Transgenes

The aim of this study was to evaluate the effects of serine/threonine protein phosphatase (PP) inhibitors on morphine-induced antinociception in the tail flick test in mice, and on [3H]naloxone binding to the forebrain crude synaptosome fraction. Neither okadaic acid nor cantharidin (1-10000 nM) displaced [3H]naloxone from its specific binding sites, which indicates that they do not interact at the opioid receptor level. The i.c.v. administration of very low doses of okadaic acid (0.001-1 pg/mouse) and cantharidin (0.001-1 ng/mouse), which inhibit PP2A, produced a dose-dependent antagonism of the antinociception induced by morphine (s.c.). However, L-nor-okadaone (0.001 pg/mouse-1 ng/mouse, i.c.v.), an analogue of okadaic acid lacking activity against protein phosphatases, did not affect the antinociceptive effect of morphine. On the other hand, high doses of okadaic acid (10 ng/mouse, i.c.v.) and cantharidin (1 microg/mouse, i.c.v.), which also block PP1, and calyculin-A (0.1 fg/mouse-1 ng/mouse, i.c.v.), which inhibits equally both PP1 and PP2A, did not modify the morphine-induced antinociception. These results suggest that the activation of type 2A serine/threonine protein phosphatases may play a role in the antinociceptive effect of morphine, and that PP1 might counterbalace this activity.

Topics: Analgesics, Opioid; Animals; Binding, Competitive; Cantharidin; Dose-Response Relationship, Drug; Enzyme Inhibitors; Female; Injections, Intraventricular; Marine Toxins; Mice; Morphine; Naloxone; Nociceptors; Okadaic Acid; Oxazoles; Pain; Pain Measurement; Phosphoprotein Phosphatases; Prosencephalon; Synaptosomes; Tritium

Anabolic-androgenic steroid exposure has been proposed to present a risk factor for the misuse of other drugs of abuse. We now examined whether the exposure to the anabolic-androgenic steroid, nandrolone, would affect the acute morphine responses, tolerance and dependence in rodents. For this purpose, mice received nandrolone using pre-exposure (for 14 days before morphine experiments) or co-administration (1 h before each morphine injection) procedures. Nandrolone treatments increased the acute hypothermic effects of morphine without modifying its acute antinociceptive and locomotor effects. Nandrolone also attenuated the development of tolerance to morphine antinociception in the hot plate test, but did not affect tolerance to its hypothermic effects, nor the sensitisation to morphine locomotor responses. After nandrolone pre-exposure, we observed an attenuation of morphine-induced place preference and an increase in the somatic manifestations of naloxone-precipitated morphine withdrawal. These results indicate that anabolic-androgenic steroid consumption may induce adaptations in neurobiological systems implicated in the development of morphine dependence.

Topics: Anabolic Agents; Analgesics, Opioid; Animals; Behavior, Animal; Conditioning, Psychological; Dose-Response Relationship, Drug; Drug Tolerance; Male; Mice; Morphine; Morphine Dependence; Motor Activity; Naloxone; Nandrolone; Nociceptors; Pain; Pain Measurement; Reward; Substance Withdrawal Syndrome; Time Factors

The recent development of rodent models of bone cancer pain has started to provide the basis for demonstrating the particular neurochemical and behavioral entity of cancer pain. Behaviourally, both spontaneous pain and hyperalgesia related to mechanical, but not thermal, noxious stimuli have been described in cancer-bearing animals. We have carried out a histological and behavioural study focused on the reactivity to noxious heat in C3H/HeJ mice receiving an intratibial injection of 10(5) NCTC 2472 cells. These cells, able to induce an osteosarcoma, break through bone into soft tissues 2 weeks after cell inoculation, producing a macroscopical increase of the limb size from the fourth week. Thermal reactivity is diminished during the first 2 weeks after cell implantation, this hypoalgesia being reversed by the administration of naloxone (10 mg/kg). In contrast, during the fourth and fifth weeks after NCTC 2472 cell implantation, an increased nociceptive heat reactivity, instead of hypoalgesia, was obtained. This thermal hyperalgesia was prevented by the systemic administration of morphine (15 mg/kg). Throughout the whole period studied, mice showed signs of spontaneous pain behaviour that reached its maximum 3 weeks after inoculation. In conclusion, we show that the presence of thermal heat hyperalgesia is preceded by an initial opioid-mediated hypoalgesic state, in this murine model of bone cancer pain.

Topics: Animals; Bone Neoplasms; Hot Temperature; Hyperalgesia; Mice; Models, Animal; Morphine; Naloxone; Narcotic Antagonists; Narcotics; Nociceptors; Osteosarcoma; Pain; Physical Stimulation; Tibia; Time Factors; Tumor Cells, Cultured

The effects of the S enantiomer of RB101, a complete inhibitor of enkephalin-catabolizing enzymes, alone or in combination with a functional NMDA receptor antagonist, (+)-HA966 were studied on the spinal c-Fos protein expression in the carrageenan model of inflammatory nociception. One hour 30min after intraplantar carrageenan in awake rats, c-Fos immunoreactive (c-Fos-IR) nuclei were preferentially located in the laminae I-II and V-VI of the spinal dorsal horn, i.e., spinal areas containing numerous neurons responding exclusively, or not, to peripheral nociceptive stimuli. RB101(S) (5, 10, 20 and 40mg/kg i.v.) dose-dependently reduced the total number of carrageenan-evoked c-Fos-IR nuclei (r=0.63, P<0.01), with 49+/-3% reduction (P<0.001) for the highest dose. Two highest doses of RB101(S) (20 and 40mg/kg) significantly reduced the number of carrageenan-evoked c-Fos-IR nuclei in both superficial I-II (32+/-7% and 36+/-5% reduction, respectively, P<0.05 for both) and deep V-VI (42+/-6% and 61+/-2% reduction, respectively, P<0.001 for both) laminae. The effects of RB101(S) were naloxone-reversible. Combination of low doses of RB101(S) (2.5 or 10mg/kg i.v.) and an inactive dose of (+)-HA966 (2.5mg/kg s.c.) produced supra-additive effects (39+/-4% and 51+/-5% reduction of the total number of c-Fos-IR nuclei, respectively, P<0.001 for both). These effects were partially reversed by naloxone. These results provide evidence for the potent effects of combination of RB101(S) and (+)-HA966. Considering the absence of major opioid side effects of RB101(S) and the marked increase of its antinociceptive effects by NMDA receptor antagonist, this type of drug combination could have beneficial therapeutical application.

Topics: Analgesics; Animals; Carrageenan; Disulfides; Drug Therapy, Combination; Enkephalins; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Immunohistochemistry; Inflammation; Male; Naloxone; Narcotic Antagonists; Pain; Phenylalanine; Proto-Oncogene Proteins c-fos; Pyrrolidinones; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Spinal Cord

We have recently described a population of neurons in the lateral part of the ventromedial thalamus (VMl), that respond exclusively to noxious cutaneous stimuli, regardless of which part of the body is stimulated. The purpose of the present study was to investigate the convergence of cutaneous, muscular and visceral noxious inputs onto single, VMl neurons in anesthetized rats. VMl neurons were characterized by their responses to Adelta- and C-fiber activation as well as noxious heat applied to the hindpaw. We investigated whether they responded also to colorectal distensions. In an additional series of experiments, we tested the effects of colorectal, intraperitoneal, intramuscular and subcutaneous applications of the chemical irritant mustard oil (MO). The present study shows that a population of neurons located within the thalamic VMl nucleus, carries nociceptive somatosensory signals from the entire body. All these neurons responded to noxious cutaneous and intramuscular stimuli but not to levels of distension that could be considered innocuous or noxious, of the intact and inflammed colon and rectum. Although colorectal distension did not elicit VMl responses, convergence of visceral as well as muscle and cutaneous nociceptors was demonstrated by the increases in ongoing (background) discharges following intracolonic MO. A distinct effect is seen after MO injection into the lumen of the colon: an increase in ongoing activity for 15min but still a lack of effect of colorectal distension. Moreover, following inflammation induced by subcutaneous injections of MO VMl neurons developed responses to both thermal and mechanical innocuous skin stimulation, reminiscent of allodynia phenomena. It is suggested that the VMl contributes to attentional aspects of nociceptive processing and/or to the integration of widespread noxious events in terms of the appropriate potential motor responses.

Topics: Action Potentials; Afferent Pathways; Animals; Drug Administration Routes; Electric Stimulation; Male; Morphine; Muscles; Mustard Plant; Naloxone; Narcotic Antagonists; Narcotics; Neurons; Pain; Physical Stimulation; Plant Extracts; Plant Oils; Rats; Rats, Sprague-Dawley; Skin; Stimulation, Chemical; Ventral Thalamic Nuclei; Viscera

We evaluated the modulation by Na+,K+-ATPase inhibitors of morphine-induced antinociception in the tail-flick test and [3H]naloxone binding to forebrain membranes. The antinociception induced by morphine (1-32 mg/kg, s.c.) in mice was dose-dependently antagonized by ouabain (1-10 ng/mouse, i.c.v.), which produced a significant shift to the right of the morphine dose-response curve. The i.c.v. administration of three Na+,K+-ATPase inhibitors (ouabain at 0.1-100, digoxin at 1-1000, and digitoxin at 10-10000 ng/mouse) dose-dependently antagonized the antinociceptive effect of morphine (4 mg/kg, s.c.) in mice, with the following order of potency: ouabain > digoxin > digitoxin. This effect cannot be explained by any interaction at opioid receptors, since none of these Na+,K+-ATPase inhibitors displaced [3H]naloxone from its binding sites, whereas naloxone did so in a concentration-dependent manner. The antinociception induced by morphine (5 mg/kg, s.c.) in rats was antagonized by the i.c.v. administration of ouabain at 10 ng/rat, whereas it was not significantly modified by intrathecally administered ouabain (10 and 100 ng/rat). These results suggest that the activation of Na+,K+-ATPase plays a role in the supraspinal, but not spinal, antinociceptive effect of morphine.

Topics: Analgesia; Analgesics, Opioid; Animals; Drug Interactions; Mice; Morphine; Naloxone; Ouabain; Pain; Rats; Rats, Wistar; Sodium-Potassium-Exchanging ATPase

Antinociceptive profiles of decursinol were examined in ICR mice. Decursinol administered orally (from 5 to 200 mg/kg) showed an antinociceptive effect in a dose-dependent manner as measured by the tail-flick and hot-plate tests. In addition, decursinol attenuated dose-dependently the writhing numbers in the acetic acid-induced writhing test. Moreover, the cumulative response time of nociceptive behaviors induced by an intraplantar formalin injection was reduced by decursinol treatment during the both 1st and 2nd phases in a dose-dependent manner. Furthermore, the cumulative nociceptive response time for intrathecal (i.t.) injection of TNF-alpha (100 pg), IL-1 beta (100 pg), IFN-gamma (100 pg), substance P (0.7 microg) or glutamate (20 microg) was dose-dependently diminished by decursinol. Intraperitoneal (i.p.) pretreatment with yohimbine, methysergide, cyproheptadine, ranitidine, or 3,7-dimethyl-1-propargylxanthine (DMPX) attenuated inhibition of the tail-flick response induced by decursinol. However, naloxone, thioperamide, or 1,3-dipropyl-8-(2-amino-4-chloro-phenyl)-xanthine (PACPX) did not affect inhibition of the tail-flick response induced by decursinol. Our results suggests that decursinol shows an antinociceptive property in various pain models. Furthermore, antinociception of decursinol may be mediated by noradrenergic, serotonergic, adenosine A(2), histamine H(1) and H(2) receptors.

Topics: Administration, Oral; Adrenergic alpha-Antagonists; Analgesics; Animals; Benzopyrans; Butyrates; Cyproheptadine; Dose-Response Relationship, Drug; Glutamic Acid; Histamine H2 Antagonists; Interferon-gamma; Interleukin-1; Male; Methysergide; Mice; Mice, Inbred ICR; Models, Chemical; Naloxone; Narcotic Antagonists; Pain; Piperidines; Protein Kinase C; Ranitidine; Receptors, Adrenergic; Receptors, Histamine; Receptors, Purinergic P1; Receptors, Serotonin; Serotonin Antagonists; Substance P; Theobromine; Tumor Necrosis Factor-alpha; Xanthines; Yohimbine

We tested whether intrathecal electric stimulation would reduce the tolerance to chronic morphine use and the severity of precipitated morphine withdrawal. Rats received intrathecal electrode catheter implantation and a continuous intrathecal infusion of morphine (2 nmol/h) or saline for 7 days. Intrathecal electric stimulations (0, 20, or 200 V) were performed once daily during the same period. Daily tail-flick and intrathecal morphine challenge tests were performed to assess the effect of intrathecal electric stimulation on antinociception and tolerance to morphine. Naloxone withdrawal (2 mg/kg) was performed to assess morphine dependence, and changes in spinal neurotransmitters were monitored by microdialysis. The antinociceptive effect of intrathecal morphine was increased by 200 V of electric stimulation. The magnitude of tolerance was decreased in the rats receiving the 2 nmol/h infusion with 200 V of intrathecal electric stimulation compared with the control group (morphine 2 nmol/h alone) (AD(50), 13.6 vs 124.7 nmol). The severity of naloxone-induced withdrawal was less in the rats receiving 200 V of stimulation. Intrathecal stimulation thus enhances analgesia and attenuates naloxone-induced withdrawal symptoms in rats receiving chronic intrathecal morphine infusion. Increases in spinal glycine release may be the underlying mechanism. This method may merit further investigation in the context of the long-term use of intrathecal opioids for controlling chronic pain.. Control of chronic pain is a major health problem. We show here that direct electrical stimulation of the spinal cord in rats enhances analgesia and attenuates naloxone-induced withdrawal symptoms. This may warrant further investigation in the context of long-term use of intrathecal opioids for controlling chronic pain.

Topics: Amino Acids; Analgesics, Opioid; Animals; Dose-Response Relationship, Drug; Drug Tolerance; Electric Stimulation Therapy; Injections, Spinal; Male; Microdialysis; Morphine; Morphine Dependence; Naloxone; Narcotic Antagonists; Pain; Pain Management; Pain Measurement; Rats; Rats, Sprague-Dawley; Reaction Time; Spinal Cord; Substance Withdrawal Syndrome

Acute uterine cervical distension (UCD) forms the basis for obstetric and some gynecologic pain. Systemic morphine inhibits the visceromotor response to UCD in rats by an action in the central nervous system, but the effect of morphine is blocked by exposure to estrogen. The purpose of the present study was to determine whether this estrogen blockade of the action of morphine reflects a spinal mechanism.. Virgin Sprague-Dawley rats received estrogen or placebo treatment for 1 week after ovariectomy. Rats were then anesthetized, and the electromyographic response in the rectus abdominis muscle to UCD was recorded in the absence and presence of cumulative dosing with intrathecal morphine.. Estrogen treatment did not alter the stimulus- response relationship between UCD and reflex muscle contraction. Intrathecal morphine reduced the visceromotor reflex response to UCD in a dose-dependent manner that was unaffected by estrogen treatment.. These data suggest that intrathecal morphine is effective in reducing the visceromotor response to UCD and that the reduction in efficacy of systemic morphine in this model is unlikely to reflect a reduction of the efficacy of morphine at the spinal level. These data agree with clinical studies that indicate that systemic morphine, in doses that reduce acute postoperative pain, have minimal to no effect in women in labor, yet intrathecal injection of opioids provides rapid, complete analgesia.

Topics: Analgesics, Opioid; Animals; Blood Pressure; Body Weight; Cervix Uteri; Dose-Response Relationship, Drug; Electromyography; Estradiol; Estrogens; Female; Injections, Spinal; Morphine; Muscle Contraction; Muscle, Smooth; Naloxone; Narcotic Antagonists; Ovariectomy; Pain; Physical Stimulation; Rats; Rats, Sprague-Dawley; Uterus

This study concerned the effect of swim stress on imipramine-induced antinociception in mice. The data showed that intraperitoneal (i.p.) administration of different doses of imipramine (10-40 mg/kg) and 0.5-3 min of swim stress (17 degrees C) induced antinociception in the first and second phases of the formalin test. Low period of swim stress (10 s) with low doses of imipramine (2.5, 5 and 10 mg/kg i.p.), which did not have any effect by themselves, in combination showed antinociception in the second phase of the test. Either yohimbine (0.5 mg/kg i.p.) or naloxone (1 mg/kg i.p.) reversed the response induced by the combination of low doses of imipramine plus swim stress. Yohimbine (1 mg/kg i.p.) decreased the response of imipramine (20 mg/kg i.p.) but not that of 30 s swim stress in the second phase. However, naloxone (1 mg/kg i.p.) reduced the antinociception induced by imipramine (20 mg/kg i.p.) or 30 s swim stress in the second phase of the test, the combination of imipramine with swim stress was not altered by yohimbine or naloxone. Prazosin induced antinociception by itself in the first phase of the test and increased swim-stress-induced antinociception with no interaction. It is concluded that antinociception induced by imipramine in the second phase of formalin test may be mediated through alpha(2)-adrenoceptor antagonists. The results indicate that the responses of swim stress and imipramine may be mediated by an opioid mechanism, but the combination of both drugs induced higher antinociceptive effects.

Topics: Animals; Dose-Response Relationship, Drug; Imipramine; Injections, Intraventricular; Male; Mice; Mice, Inbred Strains; Naloxone; Nociceptors; Pain; Pain Measurement; Prazosin; Stress, Physiological; Swimming; Yohimbine

Topics: alpha-Methyltyrosine; Analgesics; Animals; Antidepressive Agents; Cyclohexanols; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Enzyme Inhibitors; Fenclonine; Male; Mononeuropathies; Motor Activity; Naloxone; Narcotic Antagonists; Pain; Pain Threshold; Rats; Rats, Sprague-Dawley; Sciatic Nerve; Venlafaxine Hydrochloride; Vocalization, Animal

Naloxone administration in the opioid dependent rat is associated with spinal glutamate release and NMDA receptor activation which reportedly is also responsible for opioid tolerance. We hypothesized that episodic withdrawal during chronic infusion of spinal morphine might paradoxically enhance tolerance. Rats (24/group) infused with intrathecal morphine (M) for 4 days (20 nmol/microl per h) were given a daily subcutaneous (s.c.) injection of naloxone 0.6 mg/kg per 0.2 ml (MN) or saline 0.2 ml (MS). A third saline infused group was given daily s.c. saline 0.2 ml (SS). Latencies (rear paw hot box) were tested immediately prior to each daily injection. After termination of each infusion, the dose effect of spinal morphine (0.1, 1, 10, and 100 nmol) was examined. The MN group showed a significantly greater decline in daily latencies compared with the MS group, but also had greater withdrawal hyperalgesia upon termination of the infusion. Dose response to spinal morphine was not significantly different in either MS or MN groups. Periodic abstinence thus enhanced nociception without significantly altering the antinociceptive effect of spinal morphine in this group.

Topics: Analgesics, Opioid; Animals; Dose-Response Relationship, Drug; Drug Tolerance; Injections, Spinal; Injections, Subcutaneous; Male; Morphine; Morphine Dependence; Naloxone; Narcotic Antagonists; Pain; Rats; Rats, Sprague-Dawley; Reaction Time; Substance Withdrawal Syndrome

Topics: Analgesia; Anesthesia, Spinal; Animals; History, 20th Century; Naloxone; Narcotic Antagonists; Narcotics; Pain; Rats; Reflex

Previous reports have shown that systemic administration of morphine can prevent the thermal hyperalgesia induced by the development of an osteosarcoma in C3H/HeJ mice after the implantation of NCTC 2472 cells. We show here that this type of hyperalgesia is also abolished by the local administration of morphine given at low doses (10 nmol), or the peripheral acting opioid receptor agonist loperamide (146 nmol). The analgesic effect of loperamide is prevented by the administration of the opioid receptor antagonist naloxone methiodide (10 mg/kg, i.p.), which is unable to cross the blood-brain barrier. These results provide evidence which supports the fact that peripheral opioids could be useful tools in the management of some types of cancer pain.

Topics: Analgesics, Opioid; Animals; Bone Neoplasms; Cell Culture Techniques; Hyperalgesia; Loperamide; Mice; Mice, Inbred C3H; Morphine; Naloxone; Narcotic Antagonists; Osteosarcoma; Pain; Quaternary Ammonium Compounds

We investigated the relationship between the antinociceptive effect of the opiate agonist loperamide at the spinal level and its inhibitory effect on calcium influx. Intrathecal administration of loperamide showed a significant antinociceptive effect in the formalin test, which was not prevented by naloxone. On the other hand, no significant effects were observed by nicardipine, an L-type specific blocker, or by BAY K8644, an L-type specific agonist, suggesting no significant role of L-type calcium channels in nociceptive signal transduction. Loperamide suppressed the calcium influx in dorsal root ganglion neurons. As the antinociceptive effect of loperamide was not affected by naloxone or other calcium channel blocking toxins, and loperamide showed a direct inhibitory effect on calcium-influx, the analgesic effect of intrathecally injected loperamide might be due to its blockade of the voltage-dependent calcium channels at the terminals of the primary afferent fibers.

Topics: 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; Analgesia; Analgesics; Animals; Calcium; Calcium Channel Agonists; Calcium Channel Blockers; Calcium Channels; Dose-Response Relationship, Drug; Drug Interactions; Extracellular Space; Fluorescent Dyes; Fura-2; Loperamide; Mice; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Posterior Horn Cells; Potassium Chloride

The authors recently demonstrated that administration of the melanocortin-4 receptor antagonist SHU9119 decreased neuropathic pain symptoms in rats with a sciatic chronic constriction injury. The authors hypothesised that there is a balance between tonic pronociceptive effects of the spinal melanocortin system and tonic antinociceptive effects of the spinal opioid system. Therefore, they investigated a possible interaction between these two systems and tested whether opioid effectiveness could be increased through modulation of the spinal melanocortin system activity.. In chronic constriction injury rats, melanocortin and opioid receptor ligands were administered through a lumbar spinal catheter, and their effects on mechanical allodynia were assessed by von Frey probing.. Naloxone (10-100 microg) dose-dependently increased allodynia (percent of maximum possible effect of -67 +/- 9%), which is in agreement with a tonic antinociceptive effect of the opioid system. SHU9119 decreased allodynia (percent of maximum possible effect of 60 +/- 13%), and this effect could be blocked by a low dose of naloxone (0.1 microg), which by itself had no effect on withdrawal thresholds. Morphine (1-10 microg) dose-dependently decreased allodynia (percent of maximum possible effect of 73 +/- 14% with the highest dose tested). When 0.5 microg SHU9119 (percent of maximum possible effect of 47 +/- 14%) was given 15 min before morphine, there was an additive antiallodynic effect of both compounds.. Together, these data confirm that there is an interaction between the spinal melanocortin and opioid systems and that combined treatment with melanocortin-4 receptor antagonists and opioids might possibly contribute to the treatment of neuropathic pain.

Topics: alpha-MSH; Analgesics, Opioid; Animals; Drug Interactions; Endorphins; Male; Melanocyte-Stimulating Hormones; Morphine; Naloxone; Narcotic Antagonists; Pain; Physical Stimulation; Rats; Rats, Wistar; Receptor, Melanocortin, Type 4; Receptors, Corticotropin; Sensory Thresholds; Spinal Cord

The acute treatment of rats and mice with a hydroalcoholic extract from the seeds of Dioclea grandiflora (EHDg) at doses of 250 and 500 mg/kg, by intraperitoneal or oral administration, produced a significant antinociceptive effect in the tail flick and hot plate tests, an effect which was inhibited by naloxone. EHDg given to mice daily for 30 days at a dose of 500 mg/kg, did not cause any observable toxic effect nor any alteration in the pattern of antinociceptive response by the tail immersion test during the course of this treatment. These results suggest that EHDg has a central antinociceptive action devoid of tolerance effect typical of opioid drugs.

Topics: Analgesics, Non-Narcotic; Animals; Brazil; Ethanol; Fabaceae; Female; Male; Mice; Models, Animal; Morphine; Naloxone; Nociceptors; Pain; Phytotherapy; Plant Extracts; Rats; Rats, Wistar; Reaction Time; Seeds

Topics: Aged; Analgesics, Opioid; Dose-Response Relationship, Drug; Drug-Related Side Effects and Adverse Reactions; Humans; Lymphoma, Non-Hodgkin; Male; Morphine; Naloxone; Narcotic Antagonists; Pain

The present study was conducted on rats with inflammation induced by subcutaneous injection of carrageenan into the left hindpaw. Intrathecal administration of oxytocin produced dose-dependent increases in the hindpaw withdrawal latency (HWL) to thermal and mechanical stimulation in rats with inflammation. The antinociceptive effect of oxytocin was blocked by intrathecal administration of atosiban, a selective oxytocin antagonist, indicating that oxytocin receptor mediates oxytocin-induced antinociception in the spinal cord. The oxytocin-induced antinociceptive effect was attenuated by intrathecal administration of the opioid antagonist naloxone, suggesting an involvement of the endogenous opioid system in oxytocin-induced antinociception in the spinal cord of rats with inflammation. Furthermore, the antinociceptive effect of oxytocin was attenuated by intrathecal injections of the mu-receptor antagonist beta-funaltrexamine and the kappa-receptor antagonist nor-binaltorphimine, but not by the delta-receptor antagonist naltrindole, illustrating that mu- and kappa-receptors, but not delta-receptor, are involved in oxytocin-induced antinociception in the spinal cord of rats with inflammation. Moreover, intrathecal administration of atosiban alone induced a hyperalgesia in rats with inflammation, indicating that endogenous oxytocin is involved in the transmission and regulation of nociceptive information in the spinal cord of rats with inflammation. The present study showed that both exogenous and endogenous oxytocin displayed antinociception in the spinal cord in rats with inflammation, and mu- and kappa-receptors were involved in oxytocin-induced antinociception.

Topics: Analgesics; Animals; Carrageenan; Hot Temperature; Inflammation; Injections, Spinal; Male; Naloxone; Naltrexone; Narcotic Antagonists; Oxytocin; Pain; Pain Measurement; Physical Stimulation; Rats; Rats, Wistar; Spinal Cord; Vasotocin

The effect of food hardness during mastication on nociceptive transmission in the spinal cord was studied by analyzing complete Freund's adjuvant (CFA) induced nocifensive behavior and Fos expression. The behavioral study showed that the shortening of the withdrawal latency following CFA injection into the hind paw was depressed after a change in the given food hardness from soft to hard. The depression of nocifensive behavior in the rats with hard food was reversed after i.v. injection of naloxone. Fos protein-like immunoreactive cells (Fos protein-LI cells) were expressed in the superficial and deep laminae of the L4-6 spinal dorsal horn after s.c. injection of CFA into the hind paw during soft food mastication. The number of Fos protein-LI cells was decreased in the rats with hard food mastication followed by soft food. This reduction of Fos protein-LI cells following change in food hardness was reversed after i.v. application of naloxone. Furthermore, the depression of Fos protein-LI cells following hard food intake was significantly inhibited after bilateral inferior alveolar nerve transection or bilateral ablation of the somatosensory cortex. These findings suggest that the change in food hardness during mastication might drive an opioid descending system through the trigeminal sensory pathway and somatosensory cortex resulting in an antinociceptive effect on chronic pain. However, IAN transection and cortical ablation did not induce 100% reversal of Fos expression, suggesting other than trigeminal sensory system may be involved in this phenomena, such as the pathway through the brainstem reticular formation.

Topics: Animals; Behavior, Animal; Cell Count; Denervation; Food; Freund's Adjuvant; Functional Laterality; Hindlimb; Male; Mandibular Nerve; Mastication; Naloxone; Narcotic Antagonists; Pain; Pain Threshold; Physical Stimulation; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Reaction Time; Somatosensory Cortex; Spinal Cord; Time Factors

Estradiol (E(2)) and/or progesterone (P) to the amygdala may influence stress-induced analgesia following predator odor, trimethylthiazoline (TMT), exposure. Ovariectomized (ovx) rats were administered subcutaneous (SC) or intra-amygdala vehicle, E(2), P, or E(2)+P. The effects on performance in a test of pain sensitivity, the tailflick task, was observed in animals that experienced an acute exposure to TMT or no odor (control) in a small chamber. Rats that were exposed to TMT had increased tailflick latencies compared to rats not exposed to TMT, this was partially attenuated by the opiate antagonist naloxone. Systemic E(2), P, or E(2)+P increased tailflick latencies compared to vehicle administration to ovx rats. Ovx rats administered E(2)+P to the amygdala had increased tailflick latencies compared to control rats. These data suggest that following exposure to predator odor, pain sensitivity in the tailflick task is decreased and that E(2) and/or P may have actions in the amygdala to produce similar anti-nociceptive effects.

Topics: Amygdala; Animals; Corticosterone; Drug Administration Routes; Drug Administration Schedule; Drug Interactions; Estrogens; Female; Naloxone; Narcotic Antagonists; Odorants; Ovariectomy; Pain; Pain Measurement; Progesterone; Rats; Rats, Long-Evans; Reaction Time; Thiazoles

Neuroimmune interactions control pain through activation of opioid receptors on sensory nerves by immune-derived opioid peptides. Here we evaluate mechanisms of intrinsic pain inhibition at different stages of Freund's adjuvant-induced inflammation of the rat paw. We use immunohistochemistry and paw pressure testing. Our data show that in early (6 h) inflammation leukocyte-derived beta-endorphin, met-enkephalin and dynorphin A activate peripheral mu-, delta- and kappa-receptors to inhibit nociception. In addition, central opioid mechanisms seem to contribute significantly to this effect. At later stages (4 days), antinociception is exclusively produced by leukocyte-derived beta-endorphin acting at peripheral mu and delta receptors. Corticotropin-releasing hormone (CRH) is an endogenous trigger of these effects at both stages. These findings indicate that peripheral opioid mechanisms of pain inhibition gain functional relevance with the chronicity of inflammation.

Topics: Animals; Corticotropin-Releasing Hormone; Dynorphins; Edema; Endorphins; Enkephalin, Methionine; Freund's Adjuvant; Hindlimb; Inflammation; Injections, Subcutaneous; Leukocytes; Male; Naloxone; Pain; Pain Threshold; Rats; Rats, Wistar; Stress, Physiological; Time Factors

Joint manipulation has long been used for pain relief. However, the underlying mechanisms for manipulation-related pain relief remain largely unexplored. The purpose of the current study was to determine which spinal neurotransmitter receptors mediate manipulation-induced antihyperalgesia. Rats were injected with capsaicin (50 microl, 0.2%) into one ankle joint and mechanical withdrawal threshold measured before and after injection. The mechanical withdrawal threshold decreases 2 h after capsaicin injection. Two hours after capsaicin injection, the following drugs were administered intrathecally: bicuculline, blocks gamma-aminobutyric acid (GABAA) receptors; naloxone, blocks opioid receptors; yohimbine blocks, alpha2-adrenergic receptors; and methysergide, blocks 5-HT(1/2) receptors. In addition, NAN-190, ketanserin, and MDL-72222 were administered to selectively block 5-HT1A, 5-HT2A, and 5-HT3 receptors, respectively. Knee joint manipulation was performed 15 min after administration of drug. The knee joint was flexed and extended to end range of extension while the tibia was simultaneously translated in an anterior to posterior direction. The treatment group received three applications of manipulation, each 3 min in duration separated by 1 min of rest. Knee joint manipulation after capsaicin injection into the ankle joint significantly increases the mechanical withdrawal threshold for 45 min after treatment. Spinal blockade of 5-HT(1/2) receptors with methysergide prevented, while blockade of alpha2-adrenergic receptors attenuated, the manipulation-induced antihyperalgesia. NAN-190 also blocked manipulation-induced antihyperalgesia suggesting that effects of methysergide are mediated by 5-HT1A receptor blockade. However, spinal blockade of opioid or GABAA receptors had no effect on manipulation induced-antihyperalgesia. Thus, the antihyperalgesia produced by joint manipulation appears to involve descending inhibitory mechanisms that utilize serotonin and noradrenaline.

Topics: Adrenergic alpha-Antagonists; Animals; Bicuculline; GABA Antagonists; Hyperalgesia; Joints; Male; Methysergide; Naloxone; Narcotic Antagonists; Pain; Pain Management; Physical Stimulation; Physical Therapy Modalities; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic; Receptors, GABA; Receptors, Opioid; Receptors, Serotonin; Serotonin Antagonists; Spinal Cord; Yohimbine

Experiments on anaesthetized male Sprague-Dawley rats were performed to study the effects of adrenocorticotropic hormone (ACTH) on pain sensitivity. Systemic administration of ACTH to animals with normal hormone production induced rapidly developing (starting at 3 min) and prolonged (30 min) increases in pain response thresholds. Blockade of opiate receptors led to suppression of the initial stage of the analgesic effect of ACTH: the response was seen only from 15 to 30 min. In animals with deficient glucocorticoid production, the duration of the analgesic action of ACTH decreased to 15 min. Analgesia was completely eliminated by the combination of suppression of glucocorticoid production and blockade of opiate receptors. The analgesic effect of ACTH was mediated by two mechanisms: 1) a rapidly-acting (from 3 to 15 min) mechanism associated with opiate receptors and not related to glucocorticoids, and 2) a delayed (from 15 to 30 min) mechanism associated with glucocorticoids but not opiate receptors.

Topics: Adrenocorticotropic Hormone; Animals; Drug Interactions; Hydrocortisone; Male; Naloxone; Naltrexone; Narcotic Antagonists; Pain; Pain Threshold; Rats; Rats, Sprague-Dawley; Time Factors

A 47-year-old woman was diagnosed with secondary progressive multiple sclerosis, and was treated with intrathecal morphine for chronic pain via a slow-release subcutaneous pump. She accidentally received a 35-ml (510 mg) bolus injection of morphine by this route, which led to status epilepticus. She was treated with continuous intravenous naloxone infusion, and with medication to control hypertension and stop the seizure activity. The outcome was excellent, and the patient returned to her neurological baseline. This report describes the complications and the successful treatment of intrathecal morphine overdose. In order to prevent these serious errors, it is vital that only care providers who are proficient with these devices perform the refilling procedure.

Topics: Analgesics, Opioid; Drug Overdose; Female; Humans; Injections, Spinal; Medication Errors; Middle Aged; Morphine; Multiple Sclerosis, Chronic Progressive; Naloxone; Narcotic Antagonists; Pain

Intraplantar formalin injection is widely used as an experimental model of tonic pain. We investigated the role of endogenous micro-opioid receptor mechanisms in formalin-induced nocifensive behavior in mice. The flinching response induced by formalin (2%, 20 microl) was studied in mice with normal (wild type, n = 8) and absent (homozygous micro-opioid receptor knockout, n = 8) micro-opioid receptor levels. The flinch responses were counted every 5 min for 60 min post-formalin injection. Lumbar spinal cord (L4, 5) was harvested 2 h post-formalin injection to examine c-Fos expression using immunohistochemistry. The effects of naloxone (5 mg/kg, sc) administered 30 min before the intraplantar formalin injection on the flinching response of wild-type mice (n = 7) were also recorded. The second-phase formalin response (10-60 min after formalin) was higher in homozygous micro-opioid receptor knockout mice compared to the wild-type mice (P < 0.01). Naloxone administration in wild-type mice before formalin injection resulted in pain behavior similar to that observed in homozygous micro-opioid receptor knockout mice (P > 0.05). The c-Fos expression induced by formalin injection in the knockout mice was not different from that observed in wild-type mice. Our results suggest that the endogenous micro-opioid system is activated by intraplantar formalin injection and exerts a tonic inhibitory effect on the pain behavior. These results suggest an important modulatory role of endogenous micro-opioid receptor mechanisms in tonic pain states.

Topics: Animals; Behavior, Animal; Formaldehyde; Immunohistochemistry; Male; Mice; Mice, Knockout; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Proto-Oncogene Proteins c-fos; Receptors, Opioid, mu; Spinal Cord

This paper describes the synthesis of new cyclic imides obtained by reaction with aminophenazone (CAS 58-15-1, 4-aminoantipyrine) and different anhydrides with further cyclization with acetic acid under reflux. Their structures were confirmed by spectral data (IR and NMR) and elemental analysis. The analgesic activity of the synthesized compounds was investigated initially with the writhing test in mice and the most promising compound, a 3,4-dichloromaleimide derivative (3), was analyzed using other models of nociception. The results indicated that compound 3 exerts potent analgesic activity in mice, being more active than some reference drugs. The analgesia caused by this compound was not reversed by naloxone in the writhing test. In the hotplate test, compound 3 did not increase the latency period of pain induced by thermal stimuli, confirming that it does not interact with opioid systems.

Topics: Acetic Acid; Aminopyrine; Analgesics, Non-Narcotic; Animals; Capsaicin; Formaldehyde; Imides; Indicators and Reagents; Male; Mice; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Peritonitis; Reaction Time; Structure-Activity Relationship

The present study investigates the involvement of opioid receptors in the antinociceptive effects of nociceptin in the spinal cord of the rat. Intrathecal administrations of 5 and 10 nmol of nociceptin significantly increase the withdraw response latencies to noxious thermal and mechanical stimulations. This nociceptin-induced antinociceptive effect is significantly attenuated by intrathecal injection of (Nphe(1))nociceptin(1-13)-NH(2), a selective antagonist of the nociceptin receptor (opioid receptor-like receptor ORL1), indicating an ORL1 receptor-mediated mechanism. This antinociceptive effect is also significantly attenuated by intrathecal injections of naloxone (a nonselective opioid receptor antagonist), naltrindole (a selective delta-opioid receptor antagonist), and beta-funaltrexamine (a selective mu-opioid receptor antagonist) in a dose-dependent manner, but not by the selective kappa-opioid receptor antagonist norbinaltorphimine. Since it is unlikely that nociceptin acts by direct binding to opioid receptors, these results suggest a possible interaction between the nociceptin/ORL1 and opioid systems in the dorsal horn of the rat spinal cord.

Topics: Animals; Endorphins; Hindlimb; Hot Temperature; Injections, Spinal; Male; Naloxone; Naltrexone; Narcotic Antagonists; Nociceptin; Nociceptors; Opioid Peptides; Pain; Pain Measurement; Peptide Fragments; Physical Stimulation; Rats; Rats, Sprague-Dawley; Spinal Cord

Pharmacological studies have implicated the anti-opioid neuropeptide FF (NPFF) in the modulation of pain transmission. Since its physiological role has not yet been fully elucidated, the present study examined whether antisense peptide nucleic acid (PNA) complementary to the NPFF precursor (proNPFF(A)) modified pain sensitivity. Mice received three intraperitoneal (i.p.) injections (10mg/kg) of antisense PNA (As-proNPFF(A)) over a period of 24h. As-proNPFF(A) treatment significantly increased the basal tail withdrawal latency in the tail-flick test. This analgesia persisted during 2 days and was completely reversed by naloxone. Thus, antisense PNAs, by decreasing anti-opioid effects, revealed a basal endogenous opioid activity. Our results evidence a physiological interplay between NPFF and opioid systems and further support the use of PNA as effective antisense agents, for studying gene function in vivo.

Topics: Animals; Chromatography, High Pressure Liquid; Mice; Morphine; Naloxone; Narcotic Antagonists; Narcotics; Oligonucleotides, Antisense; Oligopeptides; Pain; Peptide Nucleic Acids; Radioimmunoassay; Spinal Cord; Time Factors

Our previous studies have indicated that the thalamic nucleus submedius (Sm) is involved in modulation of nociception and plays an important role in an endogenous analgesic system (a feedback loop) consisting of spinal cord-Sm-ventrolateral orbital cortex-periaqueductal gray-spinal cord. To investigate whether opioids are involved in this antinociception pathway, the effects of microinjection of morphine and naloxone into the Sm on the nociceptive behavior (agitation) evoked in the formalin test were investigated in the awake rat using an automated movement detection system. The results indicate that a unilateral microinjection of morphine (5 micro g, 0.5 microl) into the Sm suppresses the formalin-induced agitation response, but does not influence spontaneous motor activity, and that the morphine-induced depression can be reversed by microinjection of the opioid receptor antagonist naloxone (1.0 micro g, 0.5 microl) into the same Sm site. The results suggest that opioid receptors in the Sm may be involved in the Sm-mediated depression of persistent inflammatory pain.

Topics: Afferent Pathways; Animals; Behavior, Animal; Efferent Pathways; Female; Male; Microinjections; Morphine; Naloxone; Narcotic Antagonists; Neural Inhibition; Nociceptors; Opioid Peptides; Pain; Pain Measurement; Pain Threshold; Posterior Thalamic Nuclei; Psychomotor Agitation; Rats; Rats, Sprague-Dawley; Receptors, Opioid

We showed previously that subcutaneous injection of the injury-associated peptide mediator endothelin-1 (ET-1) into the rat plantar hindpaw produces pain behavior and selective excitation of nociceptors, both through activation of ET(A) receptors likely on nociceptive terminals. The potential role of ET(B) receptor activation in these actions of ET-1-has not been examined. Therefore, in these experiments, we studied the effect of blocking or activating ET(B) receptors on ET-1-induced hindpaw flinching and excitation of nociceptors in rats. An ET(B) receptor-selective antagonist, BQ-788 (3 mm), coinjected with ET-1 (200 microm) reduced the time-to-peak of flinching and significantly enhanced the average maximal flinch frequency (MFF). In contrast, coinjection of an ET(B) receptor selective agonist, IRL-1620 (100 or 200 microm), with ET-1 reduced the average MFF and the average total number of flinches. Interestingly, this unexpected inhibitory effect of IRL-1620 was prevented by the nonselective opioid receptor antagonist naloxone (2.75 mm). To confirm these inhibitory actions, we studied the effects of IRL-1620 on ET-1-induced spike responses in single, physiologically characterized nociceptive C-fibers. IRL-1620 suppressed spike responses to ET-1 in all (n = 12) C-units, with mean and maximum response frequencies of 0.08 +/- 0.02 and 1.5 +/- 0.4 impulses/sec versus 0.32 +/- 0.07 and 4.17 +/- 0.17 impulses/sec for ET-1 alone. In additional support of the behavioral results, coinjection of naloxone (2.75 mm) completely prevented this inhibitory action of IRL-1620. These results establish that ET(B) receptor activation inhibits ET-1-induced pain behavior and nociception in a naloxone-sensitive manner and point to a previously unrecognized dual modulation of acute nociceptive signaling by ET(A) and ET(B) receptors in cutaneous tissues.

Topics: Action Potentials; Animals; Behavior, Animal; Dose-Response Relationship, Drug; Drug Antagonism; Drug Synergism; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Hindlimb; Injections, Subcutaneous; Male; Naloxone; Nerve Fibers; Nociceptors; Oligopeptides; Pain; Pain Measurement; Peptide Fragments; Piperidines; Rats; Rats, Sprague-Dawley; Reaction Time; Receptor, Endothelin B; Receptors, Endothelin

The present study was to investigate the effect of intrathecal (i.t.) injection of interleukin-1 beta (IL-1 beta) on nociception in normal and inflammatory rats. Peripheral inflammation was induced by intraplantar injection (i.pl.) of carrageenan into unilateral hind paw. The nociceptive threshold to noxious thermal stimulation was measured by the paw withdrawal latency (PWL). Intrathecal injection of IL-1 beta (10 ng, 100 ng) significantly increased PWL in normal rats, the peak occurred at 5 min and the effect lasted for 30 min. Similarly, IL-1 beta (10 ng, 100 ng, i.t.) significantly increased the PWL and lasted for more than 60 min in inflammatory rats. Both in normal and inflammatory rats, the IL-1 beta-induced antinociceptive effect was completely abolished by IL-1ra (50 ng, i.t.), and apparently attenuated by naloxone (10 microg, i.t.) or mianserin (20 microg, i.t.). These results suggest that IL-1 beta produces antinociceptive effect by binding IL-1 receptor at the spinal level, and is related to the activation of opioid and 5-HT systems.

Topics: Animals; Carrageenan; Inflammation; Injections, Spinal; Interleukin-1; Male; Mianserin; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Pain Threshold; Rats; Rats, Sprague-Dawley; Serotonin Antagonists; Time Factors

The relatively low expression levels achieved from transferred genes have limited the application of nonviral vectors for gene transfer into the spinal cord in vivo. Thus, the aim of this study was to evaluate the efficacy of electroporation-mediated pro-opiomelanocortin (POMC) gene therapy for neuropathic pain using an animal model of chronic constrictive injury (CCI). Firstly, the optimal pulse characteristics (voltage, pulse duration, number of shocks) were investigated for in vivo electroporation-mediated gene transfer into the spinal cord. The electroporation process makes use of plasmid DNA, which expresses the POMC gene. Expression levels were evaluated in this study by Western blot. We conclude that the optimal conditions for electroporation are a pulse voltage of 200 V, 75-ms duration, 925-ms interval, for five iterations. Secondly, electroporation treatment for neuropathic pain was attempted on CCI rats using plasmid DNA that expresses the POMC gene. Intrathecal administrations of the POMC vector elevated spinal beta-endorphin levels, as manifested in a significantly elevated pain threshold for the CCI limbs. This result suggests that gene therapy for neuropathic pain using this novel technique is very efficacious, and thus shows promise for further clinical trials.

Topics: Analysis of Variance; Animals; Blotting, Western; Electroporation; Genetic Therapy; Humans; Immunohistochemistry; Lumbar Vertebrae; Male; Naloxone; Narcotic Antagonists; Pain; Pain Management; Pain Measurement; Pro-Opiomelanocortin; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Spinal Cord Compression

The peptide nociceptin/orphanin FQ (N/OFQ) and its receptor ORL-1, also designated opioid receptor 4 (OP(4)) are involved in the modulation of nociception. Using OP(4)-knockout mice, we have studied their response following opioid receptor stimulation and under neuropathic conditions.In vas deferens from wild-type and OP(4)-knockout mice, DAMGO (mu/OP(3) agonist), deltorphine II (delta/OP(1) agonist) and (-)-U-50488 (kappa/OP(2) agonist) induced similar concentration-dependent inhibition of electrically-evoked contractions. Naloxone and naltrindole (delta/OP(1) antagonists) shifted the curves of DAMGO (pA(2)=8.6) and deltorphine II (pA(2)=10.2) to the right, in each group. In the hot-plate assay, N/OFQ (10 nmol per mouse, i.t.) increased baseline latencies two-fold in wild-type mice while morphine (10mg/kg, s.c.), deltorphine II (10 nmol per mouse, i.c.v.) and dynorphin A (20 nmol per mouse, i.c.v.) increased hot-plate latencies by about four- to five-fold with no difference observed between wild-type and knockout mice. Furthermore, no change was evident in the development of the neuropathic condition due to chronic constriction injury (CCI) of the sciatic nerve, after both thermal and mechanical stimulation. Altogether these results suggest that the presence of OP(4) receptor is not crucial for (1) the development of either acute or neuropathic nociceptive responses, and for (2) the regulation of full receptor-mediated responses to opioid agonists, even though compensatory mechanisms could not be excluded.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics, Non-Narcotic; Analgesics, Opioid; Animals; Dose-Response Relationship, Drug; Dynorphins; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Female; Male; Mice; Mice, Knockout; Morphine; Naloxone; Naltrexone; Narcotic Antagonists; Nociceptin; Nociceptin Receptor; Oligopeptides; Opioid Peptides; Pain; Receptors, Opioid; Time Factors; Vas Deferens

To investigate interleukin-2-induced antinociception in morphine-insensitive rats.. Paw withdrawal latencies (PWL) to noxious radiant heat were taken as the measurement of pain threshold.. Intraplantar injection of human recombinant interleukin-2 (1.5 x10(4) U) significantly increased PWL in normal rats. PWL was also markedly increased by IL-2 in 45-d-post-complete Freund's adjuvant (CFA)-treated rats, which have been proven morphine-insensitive. IL-2-induced antinociception in CFA-treated rats were significantly lower than that in normal rats. IL-2-induced antinociception was partially blocked by naloxone (1 mg/kg, ip) in normal rats but remained unchanged in CFA group.. IL-2-induced antinociception is partially mediated by mu-opioid receptors. Therapeutic applications of IL-2 may also be expanded to relieve morphine-insensitive pain.

Topics: Analgesics; Animals; Drug Tolerance; Freund's Adjuvant; Interleukin-2; Male; Morphine; Naloxone; Pain; Pain Threshold; Random Allocation; Rats; Rats, Sprague-Dawley; Receptors, Opioid, mu; Recombinant Proteins

The influence of testosterone on the postnatal development of reflex electromyographic (EMG) jaw muscle activity evoked by injection of mustard oil (MO) into the temporomandibular joint region and the later recurrence of this EMG activity after intravenous injection of naloxone, was studied in male rats. MO-evoked EMG activity in the contralateral digastric muscle and naloxone-induced recurrence of this EMG activity were fully developed in intact, 8-week-old rats. Castration at 4 weeks of age inhibited the development of the contralateral MO-evoked EMG activity, but did not influence the naloxone-induced recurrence. Contralateral MO-evoked responses were observed in 8-week-old castrated rats if they received testosterone replacement therapy beginning at 4 weeks of age. These data suggest that testosterone is required for the development of a contralateral nociceptive reflex in the digastric muscle of male rats.

Topics: Aging; Analysis of Variance; Animals; Area Under Curve; Castration; Electromyography; Functional Laterality; Jaw; Male; Masseter Muscle; Muscle, Skeletal; Mustard Plant; Naloxone; Narcotic Antagonists; Pain; Plant Extracts; Plant Oils; Rats; Reflex; Temporomandibular Joint; Testosterone; Time Factors

Tolerance to morphine analgesia was determined by daily exposing rats either to the same box or different boxes during repeated administration of formalin (2.5%, 0.4 mL/body, sc) and morphine (5 mg/kg, sc). The analgesic effect was determined daily for four consecutive days by exposing rats to either the same box or different boxes, and the process of tolerance development was assessed by a hot plate test (52.5 degrees C). The rats were divided into four groups: one group received formalin and morphine in the same context (Group FM-Same), one group in the different context (Group FM-Diff), one group received saline and morphine in the same context (Group SM-Same), two groups received formalin in the same or different contexts (Groups FS-Same or FS-Diff), and one group received saline in the same context (Group SS-Same). The response latency of Group SM-Same was decreased from Day 2 to a level similar to that of Group SS-Same on Day 4, while that of FM-Same decreased more slowly. The latency of Group FM-Diff maintained the level of Day 2 until Day 4, being significantly longer than that of FM-Same. In the Extinction Phase, all rats received formalin and saline injections in the same box they had been exposed to on Day 1. On the first day, hyperalgesia was evident in Group SM-Same alone. In the Re-test Phase, the rats underwent a second morphine injection, and showed recovery from tolerance. These results indicate that formalin-induced chronic stress pain reduces tolerance development to morphine, and the mutual influence of pain, counterirritation, between formalin and hot-plate, facilitates the effect of contextual cues by inhibiting an associative learning.

Topics: Analgesics, Opioid; Animals; Conditioning, Operant; Cues; Dose-Response Relationship, Drug; Drug Tolerance; Extinction, Psychological; Formaldehyde; Hot Temperature; Irritants; Male; Morphine; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Rats; Rats, Sprague-Dawley; Reaction Time

Self-mutilation or self-injurious behaviour is a well known behavioural disorder in humans. The proposition that this behaviour in animals is a response to chronic pain of peripheral nerve injury has been met with controversy. In the present study a pharmacological model, which produces no sensory or motor loss was used to study how autotomy is related to pain. In a group of rats autotomy was induced by amphetamine in phenoxybenzamine and reserpine treated animals. The pain tests, both phasic and tonic were then performed. The results of this study showed that a total analgesia was produced in both phasic and tonic pain tests, in animals that exhibited autotomy. Injection of naloxone in these animals prevented autotomy. A correlation between autotomy and no pain is suggested in this pharmacological model of autotomy.

Topics: Adrenergic alpha-Antagonists; Adrenergic Uptake Inhibitors; Amphetamine; Analgesia; Animals; Behavior, Animal; Central Nervous System Stimulants; Chronic Disease; Denervation; Disease Models, Animal; Male; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Phenoxybenzamine; Rats; Rats, Wistar; Reserpine; Self Mutilation

The lateral part of the ventromedial thalamus (VM l) relays nociceptive inputs from the whole body surface to the dorsolateral frontal cortex. The aim of the present study was to investigate the effects of systemic morphine on nociceptive activity evoked in VM l neurones either by thermal (48 degrees C) or by supramaximal percutaneous electrical stimuli. The noxious thermal evoked responses were depressed by 10.8 +/- 10.1%, 48.3 +/- 23.0% and 67.3 +/- 10.1%, 5 min after i.v. injections of 1.0, 1.73 and 3.0 mg/kg of morphine, respectively. Moreover, strong depressive effects on the Adelta- and C-fibre responses were already present 5 min after the injection. The responses were significantly reduced by 7.2 +/- 5.9%, 32.5 +/ 11.1% and 37.2 +/- 11.8% for Adelta fibres after i.v. injections of 1.0, 1.73 and 3.0 mg/kg of morphine, respectively. The corresponding values for C-fibre evoked responses were 16.3 +/- 16.2%, 57.0 +/- 12.0% and 69.0 +/- 8.2%. The dose of morphine that reduced VM l neuronal nociceptive responses by 50% (1.73 mg/kg) was around 3.5 times lower than that necessary to inhibit the responses of its spinal or medullary relays under similar experimental conditions. These results, added to the data of the literature, suggest that supraspinal effects of morphine are primarily mediated at the thalamic level. It is tempting to speculate that morphine-induced reductions of attentional or psychomotor responses related to pain may be mediated by its action on VM l.

Topics: Action Potentials; Analgesics, Opioid; Animals; Blood Pressure; Dose-Response Relationship, Drug; Electric Stimulation; Hyperalgesia; Male; Morphine; Naloxone; Narcotic Antagonists; Nerve Fibers; Nerve Fibers, Myelinated; Neural Conduction; Neural Pathways; Neurons; Nociceptors; Pain; Physical Stimulation; Prefrontal Cortex; Rats; Rats, Sprague-Dawley; Ventral Thalamic Nuclei

The present study was designed to determine whether chronic morphine treatment could influence the activity of extracellular signal regulated kinase (ERK) in the mouse brain. The single subcutaneous injection of morphine produced profound antinociception and an increase in phosphorylated-ERK (p-ERK) immunoreactivity in the pons/medulla, and these effects were blocked by a mu-opioid receptor antagonist, naloxone. The potency of antinociception induced by the second morphine injection at 24 h after the first morphine injection was similar to that by the first morphine injection. The p-ERK immunoreactivity in the pons/medulla obtained at 24 h after a single injection of morphine was not different from the control level. Repeated morphine injection once a day for 7 days resulted in a marked reduction of antinociception by morphine. The p-ERK immunoreactivity in the pons/medulla increased remarkably after 7 days repeated morphine injection. These data suggest that the sustained activation of ERK activity be associated with the development of antinociceptive tolerance to morphine in mice.

Topics: Analgesics, Opioid; Animals; Drug Administration Schedule; Drug Tolerance; Male; Mice; Mice, Inbred ICR; Mitogen-Activated Protein Kinases; Morphine; Morphine Dependence; Naloxone; Narcotic Antagonists; Neural Pathways; Neurons; Nociceptors; Pain; Pain Measurement; Pain Threshold; Receptors, Opioid, mu; Rhombencephalon; Up-Regulation

Antinociceptive and anti-inflammatory effects and acute toxicity of aqueous infusion and ethanolic maceration extracts of the aerial parts of Zhumeria majdae were studied in mice and rats. Antinociceptive activity was determined using hot-plate and writhing tests. The effect of the extracts against acute inflammation was studied by acetic acid increased vascular permeability and xylene-induced ear edema in mice. The activity of the extracts against chronic inflammation was assessed using the cotton pellet test in rats. LD50 values of the infusion and maceration extracts were 3.09 g/kg body wt., and 3.94 g/kg body wt., respectively. Phytochemical screening of the extracts indicated the presence of flavonoids and tannins. In the hot-plate test, the intraperitoneal injection of both extracts showed significant and dose-dependent antinociceptive activity in mice. Naloxone, an opioid antagonist, on pretreatment inhibited the antinociceptive activity of the extracts. The extracts exhibited antinociceptive activity against acetic acid-induced writhing, which was partially blocked by naloxone. Both extracts showed significant effect against acute inflammation induced by acetic acid in mice. In the chronic inflammation test, efficacy of the extracts was similar to that of baclofen and dexamethasone in rats. It is concluded that the aqueous infusion and ethanolic maceration extract of the aerial parts of Zhumeria majdae have antinociceptive effects and this may be mediated by opioid receptors. The extracts also showed anti-inflammatory effects against acute and chronic inflammation.

Topics: Acetic Acid; Analgesics; Analgesics, Opioid; Animals; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Chromatography, High Pressure Liquid; Dexamethasone; Diclofenac; Edema; Female; Inflammation; Lamiaceae; Lethal Dose 50; Male; Mice; Morphine; Naloxone; Narcotic Antagonists; Pain; Phytotherapy; Plant Extracts; Rats; Rats, Wistar; Spectrum Analysis; Toxicity Tests, Acute; Xylenes

Previous research has revealed an antinociceptive (analgesic) effect of interleukin-2 (IL-2) in central and peripheral nervous systems. Unfortunately IL-2 is very short-lived in vivo, so it is impractical to apply IL-2 for analgesia in clinic. This study was performed to evaluate the effect of intrathecal delivery of human IL-2 gene on rat chronic neuropathic pain induced by chronic constriction injury of the sciatic nerve. Human IL-2 cDNA was cloned into pcDNA3 containing a cytomegalovirus promoter. The paw-withdrawal latency induced by radiant heat was used to measure the pain threshold. The results showed that recombinant human IL-2 had a dose-dependent antinociceptive effect, but that this only lasted for 10-25 min. The pcDNA3-IL-2 or pcDNA3-IL-2/lipofectamine complex in contrast also showed dose-dependent antinociceptive effects, but these reached a peak at day 2-3 and were maintained for up to 6 days. Liposome-mediated pcDNA3-IL-2 produced a more powerful antinociceptive effect than pcDNA3-IL-2 alone. The paw-withdrawal latencies were not affected by control treatments such as vehicle, lipofectamine, pcDNA3, or pcDNA3-lipofectamine. In the experimental groups, human IL-2 mRNA was detected by reverse transcription-polymerase chain reaction in the lumbar spinal pia mater, dorsal root ganglion, sciatic nerve, and spinal dorsal horn, but not in gastrocnemius muscle. The expressed IL-2 profile detected by western blot coincided with its mRNA profile except it was present in the spinal dorsal horn at a higher level. Furthermore, human IL-2 assayed by enzyme-linked immunosorbent assay in cerebrospinal fluid could still be detected at day 6, but lower than day 3. The antinociceptive effect of pcDNA3-IL-2 could be blocked by naloxone, showing some relationship of the antinociceptive effect produced by IL-2 gene to the opioid receptors. It is hoped that the new delivery approach of a single intrathecal injection of the IL-2 gene described here may be of some practical use as a part of a gene therapy for treating neuropathic pain.

Topics: Animals; Cation Exchange Resins; Chronic Disease; COS Cells; Disease Models, Animal; DNA, Complementary; Dose-Response Relationship, Drug; Genetic Therapy; Humans; Injections, Spinal; Interleukin-2; Ligation; Lipids; Liposomes; Male; Naloxone; Narcotic Antagonists; Organ Specificity; Pain; Pain Management; Pain Measurement; Rats; Rats, Sprague-Dawley; Recombinant Proteins; RNA, Messenger; Sciatic Neuropathy; Signal Transduction; Tissue Distribution; Transfection

The effect of an experimental neuropathy on the viscero-somatic inhibition was studied in lightly anesthetized rats. In controls, colo-rectal distension at noxious intensities produced a multisegmental prolongation of the withdrawal response induced by noxious stimulation of the skin. In rats with a spinal nerve-ligation induced neuropathy this viscero-somatic inhibition was significantly reduced within the neuropathic segment (the hindlimb) but not outside of it (the tail). Naloxone, an opioid antagonist, attenuated this viscero-somatic inhibition in controls and it did not restore the inhibition in neuropathic rats. The results indicate that somatic neuropathy produces a segmental attenuation of viscero-somatic inhibition and this attenuation cannot be explained by a nerve injury-induced release of endogenous opioids. The decreased inhibition of somatic signals may contribute to the hypersensitivity observed in neuropathic conditions.

Topics: Animals; Colon; Hot Temperature; Hyperalgesia; Male; Naloxone; Narcotic Antagonists; Neural Inhibition; Neurons, Afferent; Nociceptors; Pain; Pain Measurement; Pain Threshold; Peripheral Nervous System Diseases; Physical Stimulation; Rats; Rats, Wistar; Reaction Time; Reflex, Abnormal; Skin; Spinal Cord; Spinal Nerves; Visceral Afferents

The extra-hypothalamic actions of corticotropin-releasing hormone (CRH) have been accorded an important role in coordinating responses to stressors and contributing to the consequences of drug abuse. Recent proposals suggest that CRH actions in the bed nucleus of the stria terminalis coordinate responses to tonic/unpredictable stressors whereas these actions in the central nucleus of the amygdala coordinate responses to phasic/predictable stressors. We used in situ hybridization histochemistry and site-specific microinjections of a CRH receptor antagonist to study the role of CRH in opiate withdrawal. Rats undergoing opiate withdrawal displayed clear behavioral and autonomic changes accompanied by hyperalgesia and increased plasma corticosterone. In situ hybridization of CRH mRNA revealed significant increases in the central nucleus of the amygdala but not in the bed nucleus of the stria terminalis among rats either chronically pre-treated with morphine, given an injection of naloxone, or both (precipitated withdrawal). An increase of CRH mRNA in the paraventricular nucleus of the hypothalamus was specific to rats undergoing withdrawal. Intracerebroventricular microinjection of the CRH receptor antagonist, alpha(h)CRH(9-41), reduced the severity of opiate withdrawal. Microinjections of alpha(h)CRH(9-41) into the central nucleus of the amygdala also reduced the severity of withdrawal whereas bed nucleus of the stria terminalis microinjections of alpha(h)CRH(9-41) were without effect. These experiments provide evidence for a role of amygdala, but not bed nucleus of the stria terminalis, CRH in opiate dependence. We propose a specific role for down-regulation of opiate receptor signaling in increased expression of the CRH gene in the amygdala. Moreover, we suggest that the roles accorded to CRH in the bed nucleus of the stria terminalis versus amygdala in coordinating responses to stressors may need to be reconsidered to distinguish between external and internal/interoceptive stressors.

Topics: Amygdala; Animals; Behavior, Animal; Corticotropin-Releasing Hormone; Endocrine Glands; Humans; Injections; Injections, Intraventricular; Male; Morphine; Naloxone; Narcotic Antagonists; Narcotics; Pain; Peptide Fragments; Rats; Rats, Sprague-Dawley; RNA, Messenger; Septal Nuclei; Substance Withdrawal Syndrome

To determine if different subtypes of mu-opioid receptors were involved in antinociception induced by endomorphin-1 and endomorphin-2, the effect of pretreatment with various mu-opioid receptor antagonists beta-funaltrexamine, naloxonazine and 3-methylnaltrexone on the inhibition of the paw-withdrawal induced by endomorphin-1 and endomorphin-2 given intracerebroventricularly (i.c.v.) were studied in ddY male mice. The inhibition of the paw-withdrawal induced by i.c.v. administration of endomorphin-1, endomorphin-2 or DAMGO was completely blocked by the pretreatment with a selective mu-opioid receptor antagonist beta-funaltrexamine (40 mg/kg), indicating that the antinociception induced by all these peptides are mediated by the stimulation of mu-opioid receptors. However, naloxonazine, a mu1-opioid receptor antagonist pretreated s.c. for 24h was more effective in blocking the antinociception induced by endomorphin-2, than by endomorphin-1 or DAMGO given i.c.v. Pretreatment with a selective morphine-6 beta-glucuronide blocker 3-methylnaltrexone 0.25mg/kg given s.c. for 25 min or co-administration of 3-methylnaltrexone 2.5 ng given i.c.v. effectively attenuated the antinociception induced by endomorphin-2 given i.c.v. and co-administration of 3-methylnaltrexone shifted the dose-response curves for endomorphin-2 induced antinociception to the right by 4-fold. The administration of 3-methylnaltrexone did not affect the antinociception induced by endomorphin-1 or DAMGO given i.c.v. Our results indicate that the antinociception induced by endomorphin-2 is mediated by the stimulation of subtypes of mu-opioid receptor, which is different from that of mu-opioid receptor subtype stimulation by endomorphin-1 and DAMGO.

Topics: Analgesics; Animals; Dose-Response Relationship, Drug; Injections, Spinal; Male; Mice; Naloxone; Naltrexone; Oligopeptides; Pain; Pain Measurement; Quaternary Ammonium Compounds; Reflex; Time Factors

The N-methyl-D-aspartate (NMDA) antagonist ifenprodil and several structurally related compounds are highly selective for the NR2B-containing receptor subtype. This selectivity could provide an explanation for the reported difference of the analgesic and side-effect profile of ifenprodil-like compounds from other NMDA antagonists. In this work, we have queried if the ifenprodil-induced antinociception can be attributed to the block of NMDA receptors in the spinal cord. Ifenprodil and some other NMDA antagonists (MK-801, memantine) were tested in a model of inflammatory pain (Randall-Selitto) in rats. The in vivo NMDA antagonism was assessed in anaesthetised rats on responses of spinal dorsal horn (DH) neurones to iontophoretic NMDA and in the model of single motor unit (SMU) wind-up. Ifenprodil, MK-801 and memantine dose-dependently increased nociceptive thresholds in the Randall-Selitto model. Antinociceptive doses of the channel blockers selectively antagonised NMDA responses of DH neurones and inhibited wind-up. In contrast, antinociceptive doses of ifenprodil did not show any NMDA antagonism in electrophysiological tests. Although ifenprodil did not inhibit the SMU responses to noxious stimuli in spinalised rats, it markedly and dose-dependently inhibited nociceptive SMU responses in sham-spinalised rats. These results argue against the spinal cord being the principal site of antinociceptive action of ifenprodil; supraspinal structures seem to be involved in this effect.

Topics: Analgesics; Animals; Decerebrate State; Dizocilpine Maleate; Electric Stimulation; Excitatory Amino Acid Antagonists; Male; Memantine; Motor Activity; N-Methylaspartate; Naloxone; Narcotic Antagonists; Pain; Piperidines; Posterior Horn Cells; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Spinal Cord

1. The anti-nociceptive effects of contralateral administration of kappa-opioid agonist U-50,488H were investigated in rats. 2. Inflammation was induced by unilateral injection of 1% carrageenan into the right hindpaw. Prior to carrageenan injection, U-50,488H or saline was administered into the left hindpaw. Withdrawal responses to mechanical and heat stimulation and oedema levels were evaluated at 3, 6 and 24 h post-carrageenan injection. 3. The results showed that the inflammatory effect of 1% carrageenan peaked after 6 h with bilateral decreases in withdrawal latencies and ipsilateral oedema formation. 4. Contralateral treatment with 0.01, 0.05, 0.3 and 2 mg of U-50,488H attenuated nociceptive reflexes to mechanical stimulation on the inflamed side at 6 h. The anti-nociceptive effect of contralateral treatment was dose-dependent at 3 and 24 h. The hindpaw withdrawal latencies to heat stimulation were prolonged at 3 and 24 h after contralateral treatment with 0.3 mg U-50,488H. No effect on inflammatory oedema formation was observed, except for a decrease at 3 h after treatment with 2 mg of U-50,488H. 5. Sciatic nerve denervation on the contralateral side abolished the anti-nociceptive effects of U-50,488H (0.3 and 2 mg). In contrast, contralateral injection of 1 mg morphine prolonged paw latencies in denervated rats. 6. Both co-administration of the peripherally selective opioid antagonist naloxone methiodide with 0.3 mg U-50,488H, and alternatively, systemic administration of 0.3 mg U-50,488H reversed the anti-nociceptive effects induced by contralateral injection of U-50,488H. 7. Taken together, our findings indicate that the contralateral administration of U-50,488H attenuates nociceptive behaviour resulting from acute inflammation. The effect is mediated via peripheral neuronal kappa-opioid receptors and, possibly, spinal cord mechanisms, suggesting a new treatment approach for acute inflammatory conditions.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Acute Disease; Analgesics, Opioid; Animals; Behavior, Animal; Denervation; Hindlimb; Hot Temperature; Inflammation; Male; Naloxone; Pain; Pain Measurement; Physical Stimulation; Quaternary Ammonium Compounds; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa; Sciatic Nerve

Our previous findings have indicated that the ventrolateral orbital cortex (VLO) may be involved in modulation of nociception and plays an important role as a higher center of an endogenous analgesic system (a feedback loop) consisting of spinal cord-nucleus submedius (Sm)-VLO-periaqueductal gray (PAG)-spinal cord. To further investigate the neurotransmitter mechanism involved in this nociceptive modulatory pathway, we tested the effects of microinjection of morphine (5 microg, 0.5 microl) into VLO on the tail flick (TF) reflex. The results show that a unilateral microinjection of morphine into VLO dose-dependently suppresses the TF reflex. Furthermore, 6 min after termination of morphine injection, microinjection of opioid receptor antagonist naloxone (1.5 microg, 0.5 microl) into the same VLO site reverses this morphine-evoked inhibition of TF reflex. These results suggest that morphine application to the VLO may directly or indirectly activate VLO neurons projecting to the PAG through the opioid receptor mediation leading to activation of the brainstem descending inhibitory system and depression of the nociceptive inputs at the spinal cord level.

Topics: Analgesics, Opioid; Animals; Drug Interactions; Female; Male; Morphine; Naloxone; Narcotic Antagonists; Neural Pathways; Nociceptors; Pain; Pain Measurement; Prefrontal Cortex; Rats; Rats, Sprague-Dawley; Receptors, Opioid; Reflex

Recent studies suggest that opioids can produce analgesia through peripheral mechanisms following inflammation of peripheral tissue. This study examined whether opioids administered prior to inflammation can produce antinociception by peripheral mechanisms in a model of visceral pain. Mice were injected intraperitoneally (i.p.) with 1% acetic acid to evoke abdominal writhing, a standard model of visceral pain. The number of writhes that occurred during 30 min after acetic acid were determined. Intraperitoneal injection of morphine sulfate (60, 90, 100 or 120 microg/0.3 ml) or the peripherally acting opioid loperamide (0.12, 0.36, 1.2 or 3.6 mg/0.3 ml) given 5 min after acetic acid decreased writhing in a dose-dependent fashion. Morphine (100 microg) produced an 70% attenuation in the number of writhes while loperamide (1.2 mg) decreased writhing by 56%. These antinociceptive effects were blocked by pretreatment with the opioid receptor antagonists naloxone (10 mg/kg) and its quarternary version naloxone methiodide (10 mg/kg). To determine whether opioids produced preemptive antinociception via peripheral mechanisms, mice received i.p. injections of morphine (1, 5, and 10 microg/0.3 ml) or vehicle 5 min before acetic acid. Doses of 5 and 10 microg morphine inhibited the number of writhes by 51 and 93%, respectively. The highest dose (10 microg) was ineffective when given intravenously 5 min before acetic acid, suggesting that antinociception following i.p. administration was acting via peripheral mechanisms. These data demonstrate that low doses of opioids, given before or after acetic acid, produce visceral antinociception through peripheral mechanisms. This may be clinically relevant for the management of postoperative abdominal pain.

Topics: Acetic Acid; Analgesics, Opioid; Animals; Dose-Response Relationship, Drug; Female; Mice; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Peripheral Nervous System

The study examined the validity of oral fentanyl self-administration (FSA) as a measure of the chronic nociceptive pain that develops in rats with adjuvant arthritis independently of acute noxious challenges. Arthritic rats self-administered more of a 0.008 mg/ml fentanyl solution (up to 3.4 g/rat per day) than non-arthritic controls (0.5 g/rat per day) and did so with a biphasic time course that reached peak during weeks 3 and 4 after inoculation with Mycobacterium butyricum. The time course paralleled both the disease process and the chronic pain. Continuous infusion of dexamethasone during weeks 3 and 4 via subcutaneous osmotic pumps at 0.0025-0.04 mg/rat per day disrupted the arthritic disease and decreased FSA to a level (i.e. by 65%) similar to that observed in non-arthritic rats. Continuous naloxone (2.5 mg/rat per day) decreased FSA (by 55%) in arthritic but not in non-arthritic animals. Continuous, subcutaneous infusion of fentanyl also decreased arthritic FSA in a manner that varied with dose at 0.04-0.16 mg/rat per day doses, but leveled off at 47% of controls with 0.31 mg/rat per day. The effects of continuous fentanyl on arthritic FSA occurred only with those doses and dose-dependent dynamics with which fentanyl also induced dependence in non-arthritic rats. The findings indicate that pain, rather than the rewarding or dependence-inducing action of fentanyl mediates FSA in arthritic rats. Paralleling patient-controlled analgesic drug intake, FSA offers a specific measure allowing the dynamic effects of neurobiological agents to be studied in this unique animal model of persistent nociceptive pain.

Topics: Analgesics, Opioid; Animals; Arthritis; Behavior, Animal; Chronic Disease; Fentanyl; Male; Naloxone; Narcotic Antagonists; Narcotics; Nociceptors; Pain; Pain Measurement; Palliative Care; Rats; Rats, Inbred Lew; Reference Values; Self Administration; Substance-Related Disorders; Time Factors

The neuropeptide alpha CGRP (calcitonin gene-related peptide) is involved in the complex process of pain signaling, but the precise contribution of alpha CGRP remains unclear. Here we show that mice lacking alpha CGRP display an attenuated response to chemical pain and inflammation. Furthermore, alpha CGRP(-/-) mice do not show changes in heroin self-administration or morphine tolerance, but display a marked decrease in morphine withdrawal signs, suggesting an important contribution of alpha CGRP to opiate withdrawal.

Topics: Acetic Acid; Analgesics, Opioid; Animals; Calcitonin Gene-Related Peptide; Capsaicin; Carrageenan; Fixatives; Formaldehyde; Ganglionic Stimulants; Inflammation; Magnesium Sulfate; Mice; Mice, Transgenic; Morphine; Naloxone; Narcotic Antagonists; Nicotine; Opioid-Related Disorders; Pain; Substance Withdrawal Syndrome

1. RB 101, a complete inhibitor of enkephalin-catabolizing enzymes, has been previously shown to produce antinociception in normal rats after systemic administration. Moreover, its coadministration with a cholecystokinin-B (CCK-B) receptor antagonist has been shown to strongly enhance its antinociceptive effect in normal rats. In this work, we determined whether RB 101 was able to reduce hyperalgesia and allodynia in diabetic rats, a model of neuropathic pain. The type of opioid receptors (mu or delta) involved was determined using naloxone and naltrindole, respectively, and the interactions between endogenous enkephalins and CCK on nociception control was investigated using coadministration of RB 101 and the CCK-B receptor antagonist CI-988. 2. RB 101 suppressed mechanical hyperalgesia (paw pressure-induced vocalization test), partially alleviated mechanical allodynia (von Frey hair test), and was ineffective in thermal allodynia (tail immersion test). The analgesic effect was completely cancelled by naloxone or naltrindole, suggesting that is requires the availability of mu- and/or delta-opioid receptors. 3. The combination of an inactive dose of CI-988 with the lowest effective dose of RB 101 resulted in a stronger increase in the vocalization threshold comparatively to RB 101 alone. 4. The present study demonstrates that the antinociception generated by RB 101 induced by elevation of extracellular levels of endogenous enkephalins, can be extended to neuropathic pain in diabetic rats and that blockade of CCK-B receptors potentiated antinociceptive effects elicited by RB 101.

Topics: Aminopeptidases; Animals; Diabetes Mellitus, Experimental; Disulfides; Drug Synergism; Indoles; Male; Meglumine; Naloxone; Naltrexone; Neprilysin; Pain; Pain Measurement; Phenylalanine; Pressure; Rats; Rats, Sprague-Dawley; Receptor, Cholecystokinin B; Receptors, Cholecystokinin; Time Factors; Vocalization, Animal; Weight Loss

Electrical stimulation of the secondary somatosensory cortex (S-II), which is clinically effective in some chronic pain patients, produces a weak antinociception by itself and also strongly facilitates the antinociceptive effect of the neuronal NO synthase inhibitor 7-nitro-indazole in laboratory animals (rats). The present study thus investigated the mechanisms by which S-II stimulation facilitates the 7-nitro-indazole-induced antinociception. S-II stimulation in combination with 7-nitro-indazole at a subeffective dose, 5 mg/kg, synergistically reduced the number of cells expressing c-Fos in response to intraplantar injection of formalin in the superficial regions (laminae I and II) of the L4 and L5 spinal dorsal horn in conscious rats, although each had no significant effect. A similar synergism produced by S-II stimulation and 7-nitro-indazole was also confirmed in both the first and second phases in the formalin-induced behavioral nociception test. The synergistic antinociception exerted by S-II stimulation in combination with 7-nitro-indazole was resistant to systemic administration of the opioid antagonist naloxone or the alpha-adrenoceptor antagonist phentolamine. In contrast, intrathecally administered methysergide, a serotonin receptor antagonist, at 20 microg/rat, abolished the first-phase, but not the second-phase, antinociception following S-II stimulation in combination with 7-nitro-indazole. These findings suggest that S-II stimulation, in combination with inhibition of neuronal NO synthase, can suppress spinal nociceptive neurons, at least in part through the descending spinal serotonergic pathway, resulting in antinociception.

Topics: Adrenergic alpha-Antagonists; Animals; Electric Stimulation; Enzyme Inhibitors; Indazoles; Injections, Intraperitoneal; Injections, Spinal; Male; Methysergide; Naloxone; Narcotic Antagonists; Neural Inhibition; Neurons; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Nociceptors; Pain; Pain Measurement; Phentolamine; Proto-Oncogene Proteins c-fos; Rats; Rats, Wistar; Serotonin Antagonists; Somatosensory Cortex; Spinal Cord

An enzymatically stable analog of YGGFMKKKFMRFamide (YFa), a chimeric peptide of metenkephalin and FMRFa, was synthesised. The antinociceptive effects of intracerebroventricular injections of this analog-[D-Ala2)]YAGFMKKKFMRFamide ([D-Ala2]YFa)-was then investigated using the mouse radiant-heat tail-flick test. [D-Ala2]YFa produced modest to good antinociception at 1, 2, and 5 microg/mouse (0.64, 1.28, and 3.22 nmol, respectively). This antinociceptive effect was completely reversed by the opioid receptor antagonist naloxone (1.5 microg/mouse: 4.12 nmol, intracerebroventricular [i.c.v.]), administered 5 min prior. Pretreatment (5 min) with either neuropeptides FF (1 microg/mouse: 0.92 nmol, i.c.v.) or FMRFa (1 microg/mouse: 1.69 nmol, i.c.v.) significantly attenuated the antinociceptive effects induced by [D-Ala2]YFa (1 microg/mouse, i.c.v.). Intracerebroventricular administration of [D-Ala2]YFa at 1 microg/mouse dose with morphine (2 microg/mouse: 5.86 nmol, i.c.v.) produced an additive antinociceptive effect, suggesting that [D-Ala2]YFa may have a modulatory effect on opioid (morphine) analgesia. These results provide further support for a role of such amphiactive sequences in antinociception and its modulation.

Topics: Analgesics, Opioid; Animals; Brain; Drug Interactions; Enkephalin, Methionine; FMRFamide; Injections, Intraventricular; Mice; Mice, Inbred Strains; Morphine; Naloxone; Narcotic Antagonists; Neurons; Nociceptors; Oligopeptides; Pain; Pain Measurement; Recombinant Fusion Proteins

This study was performed to examine the antinociceptive effect after microinjection of arginine vasopressin (AVP) into the central nucleus of amygdala. We recorded the jaw opening reflex in freely moving rats. After injection of 0.2 or 0.4 nM AVP into the central nucleus of amygdala, digastric electromyogram (dEMG) was suppressed to 55 +/- 5% or 88 +/- 3 of the control. Artificial cerebrospinal fluid had no effects on the basal dEMG activity. V(1) vasopressin receptor antagonist blocked the suppressive effect produced by microinjection of 0.4 nM AVP from 53 +/- 3 to 81 +/- 3% of the control. However, V(2) vasopressin receptor antagonist did not affect changes in dEMG. We observed dEMG activity after intracerebroventricular injection of naloxone, methysergide, or phentolamine. All drugs did not affect the basal dEMG activity at our dose. Naloxone blocked the suppressive effect of 0.4 nM AVP from 42 +/- 4 to 79 +/- 5% of the control. Methysergide also inhibited the suppression of dEMG from 44 +/- 3 to 83 +/- 6% of the control. However, phentolamine, an alpha-adrenergic receptor antagonist, did not affect the suppression of dEMG. These results indicate AVP in the central nucleus of amygdala has potent analgesic effects in the orofacial area. The antinociception of central AVP seems to be mediated by opioid and serotonergic pathways.

Topics: Adrenergic alpha-Antagonists; Amygdala; Animals; Arginine Vasopressin; Dose-Response Relationship, Drug; Electric Stimulation; Electromyography; Male; Masticatory Muscles; Methysergide; Microinjections; Movement; Muscle Contraction; Naloxone; Narcotic Antagonists; Neurons; Nociceptors; Pain; Pain Measurement; Phentolamine; Rats; Rats, Sprague-Dawley; Reflex; Serotonin Antagonists

Opioids occupy a position of unsurpassed clinical utility in the treatment of pain of many etiologies. However, recent reports in laboratory animals and humans have documented the occurrence of hyperalgesia when the administration of opioids is abruptly tapered or discontinued, a condition known as opioid-induced hyperalgesia (OIH). In these studies we documented that rats administered morphine (40 mg. kg(-1). day(-1) for 6 days) via subcutaneous osmotic minipumps demonstrated thermal hyperalgesia and mechanical allodynia for several days after the cessation of morphine administration. Additional experiments using a rat model of incisional pain showed that that attributable to OIH were additive with the hyperalgesia and allodynia that resulted from incision. In our final experiments we observed that if naloxone is administered chronically before incision then discontinued (20 mg. kg(-1). day(-1) for 6 days), the hyperalgesia and allodynia that result from hind paw incision was markedly reduced. In contrast, naloxone 1 mg/kg administered acutely after hind paw incision increased hyperalgesia and allodynia. We conclude that the chronic administration of exogenous opioid receptor agonists and antagonists before incision can alter the hyperalgesia and allodynia observed in this pain model, perhaps by altering intrinsic opioidergic systems involved in setting thermal and mechanical nociceptive thresholds.. The chronic administration of opioids followed by abrupt cessation can lead to a state of hyperalgesia. In these studies we demonstrate that the hyperalgesia from opioid cessation and from hind paw incision are additive in rats. We suggest that failure to take into consideration preoperative opioid use can lead to excessive postoperative pain.

Topics: Analgesics, Opioid; Animals; Drug Implants; Hot Temperature; Hyperalgesia; Male; Morphine; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Physical Stimulation; Rats; Rats, Sprague-Dawley; Substance Withdrawal Syndrome

We determined the sites of the antinociceptive action of morphine in the experimental model of cyclophosphamide induced cystitis and investigated the afferent nerve fibers involved in nociception transmission originating from the bladder.. Cyclophosphamide (200 mg./kg.) given intraperitoneally was used to induce cystitis in male rats and their behavior was observed and scored. The effect of 2 mg./kg. systemic morphine given intravenously on cyclophosphamide induced behavioral modifications was tested when administered alone and after 100 microg. naloxone per rat given intrathecally at the L1 to L2 or L6 to S1 level. The spinal antinociceptive effect of morphine was also tested when administered intrathecally alone at 10, 100 and 200 microg. per rat at L1 to L2, alone at 100 microg. per rat at L1 to L2 or L6 to S1, alone at 100 microg. per rat at L1 to L2 and L6 to S1 simultaneously, alone at 200 microg. per rat at L1 to L2 and after 100 microg. naloxone per rat given intrathecally at L6 to S1 at 100 microg. per rat at L1 to L2.. Cyclophosphamide induced marked modifications in the behavior of the rats, including a decreased breathing rate, eye closing and specific postures. Morphine given intravenously reversed these behavioral disorders and this reversal was completely prevented by pretreatment with intrathecal naloxone. A dose of 100 microg. per rat given intrathecally also reversed these behavioral disorders by about 25% at the L1 to L2 and L6 to S1 levels. In addition, a dose of 100 microg. morphine per rat administered intrathecally and simultaneously at L1 to L2 and L6 to S1 produced an effect equal to the sum of those observed when administered separately, that is about 50%, whereas morphine at an intrathecal dose of 200 microg. at L1 to L2 produced the same effect as 100 microg. given intrathecally at the same level or at L6 to S1 (25%). Also, 100 microg. naloxone per rat administered intrathecally at L6 to S1 prevented the effect of 100 microg. morphine at L1 to L2.. These results confirm the previously reported antinociceptive effect of systemic morphine in this model of cyclophosphamide cystitis, suggest that this antinociceptive action is completely located at the spinal site and most importantly demonstrate by the pharmacological approach and behavioral analysis that nociceptive sensations originating from the bladder are conveyed by hypogastric and pelvic nerves in this cyclophosphamide cystitis model in the conscious rat.

Topics: Animals; Consciousness; Cyclophosphamide; Cystitis; Disease Models, Animal; Drug Interactions; Hypogastric Plexus; Injections, Intravenous; Injections, Spinal; Male; Morphine; Naloxone; Nerve Fibers; Nociceptors; Pain; Pain Measurement; Peripheral Nerves; Probability; Rats; Rats, Sprague-Dawley; Sensitivity and Specificity; Urinary Bladder

The present study was undertaken to reveal spatio-temporal changes in the distribution of Fos-like immunoreactive (-IR) neurons in the parabrachial nucleus (PBN), one of the important relay nuclei for processing autonomic and somatosensory information from the oro-facial regions, following the induction of experimental tooth movement in rat upper molars. The experimental tooth movement was induced by the insertion of elastic rubber between the first and second upper molars. In normal animals, the PBN contained a smaller number of Fos-IR neurons. Following experimental tooth movement, the Fos-IR neurons increased in number significantly on both the ipsilateral and contralateral PBN, reaching a maximum at 4 h (about 10 times that of normal animals), and then decreased gradually. However, a significant number of Fos-IR neurons remained at 24 h post-operation. Remarkable side-by-side differences in the number of Fos-IR neurons were recognized at 1 to 4 h following the experimental tooth movement. Their number returned to normal (basal) levels at 5 days post. All subnuclei of PBN showed similar temporal changes in the number of Fos-IR neurons, this being particularly apparent in lateral PBN. Administrations of morphine (3 and 10 mg/kg, i.p.) drastically reduced the induction of Fos-IR neurons in all subnuclei of both the ipsilateral and contralateral PBN in a dose-dependent manner, and its effect was antagonized by pretreatment with naloxone (2 mg/kg, i.p.). The reduction of Fos-IR neurons by morphine pretreatment suggests that the appearance of Fos-IR neurons in the PBN may be partly due to the noxious stimulation and/or stress arising from tooth movement. The bilateral expression of Fos-IR neurons in the PBN indicates that the experimental tooth movement causes the activation of PBN neurons for the processing of somatosensory as well as autonomic information. The prolonged expression of Fos-IR neurons in all the subnuclei of bilateral PBN reflects clinical features of the transient discomfort and/or abnormal sensations, which many patients often complain about during orthodontic treatment.

Topics: Afferent Pathways; Analgesics, Opioid; Animals; Cell Count; Functional Laterality; Immunohistochemistry; Male; Molar; Morphine; Naloxone; Narcotic Antagonists; Neurons; Nociceptors; Pain; Physical Stimulation; Pons; Proto-Oncogene Proteins c-fos; Rats; Rats, Wistar; Time Factors; Trigeminal Nerve

Spasm of the sphincter of Oddi is a well-recognized effect of the narcotic class of drugs. Although it is usually clinically silent, such spasm occasionally causes debilitating pain that may be mistaken for more serious disorders. We present the case of a patient who had undergone cholecystectomy previously, but in whom morphine given in the Emergency Department precipitated pain consistent with biliary colic; the pain resolved promptly after administration of naloxone. This entity may considered in the differential diagnosis of acute onset of colicky abdominal pain in the patient given narcotics.

Topics: Adult; Analgesics, Opioid; Biliary Tract Diseases; Cholecystectomy; Colic; Emergency Service, Hospital; Female; Humans; Morphine; Naloxone; Narcotic Antagonists; Pain; Postoperative Period; Spasm; Sphincter of Oddi

The effect of some B vitamins in chemical and thermal models of nociception in mice was investigated. The association thiamine/pyridoxine/cyanocobalamin (TPC, 20-200 mg/kg, i.p. or per os), thiamine, pyridoxine (50-200 mg/kg, i.p.) or riboflavin (3-100 mg/kg, i.p) induced an antinociceptive effect, not changed by naloxone (10 mg/kg, i.p.), in the acetic acid writhing model. Treatment for 7 days with thiamine/pyridoxine/cyanocobalamin (100 or 200 mg/kg, i.p.), thiamine (50 or 100 mg/kg) or pyridoxine (50 or 100 mg/kg) or acute treatment with riboflavin (6 or 12 mg/kg, i.p) inhibited the nociceptive response induced by formaldehyde. The B vitamins did not inhibit the nociceptive response in the hot-plate model. Both 7-day thiamine/pyridoxine/cyanocobalamin (100 mg/kg, i.p.) or acute riboflavin (25 or 50 mg/kg, i.p.) treatment partially reduced formaldehyde-induced hindpaw oedema. The B vitamins antinociceptive effect may involve inhibition of the synthesis and/or action of inflammatory mediators since it was not observed in the hot-plate model, was not reversed by naloxone, only the second phase of the formaldehyde-induced nociceptive response was inhibited, and formaldehyde-induced hindpaw oedema was reduced.

Topics: Acetic Acid; Animals; Constriction; Disease Models, Animal; Dose-Response Relationship, Drug; Edema; Formaldehyde; Hindlimb; Injections, Intraperitoneal; Injections, Subcutaneous; Male; Mice; Motor Activity; Naloxone; Nociceptors; Pain; Pain Measurement; Pyridoxine; Riboflavin; Thiamine; Vitamin B 12; Vitamin B Complex

In the present study, the effects of GABA (gamma-aminobutyric acid) receptor agonists and antagonists on hyperalgesia induced by sciatic nerve ligation was investigated in mice. The response to morphine or GABA receptor agonists was examined 14 days after unilateral nerve ligation by hot-plate test. Intraperitoneal injection of different doses of morphine (3, 6 and 9 mg/kg), muscimol (0.5, 1 and 2 mg/kg) or baclofen (1, 2.5 and 5 mg/kg) induced a dose-related antinociception in both intact and ligated mice. The response of morphine but not that of muscimol or baclofen, in nerve-ligated mice was significantly less than that induced in the intact animals. The responses induced by muscimol or baclofen in nerve-ligated animals, were reduced by bicuculline or CGP35348 [P-(3-aminopropyl)-P-diethoxymethyl-phosphinic acid], respectively. However, morphine in combination with muscimol (2 mg/kg) tends to induce higher response; the combination of the GABA receptor agonists with morphine did not show potentiation, but additive effect. The opioid receptor antagonist naloxone reduced the response induced by muscimol in nerve-ligated animals. It was concluded that although ligation of the sciatic nerve clearly reduced the analgesic effect of morphine and not that of the GABA agonists, the results nevertheless indicated that morphine and the GABA(A) agonist shared the same mechanism of action.

Topics: Animals; Baclofen; Bicuculline; Dose-Response Relationship, Drug; Drug Interactions; GABA Agonists; GABA Antagonists; Ligation; Male; Mice; Mice, Inbred Strains; Morphine; Muscimol; Naloxone; Organophosphorus Compounds; Pain; Pain Measurement; Sciatic Nerve

Two highly selective mu-opioid receptor agonists, endomorphin-1 and endomorphin-2, have been identified and postulated to be endogenous ligands for mu-opioid receptors. Intrathecal (i.t.) administration of endomorphin-1 and endomorphin-2 at doses from 0.039 to 5 nmol dose-dependently produced antinociception with the paw-withdrawal test. The paw-withdrawal inhibition rapidly reached its peak at 1 min, rapidly declined and returned to the pre-injection levels in 20 min. The inhibition of the paw-withdrawal responses to endomorphin-1 and endomorphin-2 at a dose of 5 nmol observed at 1 and 5 min after injection was blocked by pretreatment with a non-selective opioid receptor antagonist naloxone (1 mg/kg, s.c.). The antinociceptive effect of endomorphin-2 was more sensitive to the mu (1)-opioid receptor antagonist, naloxonazine than that of endomorphin-1. The endomorphin-2-induced paw-withdrawal inhibition at both 1 and 5 min after injection was blocked by pretreatment with kappa-opioid receptor antagonist nor-binaltorphimine (10 mg/kg, s.c.) or the delta(2)-opioid receptor antagonist naltriben (0.6 mg/kg, s.c.) but not the delta(1)-opioid receptor antagonist 7-benzylidine naltrexone (BNTX) (0.6 mg/kg s.c.). In contrast, the paw-withdrawal inhibition induced by endomorphin-1 observed at both 1 and 5 min after injection was not blocked by naloxonazine (35 mg/kg, s.c.), nor-binaltorphimine (10 mg/kg, s.c.), naltriben (0.6 mg/kg, s.c.) or BNTX (0.6 mg/kg s.c.). The endomorphin-2-induced paw-withdrawal inhibition was blocked by the pretreatment with an antiserum against dynorphin A-(1-17) or [Met(5)]enkephalin, but not by antiserum against dynorphin B-(1-13). Pretreatment with these antisera did not affect the endomorphin-1-induced paw-withdrawal inhibition. Our results indicate that endomorphin-2 given i.t. produces its antinociceptive effects via the stimulation of mu (1)-opioid receptors (naloxonazine-sensitive site) in the spinal cord. The antinociception induced by endomophin-2 contains additional components, which are mediated by the release of dynorphin A-(1-17) and [Met(5)]enkephalin which subsequently act on kappa-opioid receptors and delta(2)-opioid receptors to produce antinociception.

Topics: Analgesics; Animals; Benzylidene Compounds; Dose-Response Relationship, Drug; Dynorphins; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, Leucine; Enkephalin, Methionine; Immune Sera; Injections, Spinal; Injections, Subcutaneous; Male; Mice; Naloxone; Naltrexone; Narcotic Antagonists; Oligopeptides; Pain; Pain Measurement; Pain Threshold; Peptide Fragments; Time Factors

To describe an adverse effect with intravenous codeine in a chid diagnosed with sickle cell anemia.. A seven-year-old boy with sickle cell anemia was admitted to the emergency department with severe pain unresponsive to high doses of oral acetaminophen; subsequently, intravenous codeine phosphate was administered. The patient immediately developed a tonic-clonic seizure, which was treated with intravenous diazepam and naloxone.. Seizures associated with the intravenous administration of codeine phosphate have not been extensively reported in the literature, and special precautions for using the parenteral route for this drug have been vague and limited. Because of the frequent need for acute pain control in children with sicke cell crisis, they may be exposed to this type of reaction when intravenous narcotics are administered. The need for clear guidelines regarding the drug's appropriate parenteral dosing and administration is essential.. Codeine phosphate-induced seizures are not common. The need for special instructions for its intravenous administration may prevent this type of reaction, especially in patients in need of acute pain control requiring intravenous narcotics.

Topics: Analgesics, Opioid; Anemia, Sickle Cell; Anticonvulsants; Child; Codeine; Diazepam; Humans; Injections, Intravenous; Male; Naloxone; Narcotic Antagonists; Pain; Seizures; Treatment Outcome

Topics: Animals; Behavior, Animal; Female; Formaldehyde; Inflammation; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Rats; Rats, Wistar; Vitamin B Complex

Here we report the involvement of nociceptin receptor in tolerance to morphine-induced antinociception and in morphine dependence. There was no different nociceptive perception and antinociceptive effects of morphine between wild-type and the nociceptin receptor knockout mice. Tolerance to morphine (10 mg/kg)-induced antinociception was developed in both wild-type and the nociceptin receptor knockout mice after administration of morphine (10 mg/kg) twice a day for 5 days. When naloxone (5 mg/kg) was administered to mice treated with morphine repeatedly on the 6th day, morphine withdrawal syndrome was observed in both wild-type and the nociceptin receptor knockout mice, which were accompanied by the elevation of cyclic AMP levels. While naloxone benzoylhydrazone (1 mg/kg), a putative antagonist for nociceptin receptor/naloxone benzoylhydrazone-sensitive sites, also induced the morphine withdrawal signs in both wild-type and the nociceptin receptor knockout mice, the jumping signs in the nociceptin receptor knockout mice were less severe than those in wild-type mice. Treatment with naloxone benzoylhydrazone in morphine-dependent wild-type mice caused a significant increase in cyclic AMP levels in the thalamus while it had no effect in the nociceptin receptor knockout mice. The analysis of opioid mu-receptor binding showed no difference between wild-type and the nociceptin receptor knockout mice. These results suggest that the nociceptin receptor/naloxone benzoylhydrazone-sensitive sites contribute to the induction of morphine withdrawal syndrome in part. Furthermore, it is demonstrated that morphine withdrawal syndrome excepting jumping can be induced by naloxone benzoylhydrazone without any changes in the cyclic AMP levels in the thalamus.

Topics: Analgesics, Opioid; Animals; Behavior, Animal; Brain; Cyclic AMP; Drug Administration Schedule; Drug Tolerance; Mice; Mice, Knockout; Morphine; Morphine Dependence; Motor Activity; Naloxone; Narcotic Antagonists; Nociceptin Receptor; Pain; Pain Measurement; Radioligand Assay; Receptors, Opioid; Substance Withdrawal Syndrome

The present study investigated the cause effect relationship between glycemic and algesic states. The hypo- and hyperglycemic conditions were induced physiologically through exercise (3 min swim at room temperature 28 degrees - 30 degrees C) and external dextrose (2 g/kg, ip) administration respectively in mice. Besides, flavone (50 mg/kg, sc) a known antinociceptive drug was chosen to study such a cause effect relationship. The anti-nociception was assessed by acetic acid assay, blood glucose measured using glucometer (Ames) and serum insulin by radioimmunoassay. The findings revealed that irrespective of the glycemic state whether hypo-, hyper, or euglycemic induced by swim stress, dextrose or flavone per se respectively, significant antinociceptive response was recorded. Pretreatment with flavone (50 mg/kg, sc) always exhibited a tendency to reverse the hyperglycemia, if any, but enhanced the antinociceptive response either after swim stress or after dextrose. These data support the contention that changes in the glycemic state in acute condition is not responsible for antinociceptive response and thereby suggesting dissociation between these two parameters. Extended studies estimating serum insulin level after the above mentioned maneuvers showed a significant rise whenever antinociceptive response was recorded irrespective of the glycemic state. It is suggested that serum insulin level, a hormonal parameter rather than the blood glucose level, which is a metabolic parameter, appears more reliable. It appears that the changes in serum insulin level produced by various treatments may have a relationship with the antinociceptive response. However, this study has the limitation that the results can apply only for acute conditions and extrapolation to clinical conditions is debatable.

Topics: Acetic Acid; Analgesics; Animals; Blood Glucose; Flavones; Flavonoids; Glucose; Hyperglycemia; Hypoglycemia; Insulin; Male; Mice; Naloxone; Narcotic Antagonists; Pain; Pain Threshold; Radioimmunoassay; Swimming

The aim of this study was to assess the possible mediation of endogenous opioids in the effects of gonadal hormones on the responses to formalin pain. We studied the effects of intracerebroventricular injection of estradiol and/or naloxone on the magnitude and time-course of the formalin-evoked behavioural and hormonal responses of intact and gonadectomized male rats. Animals were gonadectomized or left intact; on days 20 and 21 after surgery, they were intracerebroventricularly injected with 17beta-estradiol (1 microg/5 microl) or saline. On day 22, the animals received naloxone (2.5 microg/5 microl) or saline intracerebroventricularly and then, 15 min later, were subcutaneously injected with formalin (50 microl, 5%) or only pricked with a syringe needle in the dorsal hindpaw. The rats were then introduced to a testing apparatus where the formalin-induced licking, flexing and jerking of the injected limb and the other spontaneous behaviours were recorded for 60 min. At the end of the test, the animals were killed and blood was collected from the trunk. Gonadectomy and naloxone increased flexing duration independently of the other treatments. In gonadectomized rats, estrogen increased licking duration and decreased paw-jerk frequency during the first phase (0-15 min) of the formalin test. During the second phase (16-60 min), licking was increased by estrogen only in intact animals. Treatment with naloxone completely abolished all these modifications. The three measures of activity (rearing, inner and outer crossing) showed that while in sham-treated animals the gonadectomy-induced decrease in activity was completely counteracted by estrogen administration, in formalin-treated animals the gonadectomy-induced decrease was not affected by estrogen. In fact, estrogen appeared to further depress the motor activities in the formalin groups. Naloxone reversed these modifications only for outer crossing frequency, blocking the gonadectomy-induced decrease in sham-treated animals. Corticosterone plasma levels were increased by formalin only in estrogen-treated animals, independently of naloxone. In conclusion, these data indicate an important role of both male gonadal hormones and estrogen in formalin-pain responses, acting through opiate and non-opiate mechanisms.

Topics: Animals; Behavior, Animal; Corticosterone; Disinfectants; Estradiol; Formaldehyde; Hypothalamo-Hypophyseal System; Injections, Intraventricular; Male; Naloxone; Narcotic Antagonists; Orchiectomy; Pain; Pituitary-Adrenal System; Rats; Rats, Wistar; Testosterone

Trimebutine (2-dimethylamino-2-phenylbutyl 3,4,5-trimethoxybenzoate, hydrogen maleate) relieves abdominal pain in humans. In the present study, the antinociceptive action of systemic (S)-N-desmethyl trimebutine, a stereoisomer of N-monodesmethyl trimebutine, the main metabolite of trimebutine in humans, was studied in a rat model of neuropathic pain produced by chronic constriction injury to the sciatic nerve. Mechanical (vocalization threshold to hindpaw pressure) stimulus was used. Experiments were performed two weeks after surgery when the pain-related behaviour has fully developed. (S)-N-desmethyl trimebutine (1, 3, 10 mg/kg s.c.) produced dose-dependent antinociceptive effects on the nerve-injured and the contralateral hindpaw. The effect of the lowest dose (1 mg/kg s.c.) of (S)-N-desmethyl trimebutine on the nerve-injured paw was equal to that seen after a ten time stronger dose on the contralateral paw. The effect of (S)-N-desmethyl trimebutine (1 mg/kg) was not naloxone reversible. The results suggest that systemic (S)-N-desmethyl trimebutine may be useful in the treatment of some aspects of neuropathic pain.

Topics: Analgesics; Animals; Dose-Response Relationship, Drug; Hindlimb; Male; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Pain Threshold; Peripheral Nervous System Diseases; Pressure; Rats; Rats, Sprague-Dawley; Sciatic Nerve; Stereoisomerism; Trimebutine

Amikacin sulphate (30 mg kg(-1)) administered either intraperitoneally (i.p.) or subcutaneously (s.c.) produced antinociceptive effect in BALB/c mice in the acetic acid writhing test which is employed as an inflammatory pain model. The lack of difference between two routes with regard to antinociceptive potency was taken as evidence for the absence of a local effect. Amikacin sulphate-induced antinociception seems unlikely to be due to non-specific behaviour alteration, since this drug, at a dose range of 15-100 mg kg(-1)did not affect motor coordination of mice in rot-a-rod test. Morphine (1 mg kg(-1)) also caused antinociception when administered i.p. or s.c. but the effect was greater with the latter route. At the i.p. site; the concurrent use of amikacin and morphine produced more remarkable antinociception compared to their individual usages. Besides, naloxone (2 mg kg(-1)) significantly decreased antinociceptive effect of amikacin but itself also exerted antinociception. At present, we have no plausible explanation for these findings at the i.p. site.

Topics: Acetates; Amikacin; Analgesics; Animals; Disease Models, Animal; Drug Interactions; Injections, Intraperitoneal; Injections, Subcutaneous; Mice; Mice, Inbred BALB C; Morphine; Naloxone; Pain; Pain Threshold

Topics: Adult; Analgesics; Humans; Naloxone; Narcotic Antagonists; Narcotics; Pain; Respiration Disorders

Subcutaneous injection of formalin into a paw of mice caused two distinct phases of licking and biting, first phase (1-5 min) and the second phase (7-30 min) after the injection. The muscarinic antagonist atropine (0.1-10 ng, i.t.) and the M(3) receptor antagonist 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP) (0.1-20 ng, i.t.) inhibited the second phase of this response, whereas higher doses of atropine (20-100 ng, i.t.) did not cause inhibition. The M(1) muscarinic receptor antagonist pirenzepine (10-100 ng, i.t.) did not inhibit either the first or the second phase response, but a high dose of pirenzepine (1000 ng, i.t.) tended to inhibit the second phase response. On the other hand, the M(2) muscarinic receptor antagonist 11-¿(2-[(diethylamino)methyl]-1-piperidinyl¿acetyl)-5, 11-dihydro-6H-pyrido(2,3-b)(1,4)benzodiazepine-6-one (AF-DX116; 10-1000 ng, i.t.) had no effect on either the first or the second phase of response. The opioid receptor antagonist naloxone did not affect the 4-DAMP-induced anti-nociceptive response. The i.t. injection of the acetylcholinesterase inhibitor neostigmine (25 ng) significantly inhibited only the second phase. The acetylcholine (ACh) depletor hemicholinium-3 (HC-3) (1 microg, i.t.) completely abolished the 4-DAMP-induced anti-nociceptive response. The ACh content of the spinal cord was significantly increased 14 min after formalin injection. This significant increase in the ACh content was inhibited by pretreatment with 4-DAMP (10 ng, i.t.). These results suggest that endogenous ACh in the spinal cord acts as a transmitter anti-nociception, and that ACh release regulated by presynaptic M(3) muscarinic receptors in the spinal cord is involved in the second phase of nociception induced by formalin.

Topics: Acetylcholine; Animals; Atropine; Cholinergic Agents; Cholinesterase Inhibitors; Formaldehyde; Hemicholinium 3; Male; Mice; Mice, Inbred Strains; Muscarinic Antagonists; Naloxone; Narcotic Antagonists; Neostigmine; Nociceptors; Pain; Pain Measurement; Piperidines; Receptor, Muscarinic M3; Receptors, Muscarinic; Spinal Cord

In transgenic mice expressing ectopic substance P fibres in the spinal white matter, a normally innocuous mechanical stimulus induces hyperalgesia and allodynia which are reversed by substance P and N-methyl-D-aspartate receptor antagonists. This period of enhanced excitation is followed by a rebound overshoot in these animals. As previous evidence indicates opioid mechanisms in a similar rebound in normal animals, the present study was done to determine the effects of systemic administration of morphine and the opiate receptor antagonist, naloxone, on the stimulus-induced responses in the tail withdrawal reflex. Once baseline reaction times had been taken, different combinations of saline, naloxone and morphine were administered intraperitoneally to transgenic and control mice of either sex. A mechanical conditioning stimulus of 450g was then applied to the tip of the tail for 2s. This stimulus was innocuous in control mice given saline or naloxone, but provoked a nociceptive response in transgenic mice given these compounds. In control and transgenic mice, following morphine administration there was an antinociceptive effect. In control mice the subsequent mechanical stimulus had no effect. However, in transgenic mice the mechanical stimulus produced a further antinociception. Naloxone blocked the effect of morphine and the subsequent conditioning stimulus in both control and transgenic mice. The results indicate that while morphine is equally effective on the withdrawal reflex in both types of animal, in the transgenic mice morphine reveals an intrinsic, naloxone-sensitive antinociceptive mechanism. The data are interpreted to suggest that over-expression of substance P or some other factor in the spinal cord of transgenic mice is associated with the up-regulation or facilitation of an opiate-mediated intrinsic antinociceptive mechanism. This is a novel observation because the genetic manipulation in this transgenic mouse results in a transient over-expression of nerve growth factor during development that leads to the formation of ectopic primary afferent fibres in the spinal cord containing substance P. These fibres persist indefinitely after the nerve growth factor levels return to normal. Opioid mechanisms, which are likely of dorsal horn origin, do not fall under the direct influence of nerve growth factor mechanisms and therefore the intriguing possibility is raised that opioid mechanisms in the spinal cord are regulated at least in part by subst

Topics: Analgesics, Opioid; Animals; Drug Interactions; Female; Gene Expression Regulation; Male; Mice; Mice, Transgenic; Morphine; Naloxone; Narcotic Antagonists; Neurons; Nociceptors; Opioid Peptides; Pain; Pain Measurement; Reaction Time; Spinal Cord; Substance P; Up-Regulation

Previous in vitro studies showed that the degradation of dynorphin-(1-8) [dyn-(1-8)] by cerebral membrane preparations is almost completely prevented by a mixture of three peptidase inhibitors (PIs), amastatin, captopril and phosphoramidon. In the present investigations, effects of the three PIs on the anti-nociception induced by the intra-third-ventricular (i.t.v.) administration of dyn-(1-8) were examined. The inhibitory effect of dyn-(1-8) on the tail-flick response was increased more than 100-fold by the i.t.v. pretreatment of rats with the three PIs. The inhibition produced by dyn-(1-8) in rats pretreated with any combination of two PIs was significantly smaller than that in rats pretreated with three PIs, indicating that any residual single peptidase could inactivate significant amounts of dyn-(1-8). The antagonistic effectiveness of naloxone, a relatively selective mu-opioid antagonist, indicates that dyn-(1-8)-induced inhibition of tail-flick response in rats pretreated with three PIs is mediated by mu-opioid receptors. Furthermore, mu-receptor-mediated inhibition induced by dyn-(1-8) was significantly greater than that produced by [Met5]-enkephalin in rats pretreated with three PIs. The data obtained in the present investigations together with those obtained in previous studies strongly indicate that dyn-(1-8) not only has well-known kappa-agonist activity but also has high mu-agonist activity.

Topics: Analgesics, Opioid; Analysis of Variance; Angiotensin-Converting Enzyme Inhibitors; Animals; Anti-Bacterial Agents; Captopril; Drug Interactions; Dynorphins; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Glycopeptides; Injections, Intraventricular; Male; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Peptide Fragments; Peptides; Protease Inhibitors; Rats; Rats, Wistar; Receptors, Opioid, mu

Single-fiber recordings were made from the decentralized right cervical vagus nerve (hyponodosal) of the rat. A total of 56 afferent fibers that responded to gastric distension (GD) were studied: 6 fibers were stimulated by phasic balloon GD, 50 by fluid GD. All fibers gave increasing responses to increasing pressures of GD (5-60 mmHg). The effects of mu-opioid (morphine), delta-opioid (SNC80), and kappa-opioid (EMD61,753, U62,066) receptor agonists were tested on responses of afferent fibers to GD. Morphine, administered systemically over a broad dose range (10 microg to 31 mg/kg, cumulative), had no effect on either resting activity or responses of vagal afferent fibers to GD. Similarly, the delta-opioid receptor agonist SNC80 (0.05-3.2 mg/kg) did not affect resting activity or responses to GD. In contrast, cumulative intra-arterial doses of the kappa-opioid receptor agonist EMD61,753 or U62,066 dose dependently attenuated afferent fiber responses to GD. Doses producing inhibition to 50% of the control response to GD of EMD61,753 (8.0 mg/kg) and U62,066 (8.8 mg/kg) did not differ. The effect of U62,066 was moderately attenuated by a nonselective dose (4 mg/kg) of naloxone hydrochloride; the kappa-opioid receptor-selective antagonist nor-BNI (20 mg/kg) was ineffective. These results demonstrate that kappa-, but not mu- or delta-opioid receptor agonists modulate visceral sensation conveyed by vagal afferent fibers innervating the stomach. Given that kappa-opioid receptor agonists effects were only modestly antagonized by naloxone and not at all by nor-BNI, the results point to a novel site of action.

Topics: Acetamides; Analgesics; Analgesics, Opioid; Animals; Benzamides; Catheterization; Electric Stimulation; Male; Mechanoreceptors; Morphine; Naloxone; Narcotic Antagonists; Nerve Fibers; Neurons, Afferent; Pain; Piperazines; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Stomach; Vagus Nerve

We investigated the neuronal plasticity in the spinal dorsal horn and its relationship with spinal inhibitory networks using an optical-imaging method that detects neuronal excitation. High-intensity single-pulse stimulation of the dorsal root activating both A and C fibers evoked an optical response in the lamina II (the substantia gelatinosa) of the dorsal horn in transverse slices of 12- to 25-day-old rat spinal cords stained with a voltage-sensitive dye, RH-482. The optical response, reflecting the net neuronal excitation along the slice-depth, was depressed by 28% for more than 1 h after a high-frequency conditioning stimulation of A fibers in the dorsal root (3 tetani of 100 Hz for 1 s with an interval of 10 s). The depression was not induced in a perfusion solution containing an NMDA antagonist, DL-2-amino-5-phosphonovaleric acid (AP5; 30 microM). In a solution containing the inhibitory amino acid antagonists bicuculline (1 microM) and strychnine (3 microM), and also in a low Cl(-) solution, the excitation evoked by the single-pulse stimulation was enhanced after the high-frequency stimulation by 31 and 18%, respectively. The enhanced response after conditioning was depotentiated by a low-frequency stimulation of A fibers (0.2-1 Hz for 10 min). Furthermore, once the low-frequency stimulation was applied, the high-frequency conditioning could not potentiate the excitation. Inhibitory transmissions thus regulate the mode of synaptic plasticity in the lamina II most likely at afferent terminals. The high-frequency conditioning elicits a long-term depression (LTD) of synaptic efficacy under a greater activity of inhibitory amino acids, but it results in a long-term potentiation (LTP) when inhibition is reduced. The low-frequency preconditioning inhibits the potentiation induction and maintenance by the high-frequency conditioning. These mechanisms might underlie robust changes of nociception, such as hypersensitivity after injury or inflammation and pain relief after electrical or cutaneous stimulation.

Topics: 2-Amino-5-phosphonovalerate; Animals; Bicuculline; Chlorides; Conditioning, Psychological; Electric Stimulation; Electrophysiology; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; GABA Antagonists; Glycine Agents; In Vitro Techniques; Membrane Potentials; N-Methylaspartate; Naloxone; Narcotic Antagonists; Neuronal Plasticity; Optics and Photonics; Pain; Posterior Horn Cells; Potassium; Rats; Rats, Sprague-Dawley; Spinal Nerve Roots; Strychnine

The tail-flick latency (TFL) and the vocalisation test (VT) thresholds were all increased by microinjecting CCh into the dorsal periaqueductal gray (dPAG) of rats. The effects on the TFL were mimicked by dimethyl-phenylpiperazinium, and inhibited by local mecamylamine or intraperitoneal (i.p.) phenoxybenzamine. The effects on the VT were mimicked by bethanechol and inhibited by local mecamylamine, atropine or naloxone. The effects on the thresholds for motor defence reaction were inhibited by i.p. methysergide or naloxone, and prolonged by i.p. phenoxybenzamine. The effects on the threshold for vocalisation during the stimulation were blocked by i. p. methysergide and shortened by i.p. phenoxybenzamine or naloxone. No significant effect of CCh was found on open arm exploration of rats in the elevated plus maze paradigm. We conclude that the effects of CCh from the dPAG is not due to an anxiolytic effect, and depends on the activation of local cholinergic and opioid sites for the supraspinal modulation of "affective" component of pain response, and nicotinic sites for the activation of descending pain pathways.

Topics: Adrenergic alpha-Antagonists; Analgesics; Animals; Anxiety; Bethanechol; Carbachol; Cholinergic Agonists; Dimethylphenylpiperazinium Iodide; Male; Maze Learning; Methysergide; Muscarinic Agonists; Naloxone; Narcotic Antagonists; Nicotinic Agonists; Nociceptors; Pain; Pain Measurement; Periaqueductal Gray; Phenoxybenzamine; Rats; Rats, Wistar; Serotonin Antagonists; Vocalization, Animal

Inflammation or injury often lead to chronic pain states such as hyperalgesia where the perception of a normally painful stimulus is significantly exaggerated. Interleukin-1beta (IL-1beta) is a cytokine that is an important mediator of the inflammatory response. In addition, IL-1beta has been implicated in the modulation of pain transmission in both the peripheral and central nervous systems. We evaluated the spinal effect of this cytokine in the presence and absence of a peripheral carrageenan inflammation in rats since the spinal cord is a major region of the central nervous system in which nociceptive input is processed and modulated. Our results indicate that intrathecal IL-1beta has no effect on the latency of paw withdrawal in response to a noxious thermal stimuluation in normal rats. In contrast, we have observed that IL-1beta produces significant antinociception when administered intrathecally in rats with peripheral inflammation (carrageenan model). The IL-1beta effect appears to be selective as it is reversed when IL-1beta is administered in the presence of an IL-1beta neutralizing antibody. We evaluated some putative mechanisms of this IL-1beta-mediated antinociception and found it to be non-opioid-dependent. Collectively, these data indicate that intrathecal IL-1beta has no effect on the processing of thermal nociceptive information in the absence of a peripheral inflammation. Therefore, the response to acute pain remains normal in these rats. In contrast, IL-1beta is antinociceptive when applied spinally during inflammation. These results indicate that IL-1beta reduces inflammatory hyperalgesia while sparing the protective functions of acute pain. This study offers new insights into the role of IL-1beta and nociceptive processing at the level of the spinal cord and suggests that development of IL-1beta agonists may be an alternative to opiate based therapies in the treatment of inflammatory pain.

Topics: Animals; Antibodies, Blocking; Carrageenan; Dose-Response Relationship, Drug; Inflammation; Injections, Spinal; Interleukin-1; Male; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Rats; Rats, Sprague-Dawley; Time Factors

To find out if millimeter waves can decrease experimental pain response in mice using cold water tail flick test.. Male Swiss albino mice (15 mice per group) were exposed to continuous millimeter waves at a frequency of 61.22 GHz with incident power densities (IPD) ranging from 0.15 to 5.0 mW/cm2 for 15 min or sham exposed. Latency of tail withdrawal in a cold water (1 +/- 0.5 degrees C) tail flick test was measured before the exposure (baseline) and then four times after the exposure with 15 min breaks.. The mean latency of the tail flick response in mice exposed to millimeter waves was more than twice that of sham-exposed controls (p<0.05). This effect was proportional to the power of millimeter waves and completely disappeared at an IPD level of < or = 0.5 mW/cm2. Pretreatment of mice with the opioid antagonist naloxone (1 mg/kg i.p.) blocked the effect of millimeter waves.. Results suggest that the antinociceptive effect of millimeter waves is mediated through endogenous opioids.

Topics: Animals; Brain; Male; Mice; Naloxone; Pain

The present study developed a new protocol to assess shock sensitivity in rats. Male Wistar rats were subjected to footshock stimuli ranging from 0 to 1.6 mA (0.1 s) in a startle apparatus and startle responses elicited by shocks were measured. Acoustic stimuli (95, 105, or 115 dB) were dispersed within the shock series serving as a control measurement of motor performance. Results indicated that the magnitude of shock startle responses significantly increased with the shock intensity in a linear trend. Morphine (8.0 mg/kg) and buspirone (1.0, 2.5, or 5.0 mg/kg), both of which possessing analgesic effects, depressed shock startle but had no such effect on acoustic startle. The effect of morphine was readily reversed by pretreatment of naloxone (1.0 mg/kg). To investigate the neural basis underlying this response, radio-frequency lesions of various structures implicated in processing of nociceptive or aversive information were undertaken. Lesions of the ventroposterior thalamic nucleus, insular cortex, or amygdala decreased startle reactivity to electric shocks but not to acoustic stimuli. Lesions of the anterior cingulate gyrus or medial prefrontal cortex, while altered the reactivity to acoustic stimuli, had no effect on the shock-elicited startle. These results suggested that the amplitude of startle in response to electric shocks provide a quantitative measurement of shock sensitivity within an extended range of stimulus intensities. Performing this response may engage the the central nociceptive pathway.

Topics: Animals; Brain; Buspirone; Conditioning, Psychological; Dose-Response Relationship, Drug; Electroshock; Male; Morphine; Naloxone; Pain; Rats; Rats, Wistar; Reflex, Startle

The pharmacological activity of phenylacetyl-Phe-Ser-Arg-N-(2, 4-dinitrophenyl)-ethylenediamine (TKI), a tissue kallikrein specific inhibitor, was assessed using models of nociception and inflammation in mice. Injection of TKI (13.6 - 136 micromol kg(-1), i.p. or 41 - 410 micromol kg(-1), s.c.) produced a dose-related inhibition of the acetic acid-induced writhes (by 37 to 85% or 34 to 80%, respectively). The antinociceptive activity of TKI (41 micromol kg(-1), i.p.) was maximal after 30 min injection and lasted for 120 min. The effect was unaltered by pretreatment with naloxone (8.2 micromol kg(-1), s.c.) or bilateral adrenalectomy. TKI (41 and 136 micromol kg(-1), i.p.) produced a dose-related decrease of the late phase of formalin-induced nociception by 79 and 98%, respectively. At 136 micromol kg(-1), i.p., TKI also shortened the duration of paw licking in the early phase by 69%. TKI (41 and 136 micromol kg(-1), i.p.) also reduced the capsaicin-induced nociceptive response (by 51 to 79%). TKI (41 micromol kg(-1), i.p. or 410 micromol kg(-1), s.c.) reduced the oedematogenic response, from the second to the fifth hour after carrageenin injection by 36 to 30% or by 47 to 39%, respectively. Pretreatment with TKI (41 micromol kg(-1), i.p.) reduced the capsaicin-induced neurogenic inflammation in the mouse ear by 54%. It is concluded that TKI presents antinociceptive and antiinflammatory activities mediated by inhibition of kinin formation by tissue kallikrein in mice. The results also indicate that the tissue kallikrein-dependent pathway contributes to kinin generation in nociceptive and inflammatory processes in mice.

Topics: Adrenalectomy; Analgesics, Non-Narcotic; Animals; Anti-Inflammatory Agents, Non-Steroidal; Edema; Enzyme Inhibitors; Female; Inflammation; Kinins; Male; Mice; Naloxone; Oligopeptides; Pain; Peritonitis; Tissue Kallikreins

Topics: Administration, Oral; Adult; Analgesics, Opioid; Breast Neoplasms; Chemistry, Pharmaceutical; Constipation; Female; Humans; Methadone; Naloxone; Naltrexone; Narcotic Antagonists; Pain; Quaternary Ammonium Compounds

The decoction or juice of leaves of Boerhaavia diffusa L. (Nyctaginaceae) is used in Martinican folk medicine for its analgesic and anti-inflammatory properties. In the present investigation we studied the acute oral (p.o.) toxicity of a crude extract obtained from a lyophilized decoction (DE) and from the juice (JE) of fresh leaves. We observed no signs of toxicity up to the dose of 5000 mg/kg (p.o.) in mice. At the dose of 1000 mg/kg, neither extract altered sleeping time evoked by the administration of pentobarbital sodium (i.p.). The DE and JE of B. diffusa were assessed in standard rodent models of algesia and inflammation. We investigated the antinociceptive effect of DE and JE in chemical (acetic acid) and thermal (hot plate) models of hyperalgesia in mice. Dipyrone sodium (200 mg/kg), JE (1000 mg/kg) and DE at the same dose (p.o.), produced a significant inhibition of acetic acid-induced abdominal writhing in mice (100, 50 and 47% inhibition, respectively) when compared with the negative control (P<0.001). In the hot-plate test in mice, morphine and JE produced a significant increase in latency during the observation time. The DE, however, only raised the pain thresholds during the first period (30 min) of observation (P<0.05). The extracts of B. diffusa were also investigated for their anti-edematogenic effect on carrageenan-induced edema in mice. However, neither extract inhibited the paw edema induced in mice (P>0.05). In the acetic acid-induced abdominal writhing in mice, pre-treatment of the animals with naloxone (5 mg/kg, i.p.) significantly reversed the analgesic effect of morphine and JE but not that of DE. These data show that the active antinociceptive principle of B. diffusa is present mainly in the juice of fresh leaves and has a significant antinociceptive effect when assessed in these pain models. The mechanism underlying this analgesic effect of fresh leaves of B. diffusa remains unknown, but seems to be related to interaction with the opioid system.

Topics: Acetates; Analgesics, Non-Narcotic; Analgesics, Opioid; Animals; Carrageenan; Edema; Hot Temperature; Hypnotics and Sedatives; Lethal Dose 50; Male; Martinique; Mice; Morphine; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Pentobarbital; Plant Extracts; Plants, Medicinal; Reaction Time; Sleep

We examined the effects of repeated exposure to forced walking stress for 6 h once a day for 0, 6 and 9 consecutive days on formalin-induced paw licking in mice. In each observation period, stress-induced antinociception (SIA) was observed only in the late phase (from 10 to 30 min), but not in the early phase (from 0 to 10 min) of formalin-induced paw licking in mice. Moreover, it was hard to develop tolerance even by daily exposure to stress for 6 days, although SIA for 9 days decreased compared with those for 0 and 6 days. Naloxone (10 mg/kg), an opioid-receptor antagonist, was effective in reducing the SIA induced by forced walking stress for 6 days and/or 9 days, but not for 0 days. Furthermore, the experiments with selective opioid-receptor antagonists, beta-funaltrexamine (mu) naltrindol (delta), or nor-binaltorphimine (kappa) demonstrated that SIA induced by forced walking stress for 9 successive days may be mediated through opioid delta- and kappa-receptors. Finally, although SIA seemed to be a unitary phenomenon, the present results strengthened the idea that SIA is induced by exposure to forced walking stress with characteristics dependent on the duration of exposure.

Topics: Animals; Formaldehyde; Male; Mice; Naloxone; Naltrexone; Narcotic Antagonists; Pain; Pain Measurement; Receptors, Opioid; Stress, Physiological; Walking

To explore the site and mechanism of the analgesic action of melatonin, the present study was designed to evaluate the analgesic effects of intraperitoneal (i.p.) and intracerebroventricular (i.c.v. ) administration of melatonin, and to investigate the effect of i.c. v. naloxone on the analgesic effect induced by i.p. melatonin in rats. Antinociception was determined by tail-flick latency to hot water at 50 degrees C. On i.p. administration, melatonin (30, 60 and 120 mg/kg) produced the antinociceptive effect in a dose-dependent manner, with an A(50) of 72.8 mg/kg. Administered i.c.v., melatonin (0.25, 0.5 and 1 mg/kg) also resulted in dose-dependent antinociception, with an A(50) of only 0.693 mg/kg. Injected i.c.v. to rats, 10 microg of naloxone antagonized significantly the antinociceptive effect induced by i.p. melatonin. It is concluded that melatonin has an analgesic effect in rats and the central nervous system (CNS) may be the primary site for melatonin to elicit the response, and the effect of melatonin is related to the central opioid system.

Topics: Analgesics; Animals; Dose-Response Relationship, Drug; Injections, Intraperitoneal; Injections, Intraventricular; Male; Melatonin; Naloxone; Nociceptors; Pain; Rats; Rats, Sprague-Dawley

In this study we have evaluated the analgesic activity of dry latex (DL) of Calotropis procera. A single oral dose of DL ranging from 165 to 830 mg/kg produced a significant dose dependent analgesic effect against acetic acid induced writhings. The effect of DL at a dose of 415 mg/kg was more pronounced as compared to a 100 mg/kg oral dose of aspirin. On the other hand DL (830 mg/kg) produced marginal analgesia in a tail-flick model which was comparable to aspirin. The analgesic effect of DL was delayed by 1 h by naloxone at a dose of 0. 5 mg/kg, i.p., which completely blocked the analgesic effect of morphine (10 mg/kg, i.p.). However, the effect of aspirin was not blocked by naloxone. The 830 mg/kg oral dose of DL did not produce toxic effects in mice and the LD(50) was found to be 3 g/kg.

Topics: Acetic Acid; Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Drug Interactions; Injections, Intraperitoneal; Latex; Lethal Dose 50; Mice; Morphine; Naloxone; Narcotic Antagonists; Pain; Plant Extracts; Plants, Medicinal

This study examined the ability of the anti-opioid Neuropeptide FF (NPFF) to modify the endogenous activity of nitric oxide (NO). Antinociceptive and hypothermic effects of 1DMe (D.Tyr-Leu-(n.Me)Phe-Gln-Pro-Gln-Arg-Phe-NH(2)), an NPFF agonist, and of L-NAME (N(omega)nitro-L-arginine methyl ester), an inhibitor of nitric oxide synthase, were investigated in mice. Intraperitoneal (i.p.) injection of L-NAME induced, in the hot plate test, a dose-dependent antinociception not reversed by naloxone, an opioid antagonist, but inhibited by L-Arg, the NO synthesis precursor. Intracerebroventricular (i.c.v.) injections of 1DMe inhibit the antinociceptive activity of L-NAME in a dose-dependent manner. On the contrary, L-NAME markedly potentiated hypothermia induced by 1DMe injected in the third ventricle. These data show that Neuropeptide FF receptors exert a dual effect on endogenous NO functions and could modulate pain transmission independently of opioids.

Topics: Analgesics, Opioid; Animals; Area Under Curve; Arginine; Body Temperature; Dose-Response Relationship, Drug; Enzyme Inhibitors; Free Radical Scavengers; Hypothermia; Male; Mice; Morphine; Naloxone; Narcotic Antagonists; NG-Nitroarginine Methyl Ester; Nitric Oxide; Oligopeptides; Pain; Temperature

The anterior pretectal nucleus (APtN) and the dorsal raphe nucleus (DRN) are involved in descending pathways that control noxious inputs to the spinal cord and participate in the normal physiological response to noxious stimulation. Evidence has also been provided for the involvement of the APtN acting as a relay station through which the DRN partly modulates spinal nociceptive messages. In the present study, the effects of microinjecting glutamate or morphine into the DRN on the latency for the tail withdrawal reflex after noxious heating of the skin were examined in rats in which hyperbaric lidocaine (5%), naloxone (a non-selective opioid antagonist) or methiothepin (a non-selective 5-HT(1) antagonist) was previously microinjected into the APtN. Microinjection of glutamate (38 nmol/0.25 microl) into the DRN evoked strong but short-lasting antinociception that was fully inhibited by the previous administration of lidocaine (0.25 microl), naloxone (2.7 nmol/0.25 microl), or methiothepin (1 nmol/0.25 microl). A smaller dose of methiothepin (0.5 nmol/0.25 microl) significantly reduced the effect of glutamate. Microinjection of morphine (7.5 nmol/0.25 microl) into the DRN evoked strong and long-lasting antinociception that was not significantly changed by previous microinjection of lidocaine into the APtN. These results confirm that APtN integrity is at least in part necessary for the antinociceptive effects of stimulating the DRN, and that at least opioid and 5-HT1 mechanisms in the APtN participate as neuromodulators in the DRN-APtN connection. The results demonstrate that the antinociceptive effects of stimulating the DRN-APtN path depend on the activation of cell bodies in the DRN that can be excited by the local administration of glutamate, but not morphine. The study also further supports the notion that the DRN is involved in both descending and ascending pain inhibitory systems.

Topics: Analgesics; Analgesics, Opioid; Anesthetics, Local; Animals; Basal Ganglia; Glutamic Acid; Lidocaine; Male; Microinjections; Morphine; Naloxone; Narcotic Antagonists; Neural Pathways; Pain; Pain Measurement; Raphe Nuclei; Rats; Rats, Wistar; Receptors, Serotonin; Receptors, Serotonin, 5-HT1

The nociceptive response latencies increased significantly after intra-nucleus raphe magnus administration of 0.1 or 0.4 nmol of neuropeptide Y, but not 0.04 nmol, in rats. The neuropeptide Y-induced increases in hindpaw withdrawal latency were reversed by following injection of 0.42 nmol of the Y1 antagonist, NPY(28-36). The results indicate that NPY plays an antinociceptive role in nucleus raphe magnus in rats, which is mediated by the Y1 receptor. Furthermore, the neuropeptide Y-induced increases in hindpaw withdrawal latency were attenuated by following intra-nucleus raphe magnus injection of 6 nmol of the opioid antagonist naloxone, indicating that there is an interaction between NPY and opioids in nucleus raphe magnus.

Topics: Animals; Hot Temperature; Male; Microinjections; Naloxone; Neuropeptide Y; Pain; Peptide Fragments; Raphe Nuclei; Rats; Rats, Sprague-Dawley; Reaction Time; Receptors, Neuropeptide Y

In this study, the effect of imipramine on morphine antinociception in tolerant and non-tolerant mice in the formalin test, was investigated. Subcutaneous administration of different test doses of morphine (3, 6 and 9 mg/kg) and intraperitoneal injection of test doses of imipramine (10, 20 and 40 mg/kg) induced a dose-dependent antinociception in non-tolerant mice, both in the first and second phases of the formalin test. The combination of morphine (1 mg/kg) with imipramine (10 mg/kg) showed a potentiated response in the second phase of the test. Combination of a single dose of morphine (1.5 mg/kg) with lower doses of imipramine (2, 4 and 8 mg/kg) did not show potentiation. The antinociceptive response of either morphine or morphine plus imipramine was reduced by the opioid receptor antagonist naloxone (2 mg/ kg). In order to induce tolerance, mice were treated subcutaneously with morphine (50 mg/kg) once daily for 3 days. On day 4, the antinociceptive effect of test doses of morphine or imipramine were assessed. Tolerance to the responses of test doses of morphine (3, 6 and 9 mg/kg), but not imipramine (10, 20 and 40 mg/kg) in both phases of the test was observed. Administration of lower dose of imipramine (4 mg/kg) before the test doses of morphine (3, 6 and 9 mg/kg) was not able to alter the expression of morphine tolerance. When imipramine was used during development of tolerance, either on days 1 and 2 or on days 2 and 3, the morphine tolerance in the second phase of the test was reduced. It is concluded that opioid receptor mechanism(s) may mediate the antidepressant-induced antinociception, however, imipramine may be useful in inhibiting morphine tolerance.

Topics: Analgesics, Opioid; Analysis of Variance; Animals; Antidepressive Agents, Tricyclic; Disinfectants; Dose-Response Relationship, Drug; Drug Interactions; Drug Tolerance; Formaldehyde; Imipramine; Injections, Intraperitoneal; Male; Mice; Morphine; Naloxone; Pain

Non-opioid analgesics have been shown to elicit antinociception by an action upon central nervous system structures, in addition to their well known action upon peripheral tissues. Microinjection of metamizol (dipyrone), a widely used nonopioid analgesic, into the periaqueductal grey matter (PAG) of rats activates pain-modulating systems in the nucleus raphe magnus and inhibits spinal nociceptive neurons and the tail-flick reflex. Since these effects involve an activation of endogenous opioidergic systems, the possibility that metamizol induces opioid tolerance was investigated. Microinjection of metamizol into the ventrolateral PAG in awake rats induced antinociception, as demonstrated in the heat-elicited tail flick and hot plate tests. When microinjected into the ventrolateral PAG twice daily for 2 days, metamizol induced tolerance, i.e. a progressive loss of its antinociceptive effect. In contrast to rats repeatedly microinjected with saline, metamizol-tolerant rats were also tolerant to morphine microinjection into the same PAG site, and displayed signs of opioid withdrawal upon systemic administration of naloxone. These and other results suggest that metamizol activates endogenous opioid systems and that nonopioid analgesics may, by an action upon the central nervous system, lead to opioid tolerance and the risk of opioid withdrawal.

Topics: Animals; Dipyrone; Drug Tolerance; Hot Temperature; Male; Mesencephalon; Microinjections; Morphine; Naloxone; Pain; Periaqueductal Gray; Rats; Rats, Sprague-Dawley; Time Factors; Wakefulness

Opioids elicit antinociception in mammals through three distinct types of receptors designated as mu, kappa and delta. However, it is not clear what type of opioid receptor mediates antinociception in non-mammalian vertebrates. Radioligand binding techniques were employed to characterize the site(s) of opioid action in the amphibian, Rana pipiens. Naloxone is a general opioid antagonist that has not been characterized in Rana pipiens. Using the non-selective opioid antagonist, [3H]-naloxone, opioid binding sites were characterized in amphibian spinal cord. Competitive binding assays were done using selective opioid agonists and highly-selective opioid antagonists. Naloxone bound to a single-site with an affinity of 11.3 nM and 18.7 nM for kinetic and saturation studies, respectively. A B(max) value of 2725 fmol/mg protein in spinal cord was observed. The competition constants (K(i)) of unlabeled mu, kappa and delta ranged from 2.58 nM to 84 microM. The highly-selective opioid antagonists yielded similar K(i) values ranging from 5.37 to 31.1 nM. These studies are the first to examine opioid binding in amphibian spinal cord. In conjunction with previous behavioral data, these results suggest that non-mammalian vertebrates express a unique opioid receptor which mediates the action of selective mu, kappa and delta opioid agonists.

Topics: Analgesics, Opioid; Animals; Binding, Competitive; Kinetics; Models, Animal; Naloxone; Narcotic Antagonists; Neurons; Nociceptors; Pain; Rana pipiens; Receptors, Opioid; Spinal Cord; Tritium

Laser-Doppler flowmetry was used to study cerebral cortical blood flow responses to morphine and naloxone in morphine-naive and -dependent rats. The experiments were performed in spontaneously breathing anesthetized rats. Morphine (10 mg/kg, i.p.) administration reduced regional cerebral blood flow in control, sham-operated and morphine-dependent rats, but the depressant effect of morphine in morphine-dependent animals was less than that in control and sham-operated groups. While naloxone (0.5 mg/kg, s.c.) had no considerable effect on regional cerebral blood flow in control and sham-operated groups, it increased regional blood flow in morphine dependent ones. The depressant effect of morphine in all groups and the enhancing effect of naloxone in morphine-dependent animals were not seen after local application of lidocaine at the recording site. This study may provide a framework to study the cellular and molecular mechanisms responsible for coupling neuronal electrical activity with regional alterations in blood flow during precipitation of morphine withdrawal.

Topics: Anesthesia; Anesthetics, Local; Animals; Brain; Cerebrovascular Circulation; Diarrhea; Lidocaine; Male; Morphine; Morphine Dependence; Naloxone; Narcotic Antagonists; Pain; Rats; Rats, Wistar; Substance Withdrawal Syndrome; Weight Loss

The d-enantiomer of the opioid methadone is a weak opioid with low micromolar affinity to the N-methyl-D-aspartate (NMDA) receptor. We have investigated the antinociception and in vivo NMDA antagonism after systemic administration of d-methadone in the rat spinal cord. d-Methadone caused antinociception in the Randall-Selitto model of inflammatory pain and inhibited the responses of hindlimb single motor units to noxious electrical and mechanical stimulation (ED(50) 6.6, 6.8 and 7.2 mg/kg intravenous (i.v.), respectively); the wind-up of these responses was only inhibited at the dose almost completely abolishing the baseline responses. d-Methadone inhibited the activity of spinal dorsal horn neurones evoked by both iontophoretic NMDA and (R, S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA, ED(50) 5.7 and 8.2 mg/kg i.v., respectively). After pre-treatment with naloxone, d-methadone was unable to inhibit nociception in the Randall-Selitto model, the NMDA- or AMPA-evoked neuronal activity or the motoneurone wind-up. Thus, in the antinociceptive dose range, the NMDA antagonism does not appear to contribute to the mechanism of d-methadone antinociception.

Topics: Action Potentials; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Analgesia; Analgesics, Opioid; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Male; Methadone; N-Methylaspartate; Naloxone; Nociceptors; Pain; Pain Measurement; Pain Threshold; Posterior Horn Cells; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Spinal Cord

Several reports indicate that pregnancy and parturition are associated with elevated maternal pain thresholds to noxious stimuli. The objective of this study was to examine whether the human placental extract, a clinically used preparation, can inhibit experimental nociception. Nociception was assessed in mice using acetic acid-induced writhing and hot-plate tests. The human placental extract (200 and 400 mg/kg, i.p.) elicited dose-related antinociception in the acetic acid-induced writhing test. Furthermore, it (200 mg/kg, i.p.) potentiated the morphine-induced antinociception (1.25 mg/kg, s.c.). In the hot-plate test, the human placental extract (100, 200 and 400 mg/kg, i.p.) per se, displayed no significant antinociception but potentiated the duration of morphine (10 mg/kg, s.c.) analgesia. The potentiation by the extract of the morphine-induced antinociception in both acetic acid and hot-plate tests was, however, found to be naloxone sensitive. Mice treated with the extract (400 mg/kg, i.p.) neither manifested any overt behavioural change in the open-field test nor demonstrated significant influence on pentobarbital sleeping time, suggesting that it has no central depressant or sedative activity. The data provide evidence to show that the human placental extract has a peripheral analgesic property possibly mediated by an opioid mechanism.

Topics: Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Hot Temperature; Humans; Injections, Intraperitoneal; Injections, Subcutaneous; Male; Mice; Morphine; Motor Activity; Naloxone; Narcotic Antagonists; Narcotics; Pain; Pain Measurement; Pentobarbital; Placental Extracts; Sleep

The antinociceptive activity of tramadol was investigated on the vocalization threshold to paw pressure in a rat model of unilateral mononeuropathy produced by loose ligatures around the common sciatic nerve. Despite the analgesic activity of tramadol was clearly established in motor and sensory responses of the nociceptive system in rats, the effect of this atypical opioid on experimental neuropathic pain models is not investigated. The intraperitoneally injected tramadol (2.5, 5 and 10 mg/kg) produced a potent and dose-dependent antinociceptive effect on both lesioned and non-lesioned hind paws. However, the analgesic effect on the lesioned paw was significantly more potent than the non-lesioned paw. This effect was partially antagonized by intraperitoneally administered naloxone (0.1 mg/kg) suggesting an additional non-opioid mechanism. Our results suggest that tramadol may be useful for the alleviation of some symptoms in peripheral neuropathic conditions

Topics: Analgesics, Opioid; Animals; Male; Naloxone; Narcotic Antagonists; Nervous System Diseases; Pain; Pain Measurement; Pressure; Rats; Rats, Wistar; Tramadol; Vocalization, Animal

Topics: Analgesics; Dronabinol; Humans; Multiple Sclerosis; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Receptors, Opioid

We have investigated the effect of morphine on (i) dorsal hippocampus field CA1 nociceptive response to a formalin injection, and (ii) septohippocampal neural processing. Extracellular recordings were made in urethane (1.0 g/kg)-anaesthetized rats. Previously, we reported that formalin (5%, 0.05 ml, s.c.) injection into a hindpaw evoked, in the CA1 field, a "signal-to-noise processing", i.e. a selective excitation of a few pyramidal cells with high spontaneous extracellular activity against a background of widespread pyramidal cell suppression accompanied by an increase in period of rhythmic slow activity. In the present study, morphine administered i.p. concurrent to a formalin injection reversed the pyramidal cell suppression in conjunction with a decrease in the period of evoked rhythmic slow activity. The effect was dose dependent and was prominent at the dose of 5 mg/kg. This dose, administered as a pretreatment, also truncated CA1 pyramidal cell suppression or excitation to a formalin injection. Furthermore, the drug decreased the power and frequency of the posterior hypothalamus-supramammillary region stimulation-evoked hippocampal field CA1 rhythmic slow activity. Such an effect was observed in a time-frame parallel to the decline in the period of formalin injection-induced field CA1 rhythmic slow activity. However, morphine sulphate administration per se did not alter pyramidal cell excitability or extracellular activity. Together, the above findings are consistent with the notion that morphine influences dorsal hippocampus field CA1 pyramidal cell suppression partly via an effect on the septohippocampal neural processing. However, the effect of the drug does not involve a change in the pyramidal cell basal extracellular responses. The effect of morphine on septohippocampal neural processing might be functionally relevant to the influence of the drug on the affective-motivational component of pain.

Topics: Action Potentials; Animals; Disinfectants; Formaldehyde; Hippocampus; Male; Morphine; Naloxone; Narcotic Antagonists; Narcotics; Nociceptors; Pain; Pyramidal Cells; Rats; Rats, Sprague-Dawley; Septal Nuclei; Theta Rhythm

Endogenous inhibitory controls were studied in the spinal nerve ligation model of neuropathic pain. Atipamezole, a selective alpha2-adrenoceptor antagonist, produced both mechanical and cold allodynia in those rats which had not developed clear neuropathic symptoms. The same doses (50 microg i.t. or 1 mg/kg s.c.) did not increase the severity of symptoms in rats which had developed them. The opioid receptor antagonist naloxone (20 microg i.t. or 1 mg/kg s.c.) had no effect on the neuropathic symptoms. These results indicate that mechanical and cold allodynia are under endogenous noradrenergic rather than opioidergic control in this model of neuropathic pain.

Topics: Adrenergic alpha-Antagonists; Animals; Disease Models, Animal; Imidazoles; Ligation; Male; Naloxone; Narcotic Antagonists; Norepinephrine; Pain; Pain Measurement; Peripheral Nervous System Diseases; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic; Sodium Chloride; Spinal Nerves

The effects of a new antiepileptic drug, tiagabine, (R)-N-[4,4-di-(3-methylthien-2-yl)but-3-enyl] nipecotic acid hydrochloride, were studied in mice and rats in antinociceptive tests, using three kinds of noxious stimuli: mechanical (paw pressure), chemical (abdominal constriction) and thermal (hot plate). In vivo microdialysis was performed in parallel in awake, freely moving rats in order to evaluate possible alterations in extracellular gamma-aminobutyric acid (GABA) levels in a pain-modulating region, the medial thalamus. Systemic administration of tiagabine, 30 mg kg(-1) i.p., increased nearly twofold the extracellular GABA levels in rats and increased significantly the rat paw pressure nociceptive threshold in a time-correlated manner. Dose-related significant tiagabine-induced antinociception was also observed at the doses of 1 and 3 mg kg(-1) i.p. in the mouse hot plate and abdominal constriction tests. The tiagabine antinociception was completely antagonised by pretreatment with the selective GABA(B) receptor antagonist, CGP 35348, (3-aminopropyl-diethoxy-methyl-phosphinic acid) (2.5 microg/mouse or 25 microg/rat i.c.v.), but not by naloxone (1 mg kg(-1) s.c.), both administered 15 min before tiagabine. Thus, it is suggested that tiagabine causes antinociception due to raised endogenous GABA levels which in turn activate GABA(B) receptors.

Topics: Abdomen; Animals; Baclofen; Constriction, Pathologic; Dose-Response Relationship, Drug; Escape Reaction; Extracellular Space; GABA Agonists; GABA Antagonists; gamma-Aminobutyric Acid; Male; Mice; Microdialysis; Naloxone; Narcotic Antagonists; Neurotransmitter Uptake Inhibitors; Nipecotic Acids; Nociceptors; Organophosphorus Compounds; Pain; Pain Measurement; Pain Threshold; Psychomotor Performance; Receptors, GABA-B; Thalamus; Tiagabine

We induced specific expectations of analgesia on four different parts of the body to understand how endogenous opioid systems are activated by expectancies. The left hand, right hand, left foot, and right foot were simultaneously stimulated by means of a subcutaneous injection of capsaicin, which produces a painful burning sensation. Specific expectations of analgesia were induced by applying a placebo cream on one of these body parts and by telling the subjects that it was a powerful local anesthetic. In such a way, expectancy of the anesthetic effect was directed only toward the part on which the placebo cream was applied. We found that a placebo analgesic response occurred only on the treated part, whereas no variation in pain sensitivity was found on the untreated parts. If the same experiment was performed after an intravenous infusion of the opioid antagonist naloxone, this highly spatial-specific placebo response was totally abolished, indicating that it was completely mediated by endogenous opioid systems. These findings show that a spatially directed expectation of pain reduction is capable of inducing a specific effect only on the part of the body which is the target of the expectation. Most important, this specific effect is mediated by endogenous opioids, indicating that placebo-activated opioids do not act on the entire body but only on the part where expectancy is directed. This suggests that a highly organized and somatotopic network of endogenous opioids links expectation, attention, and body schema.

Topics: Analgesia; Analysis of Variance; Anesthetics, Local; Capsaicin; Double-Blind Method; Foot; Functional Laterality; Hand; Humans; Infusions, Intravenous; Injections, Subcutaneous; Naloxone; Pain; Pain Threshold; Placebo Effect

The present study examined the role of the rostral ventrolateral medulla (RVLM) in the modulation of acetylcholine (ACh) release by morphine. We examined the effect of morphine on the release of ACh in the RVLM of freely moving rats using the in vivo microdialysis method. The basal level of ACh was 303.0 +/- 28.2 fmol/20 microliter/15 min in the presence of neostigmine (10 microM). Morphine at a low dose of 5 mg/kg (i.p.) increased ACh release by the RVLM by 42.4%. A higher morphine dose (10 mg/kg i.p.) significantly increased the release of ACh by 75.4%, with a maximal effect (86.4%) at 75 min. This enhancement following i.p. administration of morphine was reversed by naloxone (1 mg/kg i.p.). Addition of morphine (10(-4) M) to the perfusion medium increased the ACh release by 85.8% of the predrug values. The increased ACh release induced by local application of morphine was reversed by pretreatment with naloxone (1 mg/kg i.p.). The antinociceptive effect of locally applied morphine into the RVLM was assessed using the hot-plate test and tail immersion test in unanesthetized rats. Local application of morphine (10(-4) M) via a microdialysis probe induced an increase in both tail withdrawal and hot-plate response. These findings suggest that morphine seems to exert a direct stimulatory effect on ACh release by the RVLM and that morphine-induced nociception is, in part, activated by the release of ACh in freely moving rats.

Topics: Acetylcholine; Animals; Dose-Response Relationship, Drug; Extracellular Space; Infusions, Parenteral; Injections, Intraperitoneal; Male; Medulla Oblongata; Microdialysis; Morphine; Naloxone; Neostigmine; Pain; Rats; Rats, Wistar; Tetrodotoxin

The aim of this study was to determine if the application of mustard oil (MO), a small-fiber excitant and inflammatory irritant, or other algesic chemicals (capsaicin, CAP, and bradykinin, BK) to the rat maxillary molar tooth pulp induces electromyographic (EMG) activity of the masseter and digastric muscles, and also to determine if endogenous opioid mechanisms may be involved in any documented EMG changes. Application of MO to the tooth pulp induced a significant increase in EMG activity of the ipsilateral masseter up to 30 min. The application of mineral oil to the pulp or MO application to the pulp-extirpated tooth did not induce any significant EMG increases. The application of CAP or BK to the pulp in contrast had much weaker effects on EMG activity of the jaw muscles. CAP produced a small but prolonged increase in masseter EMG activity, and BK induced a short-lasting increase in digastric EMG activity. The systemic administration of the opiate antagonist naloxone significantly reactivated (i.e. rekindled) the EMG response evoked by MO application to the pulp. Naloxone did not produce any such significant rekindling effect on EMG activity following CAP, BK or mineral oil application to the pulp or following MO application to the pulp-extirpated tooth. The MO, BK and especially CAP groups showed histological evidence of vasodilatation and polymorphonuclear leukocyte infiltration in the pulp tissue and a significant increase in plasma extravasation of Evans Blue dye, whereas mineral oil did not induce these changes. These findings suggest that pulp afferent inputs to the central nervous system evoked by BK. CAP and especially MO may induce enhanced jaw muscle activity. In addition, the naloxone data suggest that an opioid suppresive mechanism may be induced by the pulpal afferent inputs evoked by MO, and may serve to limit the jaw muscle activity elicited by these inputs.

Topics: Animals; Bradykinin; Capsaicin; Dental Pulp; Electromyography; Evans Blue; Inflammation; Jaw; Male; Masseter Muscle; Mustard Plant; Naloxone; Narcotic Antagonists; Neutrophils; Pain; Plant Extracts; Plant Oils; Rats; Rats, Sprague-Dawley

This study was designed to reexamine a previous proposal of whether the opioid-like substances (OLS) being acting mainly as an intrinsic spinal mediator in the descending inhibition of nociception of the bulbospinally projecting NE-ergic, and/or 5-HT-ergic terminals in the dorsal horn by using an immunocytochemical method. The effects of intrathecal (i.t.) phentolamine (Ph), cyproheptadine (Cyp), and naloxone (Nal), administered separately or coadministered by two of them, on the expression of Fos-like-immunoreactive (FLI) neurons were observed on both sides of the lumbar dorsal horn of rats, in which equal volumes of formalin were injected into two hindpaws and the ipsilateral dorsolateral funiculus (DLF) was transected at the thoracic level antecedently. The results showed: (1) when rats were pretreated with i.t. saline, the number of nociceptive FLI neurons was significantly lowered 44% (p<0.01) on the side of the lumbar dorsal horn with intact DLF compared to the opposite side with sectioned DLF; (2) when rats were separately pretreated with i.t. Ph, Cyp and Nal, the reduction of FLI neurons on the DLF-intact side were decreased by 27% (p<0.01), 21% (p<0.01), and 25% (p<0.01), respectively; (3) when rats were pretreated with combined i.t. Ph+Cyp, the reduction on the intact side was eliminated almost completely (4%); (4) when rats were pretreated with combined i.t. Ph+Nal, the reduction on the intact side was 21% (p<0.01); and (5) when rats were pretreated with i.t. Cyp+Nal, the reduction on the intact side was 9.1%. These results suggest that: (1) nearly all the suppressive action exerted by the DLF-descending fibers are produced by the release of either NE or 5-HT as neurotransmitters at the spinal level; (2) most of the opioid-like substances act as an intrinsic spinal mediator mainly for the descending NE-ergic, but in a lesser extent for the 5-HT-ergic terminals in the dorsal horn circuitry; and (3) some OLS-ergic interneurons may only be activated by local nociceptive input.

Topics: Adrenergic alpha-Antagonists; Animals; Biogenic Monoamines; Cyproheptadine; Immunohistochemistry; Injections, Spinal; Male; Naloxone; Narcotic Antagonists; Narcotics; Neural Inhibition; Pain; Phentolamine; Rats; Rats, Wistar; Serotonin Antagonists; Spinal Cord

Abdominal contractions are a viscerosomatic reflex response to noxious colorectal irritation in rats. In this study we characterize the modulating effect of chemical and mechanical colonic irritation on this reflex response to peritoneal irritation induced by diluted acetic acid (HAc) in conscious C57BL/6N mice. Pain responses were scored by counting the number of abdominal contractions during the 30-min period after intraperitoneal (i.p.) injection of either vehicle or HAc. Abdominal contractions were induced by 0.6% but not by 0.3% HAc. Chemical irritation of the colon by intraluminal 25% turpentine did not produce abdominal contractions by itself, but significantly increased the effect of both 0.3 and 0.6% i.p. HAc, administered 60 min after the luminal stimulus. Mechanical stimulation of the anorectum and colon by insertion of a balloon did not modify the effect of 0.6% HAc, while the insertion plus the inflation to 0.1 and 0.2 ml (30 s on/30 s off for 10 min) reduced the response to i.p. HAc by 35 and 88%, respectively. This inhibitory effect was reversed by naloxone (5 mg/kg, s.c.) pretreatment, while naloxone alone did not modify the effect of 0.6% HAc. These results demonstrate that chemical irritation of visceral afferents in the colonic mucosa and peritoneum of mice interact to enhance viscerosomatic pain responses, while the activation of colonic mechanoreceptors inhibits peritoneal irritation-induced pain responses and induces a freezing behavior by a naloxone-sensitive mechanism.

Topics: Abdominal Muscles; Acetic Acid; Animals; Behavior, Animal; Catheterization; Colonic Diseases; Injections, Intraperitoneal; Irritants; Male; Mice; Mice, Inbred C57BL; Muscle Contraction; Naloxone; Narcotic Antagonists; Pain; Physical Stimulation; Stimulation, Chemical; Turpentine

Phosphorylation of the mu-opioid receptor may play a role in opioid tolerance and dependence. 3-Isobutyl-1-methylxanthine (IBMX) was found to inhibit basal mu-opioid receptor phosphorylation (IC50 < or = 10 microM) either upon acute treatment or after 8 h pre-treatment in HEK293 cells transfected with the mu-opioid receptor. In mice made acutely tolerant to and dependent on morphine, IBMX (30-100 nmol, i.c.v.) significantly attenuated the naloxone-induced withdrawal jumping and partially reversed morphine antinociceptive tolerance. IBMX also blocked changes to mu-opioid receptor signaling associated with chronic morphine treatment, specifically, the inverse agonist effect elicited by naloxone, in which naloxone paradoxically elevated the cAMP levels in cells previously exposed to morphine for > or = 12 h. These results suggest a new effect of IBMX in inhibiting basal mu-opioid receptor phosphorylation, and provide additional evidence for the involvement of receptor phosphorylation in the development of opioid tolerance and dependence.

Topics: 1-Methyl-3-isobutylxanthine; Adenylyl Cyclases; Animals; Cells, Cultured; Cyclic AMP; Drug Tolerance; Mice; Morphine Dependence; Naloxone; Pain; Pain Measurement; Phosphodiesterase Inhibitors; Phosphorylation; Receptors, Opioid, mu; Substance Withdrawal Syndrome; Time Factors

We investigated the role of mu-opioid receptor subtypes in both endomorphin-1 and endomorphin-2 induced antinociception in mice using supraspinally mediated behavior. With tail pressure as a mechanical noxious stimulus, both intracerebroventricularly (i.c.v.) and intrathecally (i.t.) injected-endomorphins produced potent and significant antinociceptive activity. Antinociception induced by i.t. and i.c.v. injection of endomorphin-1 was not reversed by pretreatment with a selective mu1-opioid receptor antagonist, naloxonazine (35 mg/kg, s.c.). By contrast, antinociception induced by i.t. and i.c.v. endomorphin-2 was significantly decreased by mu1-opioid receptor antagonist. Antinociception of both i.t. and i.c.v. endomorphin-1 and -2 was completely reversed by pretreatment with beta-funaltrexamine (40 mg/kg, s.c.). The results indicate that endomorphins may produce antinociception through the distinct mu1 and mu2 subtypes of mu-opioid receptor.

Topics: Analgesics, Opioid; Animals; Dose-Response Relationship, Drug; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalins; Injections, Intraventricular; Injections, Spinal; Male; Mice; Naloxone; Naltrexone; Narcotic Antagonists; Nociceptors; Oligopeptides; Pain; Receptors, Opioid, mu; Time Factors

The purpose of this animal investigation was to compare behavioral responses with spinal Fos-like immunoreactivity (FLI) after pre-versus postformalin administration of anesthetic doses of IV ketamine or alfentanil. Preformalin and postformalin injection (1.5% subcutaneously) treatment groups included IV saline control (1.5 mL/kg), ketamine (10 mg/kg), and alfentanil (170 microg/kg). In the behavioral study group, nociceptive behavior was evaluated 15-60 min after hindpaw formalin injection. In the spinal FLI study group, rats were perfused 2 h postformalin, and spinal cords were dissected, sliced at 30 microm, and processed by immunoperoxidase staining with an antibody against the Fos protein. Quantification and determination of the laminar distribution of Fos-labeled nuclei were performed at the L4-5 spinal level ipsilateral to formalin injection. Ketamine produced a selective preemptive analgesic effect in behavioral formalin experiments, yet failed to suppress spinal FLI. In contrast, alfentanil failed to demonstrate a selective preemptive analgesia in behavioral experiments, but did produce preemptive suppression of spinal FLI. Together with previous data from our laboratory, we conclude that behavioral analgesia and spinal Fos expression may be uncoupled under certain circumstances.. In this study, we compared pain reduction produced by IV drugs (ketamine or alfentanil) with the ability to prevent injury-induced spinal cord changes. We measured pain behavior and spinal Fos protein after rats received ketamine or alfentanil before versus after formalin injection. Fos inhibition patterns did not clearly correlate with pain reduction, providing further evidence that Fos inhibition is not always predictive of behavioral analgesia.

Topics: Alfentanil; Analgesics, Opioid; Animals; Formaldehyde; Ketamine; Male; Naloxone; Pain; Proto-Oncogene Proteins c-fos; Rats; Rats, Long-Evans; Spinal Cord

These results using herpes virus-mediated gene transfer to overexpress enkephalin in the amygdala support the role of amygdalar opioids in the anxiolytic actions of benzodiazepines and supraspinal nociception (see ref. 1). These studies also demonstrate the usefulness of recombinant herpes virus in evaluating the role of single gene products within specific brain sites in pharmacological responses and complex behaviors.

Topics: Amygdala; Animals; Anti-Anxiety Agents; beta-Galactosidase; Diazepam; Enkephalins; Gene Expression Regulation; Genetic Vectors; Herpesviridae; Humans; Male; Maze Learning; Naloxone; Pain; Pain Measurement; Protein Precursors; Rats; Recombinant Proteins; RNA, Messenger; Transcription, Genetic

The aim of our study was to investigate the effect of intracerebroventricular (i.c.v.) administration of very low doses of opioid antagonists on the pain threshold, arterial blood pressure and body temperature of spontaneously hypertensive rats (SHR) with chronic pain. We found that low doses of i.c.v. administered naloxone hydrochloride (0.3 microg) or naloxone methiodide (0.4 microg) produce paradoxical hypoalgesia. Similar results were not observed following i.c.v. administration of nor-binaltorphimine (0.6 microg). A paradoxical increase in the severity of hypertension followed i.c.v. opioid antagonist administration. This suggests an involvement of the opioid system in the mechanisms of blood pressure control. The paradoxical results obtained both for pain threshold and blood pressure after low doses of some opioid antagonists seem to confirm the role played by opioid autoreceptors in these effects. Existence of autoreceptors is suggested. Results obtained following i.c.v. administration of nor-binaltorphimine also suggest a role for the kappa autoreceptor (OP2) in the regulatory mechanisms of thermoregulation.

Topics: Analgesia; Animals; Arteries; Blood Pressure; Body Temperature; Body Weight; Brain; Chronic Disease; Hypertension; Injections, Intraventricular; Male; Naloxone; Naltrexone; Narcotic Antagonists; Pain; Pain Threshold; Quaternary Ammonium Compounds; Rats; Rats, Inbred SHR; Rats, Inbred WKY

The aim of this study was to examine the antiallodynic and antinociceptive effects of subcutaneously administered physostigmine (50, 100, 200 micrograms/kg), compared with morphine (2.5, 5, 10 mg/kg) and NaCl after spinal nerve ligation in rats. The following stimuli were used: acetone (cold allodynia), von Frey hairs (mechanical allodynia), and paw flick test (thermal nociception). Motility boxes were used to investigate the effects of the drugs on motor performance. Physostigmine attenuated both mechanical and cold allodynia dose-dependently but had no effect on the paw flick test. The effect was antagonized by atropine (muscarinic receptor antagonist) but not by mecamylamine (nicotinic receptor antagonist) or naloxone (opioid receptor antagonist). Morphine produced dose-dependent antiallodynic and antinociceptive effects. In the antiallodynic doses, morphine caused severe rigidity. Physostigmine 200 micrograms/kg impaired locomotor activity, but no rigidity was observed.. Physostigmine has different effects on allodynia and nociception, which suggests that different cholinergic (muscarinic) mechanisms may be involved in neuropathic and nociceptive pain.

Topics: Analgesics; Analgesics, Opioid; Animals; Atropine; Cholinergic Antagonists; Dose-Response Relationship, Drug; Injections, Subcutaneous; Ligation; Male; Mecamylamine; Morphine; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Pain Threshold; Peripheral Nervous System Diseases; Physostigmine; Rats; Rats, Sprague-Dawley; Spinal Nerves

In the present study the effect of dextromethorphan on naloxone-induced withdrawal signs in morphine-dependent mice was examined. In addition, the modulatory role of dopaminergic mechanisms upon the effect of dextromethorphan was investigated. Mice were rendered dependent on morphine by subcutaneous (s.c.) injections of morphine sulfate three times a day for 3 days, and withdrawal signs were induced by intraperitoneal (i.p.) administration of naloxone 2 h after the 10th injection of morphine sulfate on day 4. Dextromethorphan (20-50 mg/kg, i.p.) caused a significant decrease in withdrawal jumping, paw-shakes, grooming, burrows, writhing and diarrhea in morphine-dependent mice. The mixed dopamine D1/D2 receptor agonist apomorphine (0.5 and 1 mg/kg, s.c.) reduced the response induced by dextromethorphan. The effect of apomorphine was blocked by the dopamine D1 receptor antagonist SCH 23390 (R-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepine-7- ol maleate) (0.5 and 1 mg/kg, i.p.) but not by the dopamine D2 receptor antagonist sulpiride (25 and 50 mg/kg, s.c.) nor the peripheral dopamine receptor antagonist domperidone (5 and 10 mg/kg, s.c.). These results suggest that the dopaminergic system(s) may in part mediate the suppressive action of the NMDA receptor antagonist dextromethorphan on naloxone-induced withdrawal signs in morphine-dependent mice.

Topics: Animals; Apomorphine; Behavior, Animal; Benzazepines; Dextromethorphan; Domperidone; Dopamine Agonists; Dopamine Antagonists; Excitatory Amino Acid Antagonists; Grooming; Male; Mice; Morphine; Morphine Dependence; Naloxone; Narcotic Antagonists; Pain; Substance Withdrawal Syndrome; Sulpiride

Our previous studies have indicated that the thalamic nucleus submedius (Sm) is involved in nociceptive modulation and plays an important role in an endogenous analgesic system (a feedback loop) consisting of spinal cord - Sm - ventrolateral orbital cortex (VLO) - periaqueductal gray (PAG) - spinal cord. To further investigate the neurotransmitter and receptor mechanisms in this nociceptive modulatory pathway, we tested the effects of microinjection of morphine and naloxone into the Sm on the rat tail flick (TF) reflex. A unilateral microinjection of morphine (8.0 mM, 0.5 microl) into the Sm significantly depressed the TF reflex, whereas a unilateral microinjection of naloxone (5.0 mM, 0.5 microl) into the Sm facilitated the TF reflex. Five minutes after morphine application into Sm, injection of naloxone in this nucleus markedly reversed the inhibition evoked by applying morphine in Sm. These findings suggest that the endogenous opioid peptides may be involved in the antinociceptive effects evoked by activation of the Sm-VLO-PAG pathway which depressed the nociceptive inputs at the spinal level via the brainstem descending inhibitory system, and exert a tonic descending influence.

Topics: Analgesia; Animals; Feedback; Female; Hot Temperature; Male; Microinjections; Morphine; Naloxone; Pain; Periaqueductal Gray; Rats; Rats, Sprague-Dawley; Reflex; Spinal Cord; Thalamic Nuclei; Time Factors

The antinociceptive effects of intrathecal (IT) (1DMe)NPYF were studied in adult Sprague-Dawley rats. (1DMe)NPYF produced dose-dependent antinociception that was reduced by subcutaneous injection of naloxone. (1DMe)NPYF (0.5 nmol) also potentiated the antinociceptive effects of intrathecal morphine 7.8 nmol. This suggests that the antinociceptive effects of (1DMe)NPYF are partially mediated by opioid receptor activation. In carrageenan inflammation, 5-10 nmol of (1DMe)NPYF was effective against both thermal hyperalgesia and mechanical allodynia. In the neuropathic pain model, the lowest dose tested (0.5 nmol) showed antiallodynic effects against cold allodynia. The results suggest a potential role for (1DMe)NPYF in the treatment of pain including neuropathic pain.

Topics: Amino Acid Sequence; Analgesics, Non-Narcotic; Animals; Disease Models, Animal; Drug Antagonism; Injections, Spinal; Male; Motor Activity; Naloxone; Oligopeptides; Pain; Peripheral Nervous System Diseases; Rats; Rats, Sprague-Dawley

We investigated the antinociceptive effect of FR140423, 3-(difluoromethyl)-1-(4-methoxyphenyl)-5-[4-(methylsulfinyl)phenyl] pyrazole, in the tail-pinch test in mice, and evaluated the mechanism of action using various opioid receptor antagonists. P.o. and i.t. injection of FR140423 exerted dose-dependent antinociceptive activities with ED50 values of 21 mg/kg and 3.1 microg/mouse, respectively. However, i.c.v. injection of FR140423 did not show an antinociceptive effect. The antinociceptive effects of FR140423 were completely abolished by naloxone and naltrindole but not by naloxonazine, beta-funaltrexamine and nor-binaltorphimine. FR140423 did not affect any opioid receptor binding in mouse spinal membranes at concentrations up to 100 microM in vitro. Naloxone-induced jumping and diarrhea tests for morphine-like physical dependence of FR140423 gave negative results. These results suggest that FR140423 can induce antinociception by acting on the spinal but not the supraspinal site, and that spinal delta-opioid systems indirectly play a role in the antinociception produced by FR140423 in mice.

Topics: Administration, Oral; Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Behavior, Animal; Binding, Competitive; Diarrhea; Injections, Intraventricular; Injections, Spinal; Male; Membranes; Naloxone; Naltrexone; Narcotic Antagonists; Pain; Pain Measurement; Pyrazoles; Rats; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Spinal Cord; Sulfoxides

This study examined the effects of exposing mice to forced walking stress on formalin-induced paw licking. At each observation period (0.5-6 h) after exposure to forced walking stress, a significant antinociceptive effect (stress-induced analgesia, SIA) was observed only in the second phase (from 10 to 30 min), but not in the first phase (from 0 to 10 min) of formalin-induced paw licking in mice. The present data showed that SIA induced by exposure to forced walking stress was dependent on duration of the stress (0.5-4 h). SIA was dose-dependently antagonized by the NMDA receptor antagonist dizocilipine (0.01-0.04 mg/kg) but not by naloxone (10 mg/kg). Thus, the present results suggest that exposure to forced walking stress could cause SIA which may be involved in the nonopioid system via NMDA receptors.

Topics: Analgesia; Animals; Behavior, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Formaldehyde; Male; Mice; Naloxone; Narcotic Antagonists; Neuroprotective Agents; Pain; Pain Measurement; Physical Exertion; Receptors, N-Methyl-D-Aspartate; Stress, Physiological; Walking

We studied the mechanisms by which activation of primary afferent nociceptors inhibits bradykinin-induced plasma extravasation in the rat. First, capsaicin, administered into the plantar surface of the hindpaw, dose-dependently inhibited bradykinin-induced plasma extravasation in the knee joint, a site distant from the noxious stimulus. The inhibitory effect of capsaicin was markedly attenuated after T(12)/L(1) spinal transection combined with lumbar preganglionic sympathectomy, which interrupts ascending spinal tracts to rostral sites and to spinal sympathetic and sympathoadrenal outflow. Second, interruption of the sympathetics (cutting the L(1-3) white rami) or surgical adrenal denervation significantly attenuated capsaicin-induced inhibition of bradykinin-induced plasma extravasation. Interruption of the sympathoadrenal pathway produced the largest attenuation. Lesioning of the hypothalamic-pituitary-adrenal axis did not affect the inhibitory action of capsaicin. Third, intra-articular perfusion with phentolamine (10(-5) M, an alpha-adrenoceptor antagonist), propranolol (10(-5) M, a beta-adrenoceptor antagonist), and naloxone (10(-5) M, an opioidergic receptor antagonist) each attenuated the inhibitory action of capsaicin. Propranolol and naloxone produced the largest attenuation. Blocking glucocorticoid receptors (RU-38, 486, 30 mg/kg s.c.) did not affect the inhibitory action of intraplantar capsaicin. Fourth, the magnitude of the attenuation of capsaicin-induced inhibition of bradykinin-induced plasma extravasation after a combined treatment of surgical lumbar sympathetic decentralization with intra-articular phentolamine or surgical adrenal denervation with intra-articular propranolol or naloxone was similar to each of the surgical or pharmacological treatments of the same axis alone. These results support the suggestion that two neural/endocrine circuits, sympathoadrenal and sympathetic, account for most, if not all, of nociceptor activity-induced inhibition of bradykinin-induced plasma extravasation produced by capsaicin.

Topics: Adrenal Glands; Adrenergic alpha-Antagonists; Adrenergic beta-Antagonists; Animals; Bradykinin; Capsaicin; Electric Stimulation; Endocrine Glands; Hypophysectomy; Knee Joint; Male; Mifepristone; Naloxone; Narcotic Antagonists; Nervous System Physiological Phenomena; Neurons, Afferent; Pain; Phentolamine; Propranolol; Rats; Rats, Sprague-Dawley; Sciatic Nerve; Sympathetic Nervous System; Synovial Fluid

The tubercles of Anredera leptostachys are used as an antinociceptive and anti-inflammatory in the popular medicine of the Caribbean basin. In the present work, the anti-nociceptive and central nervous system depressant (CNS) effects of the methanolic extract from the tubercles of A. leptostachys have been evaluated. The antinociceptive activity was assayed in several experimental models in mice: acetic acid, formalin and hot plate tests. The methanolic extract (250 and 500 mg/kg) significantly and in a dose-dependent manner reduced the nociception induced by the acetic acid (P < 0.001). In the hot plate test, the extract significantly increased the latency time of jump although it slightly increased the licking time. The naloxone partially reversed the antinociception of the extract in the hot plate test. In the formalin test, the methanolic extract also significantly reduced the painful stimulus but the effect was not dose-dependent. In the study of the CNS-depressant effects, the extract was found to produce a significant reduction of the exploratory capacity with both doses assayed (P < 0.001). The muscular relaxation only decreased with the higher doses assayed (P < 0.001). The escape instinct was also significantly reduced (P < 0.001) by the two doses of the extract and both were more effective than standard drugs morphine and diazepam.

Topics: Acetic Acid; Analgesics; Animals; Behavior, Animal; Caribbean Region; Diazepam; Dose-Response Relationship, Drug; Drug Interactions; Escape Reaction; Exploratory Behavior; Formaldehyde; Hot Temperature; Male; Medicine, Traditional; Methanol; Mice; Morphine; Muscle Relaxation; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Plant Extracts; Solubility; Time Factors

Intraplantar injection of carrageenan induced significant Fos expression in the superficial and deep spinal dorsal horn at the L(4)-L(5)segments and extensive peripheral edema of the ipsilateral foot in rats. Intraplantar injection of endomorphin-1, endogenous ligand for mu opioid receptor, in the same region produced dose-dependent reduction of carrageenan-induced Fos expression and peripheral edema, which were completely blocked by co-administration of intraplantar injection of naloxone (20 microgram). The systemic injection of the highest dose of endomorphin-1 (50 microgram) had no significant reductory effect on Fos expression and peripheral edema. These results further provided a strong evidence for involvement of mu opioid receptor in peripheral analgesia, particularly in inflammation pain.

Topics: Analgesics, Opioid; Animals; Carrageenan; Male; Naloxone; Narcotic Antagonists; Nociceptors; Oligopeptides; Pain; Posterior Horn Cells; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley

Using distention of the small intestine as a visceral pain model, we investigated the effect of zaldaride maleate (ZAL), a selective inhibitor of calmodulin, on the depressor response. In pentobarbital-anesthetized rats, small intestine distention was induced by rapid application of intraluminal pressures of 40 cmH2O causing a reflex fall in arterial blood pressure. The depressor response to intestinal distention was abolished by intraperitoneal administration of capsaicin (5 mg/rat), which depletes neuropeptides such as substance P from the sensory neurons, on the mesenteric stalk and by neonatal pretreatment with capsaicin (50 mg/kg, s.c.). Morphine (20 mg/kg, s.c.) reduced the depressor response following intestinal distention. At doses of 3 mg/kg (i.v.) and higher, ZAL significantly reduced depressor response. The effect of morphine was reversed by naloxone (5 mg/kg, i.v.); the effect of ZAL was not affected. These results suggest that ZAL helps reduce the visceral pain induced by noxious stimulus and that the antinociceptive effect of ZAL is not mediated by opioid receptors.

Topics: Adrenergic alpha-Antagonists; Anesthesia; Animals; Animals, Newborn; Antidiarrheals; Atropine; Benzimidazoles; Blood Pressure; Capsaicin; Intestines; Male; Muscarinic Antagonists; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Papaverine; Pentobarbital; Phentolamine; Rats; Rats, Sprague-Dawley; Reflex; Vasodilator Agents

Baclofen (beta-p-chlorophenyl-GABA) has been used in humans to treat spasticity, as well as trigeminal neuralgia. Since GABA (gamma-aminobutyric acid) has been implicated in inhibitory and analgesic effects in the nervous system, it was of interest to study the effect of baclofen in experimental neuropathic pain. With this purpose, experiments were carried out in 17 neuropathic rats with constrictive sciatic injury, as described by Bennet and Xie (1988), taking as pain parameters scratching behaviour and the latency to the thermal nociceptive stimulus. The results showed that baclofen induces, in a dose-dependent manner, significant decrease (p < 0.05) of scratching behaviour and significant increase (p < 0.05) of the latency to the nociceptive thermal stimulus. The absence of antagonism of naloxone suggested a non-participation of an opioid-mediated mechanism in this analgesic effect of baclofen on experimental neuropathic pain.

Topics: Animals; Baclofen; Behavior, Animal; Chronic Disease; GABA Agonists; Male; Naloxone; Narcotic Antagonists; Pain; Peripheral Nervous System Diseases; Rats; Rats, Wistar; Sciatic Nerve

With the purpose of studying data on spontaneous customary changes in diabetic rats, we induced diabetes in 28 Wistar rats with streptozotocin. The animals were observed for 27 weeks in an attempt to characterize spontaneous customary changes that could suggest signs of chronic pain. Morphine, as a central-acting potent analgesic and its specific antagonist naloxone, were used. Our results evidenced in the animals a clinical syndrome similar to human diabetes. Long-term customary analysis revealed a significant (p < 0.05) increase of scratching and resting/sleeping behaviors, but diminished motor, eating and grooming customs. Moreover, the thermal tests revealed hyperalgesia in 43% of the animals, what may corroborate the meaning of scratching as a sign of pain. Pharmacological tests with morphine showed a significant (p < 0.05) inhibition of scratch, with concomitant increase of motor and eating activities and diminished rest/sleep capacity. Naloxone antagonized the effects induced by morphine. Such results suggest that these animals exhibit evoked behavior of hyperalgesia and that scratch may possibly be a spontaneous manifestation of chronic pain also in Wistar rats with this experimental model of painful diabetic neuropathy.

Topics: Animals; Behavior, Animal; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Morphine; Naloxone; Narcotic Antagonists; Pain; Pruritus; Rats; Rats, Wistar

In 1997, we described a new automated method of scoring the pain behaviors in the formalin test. The algic behavior was automatically measured with the help of a video-analysis system. The time during which the animal grooms, licks, or bites itself was used as the parameter of pain. In the present study, we tested various analgesics to realize a pharmacological validation of the system. The effect of opiate analgesic (morphine, i.v.), nonsteroidal anti-inflammatory drugs (paracetamol, i.v., piroxicam, i.v., indomethacin, i.v.), antidepressant drugs (clomipramine, desipramine, nortryptyline, and paroxetine, i.p.), and serotonin (i.t.) were analyzed. A dose of 1.25 mg/kg of morphine induced a decrease in the scores of phases 1 and 2. Naloxone (0.25 mg/kg) reversed the effect of morphine (2.5 mg/kg). A 20-mg/kg dose of indomethacin induced a decrease in the second phase, and paracetamol induced a decrease in both phases (analgesic doses were 400 mg/kg and 200 mg/kg for first and second phases, respectively). Piroxicam had no effect on the pain scores. Clomipramine, desipramine, and paroxetine at a dose of 5 mg/kg induced a significant decrease in the second phase. Nortriptyline had no effect on the pain scores. A dose of 75 microg of serotonin induced a decrease in both phases 1 and 2. This study demonstrated that this system shows a good pharmacological sensitivity, although it is lower than that of manual assessment.

Topics: Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antidepressive Agents; Automation; Behavior, Animal; Drug Interactions; Formaldehyde; Image Processing, Computer-Assisted; Male; Morphine; Naloxone; Pain; Pain Measurement; Rats; Rats, Sprague-Dawley; Reproducibility of Results; Serotonin

Activation of neurons in the midbrain periaqueductal gray (PAG) inhibits spinal dorsal horn neurons and produces behavioral antinociception in animals and analgesia in humans. Although dorsal horn regions modulated by PAG activation contain all three opioid receptor classes (mu, delta, and kappa), as well as enkephalinergic interneurons and terminal fields, descending opioid-mediated inhibition of dorsal horn neurons has not been demonstrated. We examined the contribution of dorsal horn mu-opioid receptors to the PAG-elicited descending modulation of nociceptive transmission. Single-unit extracellular recordings were made from rat sacral dorsal horn neurons activated by noxious heating of the tail. Microinjections of bicuculline (BIC) in the ventrolateral PAG led to a 60-80% decrease in the neuronal responses to heat. At the same time, the responses of the same neurons to iontophoretically applied NMDA or kainic acid were not consistently inhibited. The inhibition of heat-evoked responses by PAG BIC was reversed by iontophoretic application of the selective mu-opioid receptor antagonists, D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP) and D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP). A similar effect was produced by naloxone; however, naloxone had an excitatory influence on dorsal horn neurons in the absence of PAG-evoked descending inhibition. This is the first demonstration that endogenous opioids acting via spinal mu-opioid receptors contribute to brain stem control of nociceptive spinal dorsal horn neurons. The inhibition appears to result in part from presynaptic inhibition of afferents to dorsal horn neurons.

Topics: Adrenergic alpha-Agonists; Analgesics, Opioid; Animals; Bicuculline; Clonidine; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalins; Excitatory Amino Acid Agonists; GABA Antagonists; Hot Temperature; Iontophoresis; Kainic Acid; Male; Medulla Oblongata; N-Methylaspartate; Naloxone; Narcotic Antagonists; Nociceptors; Opioid Peptides; Pain; Peptide Fragments; Peptides; Periaqueductal Gray; Rats; Rats, Sprague-Dawley; Receptors, Opioid, mu; Somatostatin; Spinal Cord; Tail

Single-unit recordings were made in the intact anesthetized rat of the responses of dorsal horn neurons to C-, Adelta-, and Abeta-fiber stimulation. The postdischarge and windup responses of the same cells along with responses to innocuous stimuli, prod and brush, also were measured. The effects of (-)-bicuculline-methobromide (0.5, 5, 50, and 250 microg) were observed on these neuronal responses. The C- and Adelta-fiber-evoked responses were facilitated significantly in a dose-dependent manner. The input was facilitated, but as the final overall response was not increased by the same factor, windup appeared to be reduced. However, postdischarge, resulting from the increase in the excitability produced by windup, tended to be facilitated. After doses of >/=5 microg bicuculline, stimulation at suprathreshold Abeta-fiber-evoked activity caused enhanced firing, mainly at later latencies corresponding to Adelta-fiber-evoked activity in normal animals. Few cells responded consistently to brush and so no significant change was observed. Responses evoked by innocuous pressure (prod) always were observed in cells that concurrently responded to electrical stimulation with a C-fiber response. This tactile response was facilitated significantly by bicuculline. The effects of N6-cyclopentyladenosine (N6-CPA), an adenosine A1-receptor agonist, was observed after pretreatment with 50 microg bicuculline, as were the effects of morphine and 7-chlorokynurenate (7-CK). N6-CPA inhibited prod, C- and Adelta-fiber-evoked responses as well as the initial and overall final response to the train of C-fiber strength stimuli. Inhibitions were reversed with 8(p-sulphophenyl) theophylline. Morphine, the mu-receptor agonist, also inhibited the postbicuculline responses to prod, C-, and Adelta-fiber responses and initial and final responses to a train of stimuli. Inhibitory effects of morphine were reversed partly by naloxone. 7-CK, an antagonist at the glycine site on the N-methyl-D-aspartate-receptor complex, inhibited the responses to C- and Adelta-fiber-evoked activity as well as prod. The postdischarges were inhibited by this drug. Again both the initial and overall responses of the cell were inhibited. To conclude, bicuculline caused an increase in the responses of deep dorsal horn cells to prod, Adelta-fiber-evoked activity, increased C-fiber input onto these cells along with the appearance of responses at latencies normally associated with Adelta fibers, but evoked by suprathr

Topics: Adenosine; Animals; Bicuculline; Dose-Response Relationship, Drug; GABA Antagonists; Kynurenic Acid; Male; Morphine; Naloxone; Nerve Fibers; Neurons; Pain; Physical Stimulation; Purinergic P1 Receptor Agonists; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Spinal Cord; Touch

Several studies have shown that the anterior pretectal nucleus (APtN) is involved in descending inhibitory pathways that control noxious inputs to the spinal cord and that it may participate in the normal physiological response to noxious stimulation. Among other brain regions known to send inputs to the APtN, the dorsal column nuclei (DCN), pedunculopontine tegmental nucleus (PPTg), deep mesencephalon (DpMe), and dorsal raphe nucleus (DRN) are structures also known to be involved in antinociception. In the present study, the effects of stimulating these structures on the latency of the tail withdrawal reflex from noxious heating of the skin (tail flick test) were examined in rats in which saline or hyperbaric lidocaine (5%) was previously microinjected into the APtN. Brief stimulation of the PPTg, DpMe or DRN, but not the DCN, strongly depressed the tail flick reflex. The antinociceptive effect of stimulating the DRN, but not the PPTg or DpMe was significantly reduced, but not abolished, by the prior administration of the local anaesthetic into the APtN. The antinociception induced by stimulation of the PPTg or DpMe, therefore, is unlikely to depend on connections between these structures and the APtN. Similar inhibition of the effect of stimulating the DRN was obtained from rats previously microinjected with naloxone (2.7 nmol) or methysergide (2 nmol) into the APtN. Strongly labelled cells were identified in the DRN following microinjection of the fluorescent tracer Fast Blue into the APtN. These results indicate that the APtN may participate as a relay station through which the DRN partly modulates spinal nociceptive messages. In addition, they also indicate that endogenous opioid and serotonin can participate as neuromodulators of the DRN-APtN connection.

Topics: Afferent Pathways; Amidines; Anesthetics, Local; Animals; Electric Stimulation; Fluorescent Dyes; Lidocaine; Male; Mesencephalon; Methysergide; Naloxone; Narcotic Antagonists; Neural Inhibition; Neurons; Nociceptors; Pain; Pain Measurement; Raphe Nuclei; Rats; Rats, Wistar; Serotonin Antagonists; Tail

1. The present study examined the antinociceptive effects of carbamazepine on the tail flick test in stressed and nonstressed rats. 2. Carbamazepine produced a bimodal antinociceptive effect in stressed rats, the first peak appearing 30 min and the second 4 h after injection. Antinociceptive effect was not observed in nonstressed rats. 3. The secondary, but not the initial, carbamazepine antinociception in stressed rats was blocked by naloxone (0.2 mg/kg, i.p.), an opioid receptor antagonist. 4. Caffeine (5 mg/kg, i.p.), an adenosine A1/A2 receptor antagonist, inhibited the both initial and secondary antinociceptive effects of carbamazepine in stressed rats. 5. Carbamazepine increased the antinociceptive effect induced by either i.p. or i.c.v. administration of N6-cyclohexyl adenosine (CHA), an adenosine A1 receptor agonist, in stressed rats, but decreased it in nonstressed rats. 6. These results suggest that the initial antinociceptive effect of carbamazepine in stressed rats may be produced via an activation of the adenosine A1 receptors, such as was produced by CHA. The secondary long-lasting antinociceptive effects of carbamazepine may be mediated by an activation of opioid systems. 7. Furthermore, the initial activation of the adenosine A1 receptors by carbamazepine may be a triggering factor for the subsequent long-lasting activation of the opioid system, which results in the antinociception effects.

Topics: Adenosine; Analgesics, Non-Narcotic; Analysis of Variance; Animals; Caffeine; Carbamazepine; Cerebral Ventricles; Dose-Response Relationship, Drug; Injections, Intraperitoneal; Injections, Intraventricular; Male; Naloxone; Pain; Physical Stimulation; Purinergic P1 Receptor Antagonists; Rats; Rats, Wistar; Restraint, Physical; Stress, Psychological; Time Factors

We evaluated the effects of systemic administration of a low dose of naloxone in rats with bilateral lesions in the area of the locus coeruleus (LC) under conditions of unilateral inflammation, compared with those in sham-operated rats. In each group, rats received a single s.c. injection of carrageenan (6 mg in 0.15 ml saline), and effects of a low dose of naloxone (5 microg/kg, i.p.) on thermal nociception were examined at 4 h and 7 days following the induction of unilateral hindpaw inflammation. The antinociceptive effect was assessed by prolongation of the paw withdrawal latency (PWL) to noxious thermal stimuli. Prior to induction of inflammation, the low dose of naloxone had no significant effect on PWLs in either the sham-operated or the LC-lesioned rats. Four hours after carrageenan injection, the low dose of naloxone produced prolongation of PWLs in the sham-operated rats but failed to induce antinociception in the LC-lesioned rats. Antinociceptive effects were observed in both groups of rats 7 days after carrageenan injection. These results suggest that the LC is involved in naloxone-induced anti-nociception during the early phase of inflammation.

Topics: Analgesics; Animals; Carrageenan; Dose-Response Relationship, Drug; Hindlimb; Inflammation; Injections; Locus Coeruleus; Male; Naloxone; Pain; Rats; Rats, Sprague-Dawley

Mechanisms underlying the development of acute tolerance to the analgesic effect of opiates were investigated. In the rat tail-flick test, administration of naloxone (1 mg/kg, s.c.) 40 min after heroin (1 mg/kg, s.c.) was shown to induce hyperalgesia, indicative of a short-onset, opiate-activated pain facilitatory systems masking the opiate analgesia. Pretreatment with the N-methyl-D-aspartate receptor antagonist dizocilpine maleate blocked, in a dose-dependent manner, the naloxone-induced hyperalgesia and potentiated the heroin-induced analgesia. Using a schedule of two successive injections of 1 mg/kg heroin, acute tolerance was indicated by a marked reduction (-52%) in analgesia induced by the second dose. After pretreatment with dizocilpine maleate, the acute tolerance was abolished and the analgesic effects of both injections of heroin were strongly potentiated. These observations indicate that acute tolerance appears after the first exposure to opiates and stems from opiate activation of N-methyl-D-aspartate-dependent pain facilitatory systems.

Topics: Analgesics, Opioid; Analysis of Variance; Animals; Dizocilpine Maleate; Drug Tolerance; Heroin; Hyperalgesia; Male; Naloxone; Pain; Pain Measurement; Rats; Rats, Sprague-Dawley; Reaction Time

The objective of this study was to evaluate the effects of kappa-opioid receptor agonists on pressor and visceromotor responses to colorectal distension in awake, unrestrained rats, a model of visceral pain. Because visceral pain can be enhanced in the presence of inflammation, the study was conducted in rats that had been given either intracolonic saline or 5% acetic acid 6 hr before drug administration. We developed a method of staircase colorectal distension as a means of obtaining stimulus-response functions over a short period of time. Kappa-opioid receptor agonists, given i.v. in a cumulative dose paradigm, dose-dependently attenuated both the pressor and visceromotor responses to colorectal distension. In addition, all drugs tested also increased response threshold. The rank order of potency of the drugs tested was: CI977 > U69,593 > U50,488 > or = morphine > or = EMD61,753 > ICI204,448. Effective doses of these drugs were antagonized by naloxone, but not by either of two kappa-opioid receptor-selective antagonists (nor-binaltorphimine and 2-(3,4-dichlorophenyl)-N-methyl-N-(1-[3-isothiocyanate phenyl]-2-[1-pyrrolidinyl]ethyl)-acetamide). Acute inflammation of the colon did not lead to changes in the potency of the agonists tested. The present results provide further evidence that kappa-opioid receptor agonists significantly attenuate visceral nociception and, in conjunction with other information, suggest that a peripherally restricted kappa-opioid receptor agonist would be therapeutically effective in relieving visceral pain.

Topics: Acute Disease; Analgesics, Opioid; Animals; Colitis; Colon; Electromyography; Male; Naloxone; Pain; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa; Rectum

To evaluate the role of the amygdala in pain modulation and opioid-mediated antinociception, a recombinant, replication-defective herpes virus carrying the human preproenkephalin cDNA was injected bilaterally into the rat amygdala. Four days after gene delivery nociceptive behavior was assessed by the formalin test. Rats infected with the virus expressing preproenkephalin showed a selective, naloxone-reversible abolition of phase 2 flinching behavior compared to rats infected with a control virus. The results implicate the amygdala in the control of pain and in opioid analgesia and demonstrate the use of recombinant herpes viruses as tools for studying gene function in specific neural pathways of the central nervous system.

Topics: Amygdala; Animals; beta-Galactosidase; Enkephalins; Gene Transfer Techniques; Herpesviridae; Male; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Protein Precursors; Rats

Topics: Analgesics, Opioid; Humans; Naloxone; Narcotic Antagonists; Pain; Pain, Intractable; Tilidine

Nociceptin and nociceptin receptor, which show structural similarities to opioid peptides and opioid receptors, respectively, have been recently found to constitute a novel neuromodulatory system. In the brain, however, the physiological role of the modulation via the nociceptin receptor is still unclear. Administered nociceptin produces hyperalgesia and hypolocomotion, whereas the nociceptin receptor-knockout mice show no significant abnormalities in nociceptive thresholds and locomotion. To clarify possible involvement of the nociceptin receptor in the regulation of nociception and locomotion, we made use of the knockout mice and naloxone benzoylhydrazone (NalBzoH) identified originally as a ligand for opioid receptors. Experiments on the cultured cells transfected with the nociceptin receptor cDNA showed that NalBzoH competed with [3H]nociceptin binding and attenuated the nociceptin-induced inhibition of cAMP accumulation. Furthermore, behavioral studies demonstrated that NalBzoH completely inhibited nociceptin-induced hyperalgesia and hypolocomotion. It is therefore likely that NalBzoH can act as a potent antagonist for the nociceptin receptor in vivo. In wild-type mice, NalBzoH induced antinociception but did not affect locomotor activity. In contrast, in the knockout mice, no significant changes in nociception and locomotion were induced by NalBzoH. These results clearly suggest that the nociceptin system takes part in the physiological regulation of nociceptive thresholds but not in the basal modulation of locomotion.

Topics: Animals; CHO Cells; Cricetinae; Cyclic AMP; Ligands; Locomotion; Mice; Mice, Knockout; Naloxone; Narcotic Antagonists; Nociceptin; Nociceptin Receptor; Opioid Peptides; Pain; Rats; Receptors, Opioid

Endogenous analgesia induced by changes in motivation has been identified in the chicken in previous studies but either the motivational changes were difficult to interpret or the motivation was unpredictable. Experimental sodium urate (SU) arthritis of the ankle joint resulted in pain-coping behaviour (one-legged standing or sitting) for a 2-h period in non-food-deprived birds without access to food. Complete analgesia or marked hypoalgesia was observed in birds which had been food deprived overnight and given access to food immediately after SU injection. This analgesia seen during feeding behaviour in the food-deprived bird could be completely reversed by intravenous injection of naloxone. These results demonstrate that feeding motivation can totally suppress, in some animals, the severe tonic pain of SU arthritis and that this analgesia may be opioid mediated.

Topics: Adaptation, Psychological; Analgesia; Animals; Arthritis, Gouty; Behavior, Animal; Chickens; Eating; Female; Food Deprivation; Motivation; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Statistics, Nonparametric; Uric Acid

The effects of intrathecally (i.t.) administered glibenclamide, a blocker of adenosine triphosphate-sensitive potassium (K(ATP)) channels, or naloxone on the antinociception produced by i.t. apomorphine or morphine were observed and analyzed in rats by tail-flick (TF) test. The results showed that: (1) i.t. apomorphine produced a significant and dose-dependent antinociception, (2) the antinociception produced by i.t. apomorphine could be blocked dose-dependently by i.t. glibenclamide or naloxone, (3) the antinociception produced by i.t. morphine could also be blocked dose-dependently by i.t. glibenclamide. The results suggest that endogenous opioids and ATP-sensitive potassium channels might be involved in the mediation of apomorphine-induced antinociception at the spinal level.

Topics: Adenosine Triphosphate; Animals; Apomorphine; Dopamine Agonists; Endorphins; Female; Glyburide; Injections, Spinal; Male; Morphine; Naloxone; Narcotic Antagonists; Narcotics; Nociceptors; Pain; Potassium Channel Blockers; Potassium Channels; Rats; Rats, Wistar; Reaction Time; Spinal Cord

The effect of neuropeptide FF in the periaqueductal gray on pain behaviour was studied in rats with a chronic neuropathy induced by unilateral ligation of two spinal nerves. Neuropeptide FF produced in a non-monotonic fashion a significant attenuation of tactile allodynia. The antiallodynic effect was not significantly modulated by naloxone administered systemically or intracerebrally. The dose of neuropeptide FF producing a significant antiallodynic effect was not antinociceptive in a test of mechanical or thermal nociception. The thermal antinociceptive effect induced by morphine administered in the periaqueductal gray was significantly attenuated by neuropeptide FF, whereas that induced by systemically administered morphine was not. The interaction of neuropeptide FF with intracerebrally or systemically administered morphine in a test of tactile allodynia was not significant. The results indicate that neuropeptide FF in the periaqueductal gray may produce a selective attenuation of tactile allodynia in neuropathic rats. This antiallodynic effect is at least partly independent of naloxone-sensitive opioid receptors. Furthermore, neuropeptide FF in the periaqueductal gray attenuates antinociception induced by intracerebrally but not systemically administered morphine.

Topics: Animals; Drug Interactions; Hindlimb; Hyperalgesia; Male; Microinjections; Morphine; Naloxone; Narcotic Antagonists; Neuralgia; Oligopeptides; Pain; Periaqueductal Gray; Rats; Rats, Wistar; Skin; Spinal Nerves; Touch

We examined whether endothelin-1 (ET-1), a potent vasoconstrictive peptide secreted in high concentration by metastatic prostate cancer cells, produces endothelin receptor-dependent pain behavior when applied to rat sciatic nerve. ET-1 (200-800 microM) applied to the epineurial surface of rat sciatic nerve produced reliable, robust, unilateral hindpaw flinching lasting 60 min. Pre-emptive systemic morphine completely blocked this effect in a naloxone-reversible manner, suggesting that this behavior was pain-related. Equipotent doses of epineurially applied epinephrine had no effect, suggesting that ET-1 effects are on tissue sites other than sciatic nerve microvessels. Prior and co-administration of BQ-123, an endothelin-A (ET(A)) receptor antagonist, also blocked ET-1-induced hindpaw flinching establishing that pain behavior induced by ET-1 application to rat sciatic nerve is ET(A) receptor mediated.

Topics: Acute Disease; Administration, Topical; Adrenergic alpha-Agonists; Analgesics, Opioid; Animals; Behavior, Animal; Drug Interactions; Endothelin-1; Epinephrine; Male; Microcirculation; Morphine; Naloxone; Narcotic Antagonists; Pain; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptors, Endothelin; Sciatic Nerve

In a model of visceral pain consisting of intraperitoneal injection of acetic acid (writhing test), simultaneous administration of subanalgesic doses of metamizol (150 mg/kg) and morphine (0.2 mg/kg) resulted in a potent analgesia (19 +/- 1 vs. 2.3 +/- 0.8 writhes; P < 0.05). While the analgesic effect of morphine (2 mg/kg) was antagonized by naloxone (1 mg/kg), the opioid antagonist did not reverse the analgesia induced by the combination of metamizol and morphine. Potentiation by metamizol was also observed as a bilateral decrease in stimulus-evoked c-Fos induction in superficial laminas (I-II) of the dorsal spinal cord after drug combination compared to single administration (66.5 +/- 2.2 vs. 80.7 +/- 4.2; P < 0.05). Conversely, the number of nuclei immunostained with an antibody that recognizes all proteins of the Fos family was not modified by the same dose combination compared to single treatment (21.1 +/- 1.3 vs. 20.2 +/- 1.2). Furthermore, in a model of somatic pain consisting of peripheral thermal stimulation of the paws, simultaneous administration of metamizol (100-250 mg/kg) and morphine (0.5 mg/kg) failed to modify flexor reflex latency.

Topics: Acetic Acid; Analgesics, Opioid; Animals; Anti-Inflammatory Agents, Non-Steroidal; Dipyrone; Drug Synergism; Immunohistochemistry; Injections, Intraperitoneal; Male; Mice; Mice, Inbred BALB C; Morphine; Naloxone; Narcotic Antagonists; Pain; Proto-Oncogene Proteins c-fos; Spinal Cord; Visceral Afferents

Gastric acid is known to contribute to ulcer pain, but the mechanisms of gastric chemonociception are poorly understood. This study set out to investigate the pathways and mechanisms by which gastric acid challenge is signaled to the brain.. Neuronal excitation in the rat brainstem and spinal cord after intragastric administration of HCl (0.35-0.7 mol/L) was examined by in situ hybridization autoradiography for the immediate early gene c-fos.. Gastric acid challenge did not induce c-fos transcription in the spinal cord but caused many neurons in the nucleus tractus solitarii and area postrema to express c-fos messenger RNA (mRNA). The HCl concentration-dependent excitation of medullary neurons was in part associated with behavioral manifestations of pain but not directly related to the acid-induced injury and contraction of the stomach. Subdiaphragmatic vagotomy suppressed the c-fos mRNA response to intragastric acid, and morphine inhibited it in a naloxone-reversible manner, whereas pretreatment of rats with capsaicin was without effect.. Gastric acid challenge is signaled to the brainstem, but not the spinal cord, through vagal afferents that are sensitive to acid but resistant to capsaicin. It is hypothesized that the gastric acid-induced c-fos transcription in the brainstem is related to gastric chemonociception.

Topics: Afferent Pathways; Animals; Brain Stem; Capsaicin; Female; Gastric Acid; Gastric Mucosa; Genes, fos; Hydrochloric Acid; Instillation, Drug; Morphine; Naloxone; Pain; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; RNA, Messenger; Skin; Spinal Cord; Transcription, Genetic; Vagus Nerve

This study was undertaken to investigate the effects induced by the systemic administration of RB 101 [N-[(R,S)-2-benzyl-3[(S)(2-amino-4-methylthio)butyl dithio]-1-oxoprpyl]-L-phenylalanine benzyl ester], a mixed inhibitor of the enkephalin catabolism able to cross the blood-brain barrier, in antinociception produced by adrenal medullary tissue transplanted in the rat spinal subarachnoid space. For this purpose, the antinociceptive responses induced by intravenous (i.v.) administration of RB 101 were evaluated in the tail-flick in rats transplanted 28 and 56 days before the test. Systemic administration of RB 101 induced antinociceptive effects in sham-operated rats, as previously reported. RB 101 also enhanced significantly the antinociception produced by the autotransplant 28 and 56 days after surgery. The antinociceptive responses of RB 101 in both sham-operated and autotransplanted rats were blocked by naloxone, but were not modified by the noradrenergic antagonist, phentolamine, suggesting a selective involvement of opioid mechanisms. The present results indicate that the inhibitors of enkephalin catabolism enhance the antinociception induced by adrenal medullary transplants.

Topics: Adrenal Medulla; Adrenergic alpha-Antagonists; Analysis of Variance; Animals; Disulfides; Injections, Intravenous; Male; Naloxone; Narcotic Antagonists; Pain; Phentolamine; Phenylalanine; Protease Inhibitors; Rats; Rats, Wistar; Spinal Cord; Subarachnoid Space; Transplantation, Autologous

The effects of stimulation of periaqueductal gray matter on pain threshold and blood corticosterone level were studied in anesthetized rats. The stimulation resulted in a alteration of analgesia and corticosterone level. Stimuli-induced analgesia was decreased by adrenalectomy. Corticosterone implantation (50 micrograms) in periaqueductal gray matter resulted in the increase of analgesia. Pretreatment with naloxone (1 mg/kg) failed to modify the effect of stimulation of periaqueductal gray matter on analgesia and corticosterone level. Our results indicate the involvement of corticosterone in the analgesia induced the stimulation of periaqueductal gray matter.

Topics: Adrenalectomy; Animals; Anti-Inflammatory Agents; Corticosterone; Electric Stimulation; Hypothalamo-Hypophyseal System; Male; Mesencephalon; Naloxone; Pain; Pain Measurement; Periaqueductal Gray; Pituitary-Adrenal System; Rats; Rats, Sprague-Dawley

Nociceptive C fiber input to SI in the halothane-nitrous oxide anesthetized rat was assessed by recording cortical field potentials evoked by noxious thermal cutaneous stimulation with CO2-laser pulses. Morphine topically applied onto the lumbar spinal cord produced a dose-dependent inhibition of nociceptive C fiber input from the hind paw to the contralateral SI. The inhibitory effect of morphine was reversed by naloxone. Potentials evoked by CO2-laser stimulation of the forepaw were unaffected by morphine applied on the lumbar cord, indicating that the effect of morphine was exerted at the segmental level. It is concluded that input from nociceptive C fibers to SI is relayed in the spinal cord and can be inhibited by spinal opioid receptor activation. The present method offers an interesting model of ascending nociceptive transmission to the cerebral cortex.

Topics: Analgesics, Opioid; Animals; Evoked Potentials, Somatosensory; Injections, Spinal; Male; Morphine; Naloxone; Narcotic Antagonists; Nerve Fibers; Neural Inhibition; Neurons, Afferent; Nociceptors; Pain; Physical Stimulation; Rats; Rats, Wistar; Somatosensory Cortex; Spinal Cord; Synaptic Transmission

Brief electrical pulses applied to the rat tail elicit a complex vocal response which includes audible (peeps, chatters) and ultrasonic (USV) components. Aspirin and amitriptyline had no effect on the vocal responses. Morphine showed a dose-dependent and naloxone reversible antinociceptive effect on the 1st and 2nd audible peeps by decreasing their intensity (evaluated by their envelopes which correspond to the outer bounds of the soundwave amplitude plotted as a function of time), with ED50 values of 1.96 mg/kg and 0.36 mg/kg i.v. respectively. Paracetamol significantly reduced only the intensity of the second peep at the dose of 200 mg/kg iv. Chatter intensity was decreased by doses of 1 and 3 mg/kg i.v. of morphine which would suggest an effect on emotional components of pain. The intensity of USV was affected by morphine injection although the variations observed were non-significant. These data clearly implicate a specific role for the opioid analgesics in modifying the vocal pain related behaviors.

Topics: Amitriptyline; Analgesics; Animals; Aspirin; Cricetinae; Electric Stimulation; Male; Morphine; Naloxone; Pain; Rats; Rats, Sprague-Dawley; Ultrasonics; Vocalization, Animal

1. We evaluated the ability of the functional antagonist at the glycine site of the N-methyl-D-aspartate (NMDA) receptor complex, (+)-(1-Hydroxy-3-aminopyrrolodine-2-one) ((+)-HA966), to modulate the antinociceptive action of systemic morphine in a rat model of neuropathic pain produced by chronic constriction injury to the sciatic nerve. Mechanical (vocalization threshold to hindpaw pressure) and thermal (struggle latency to hindpaw immersion into a water bath) stimuli were used. 2. In the mechanical test, morphine (0.05, 0.1 and 0.3 mg kg(-1), i.v.) alone produced dose-dependent effects in both neuropathic and uninjured rats. Likewise, morphine (0.1, 0.3 and 1 mg kg(-1), i.v.) dose-dependently increased struggle latencies of the nerve-injured hindpaw in the hot noxious (46 degrees C) test but was ineffective in the non-noxious warm (44 degrees C) and cold (10 degrees C) test. 3. Pretreatment with (+)-HA966 (2.5 mg kg(-1), s.c.) dose-dependently enhanced the effect of morphine in the mechanical test with the relative potency being nerve-injured hindpaw > contralateral hindpaw > uninjured rat. 4. Likewise, (+)-HA966 dose-dependently enhanced the effect of morphine against a hot (46 degrees C) stimulus and produced, in combination with morphine, a dose-dependent effect against a warm (44 degrees C) stimulus. In the cold (10 degrees C) test, (+)-HA966 reversed the ineffectiveness of the highest dose of morphine. 5. Naloxone blocked the effect of the combination of (+)-HA966 with morphine in all tests. The drug combination produced no motor deficits in animals using the rotarod test. 6. These findings suggest that combined administration of antagonists, acting at the glycine site of the NMDA receptor complex and morphine may be a promising approach in the treatment of neuropathic and acute pain.

Topics: Analgesics, Opioid; Animals; Binding Sites; Cold Temperature; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Therapy, Combination; Excitatory Amino Acid Antagonists; Glycine; Hot Temperature; Male; Morphine; Motor Activity; Naloxone; Narcotic Antagonists; Nociceptors; Pain; Peripheral Nervous System Diseases; Pyrrolidinones; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Stress, Mechanical

CD-1 mice were treated intravenously with streptozotocin, 200 mg/kg, and tested 2 weeks later or treated with 60 mg/kg and tested 3 days later. Both treatments changed the tail flick response of heroin and 6-monoacetylmorphine (6 MAM) given intracerebroventricularly from a mu- to delta-opioid receptor-mediated action as determined by differential effects of opioid receptor antagonists. The response to morphine remained mu. Heroin and 6 MAM responses involved delta1 (inhibited by 7-benzylidenenaltrexone) and delta2 (inhibited by naltriben) receptors, respectively. These delta-agonist actions did not synergize with the mu-agonist action of morphine in the diabetic mice. The expected synergism between the delta agonist, [D-Pen2-D-Pen5]enkephalin (DPDPE), and morphine was not obtained in diabetic mice. Thus, diabetes disrupted the purported mu/delta-coupled response. In nondiabetic CD-1 mice, heroin and 6 MAM produced a different mu-receptor response (not inhibited by naloxonazine) from that of morphine (inhibited by naloxonazine). Also, these mu actions, unlike that of morphine, did not synergize with DPDPE. The unique receptor actions and changes produced by streptozotocin suggest that extrinsic in addition to genetic factors influence the opioid receptor selectivity of heroin and 6 MAM.

Topics: Analgesics, Opioid; Animals; Anti-Bacterial Agents; Benzylidene Compounds; Diabetes Mellitus, Experimental; Dose-Response Relationship, Drug; Drug Interactions; Enkephalin, D-Penicillamine (2,5)-; Enkephalins; Heroin; Injections, Intraventricular; Male; Mice; Morphine; Morphine Derivatives; Naloxone; Naltrexone; Narcotic Antagonists; Nociceptors; Pain; Receptors, Opioid, delta; Receptors, Opioid, mu; Streptozocin; Time Factors

The intra-third-ventricular (i.t.v.) administration of [Met5]-enkephalin (enk) to rats pretreated i.t.v. with three peptidase inhibitors (PIs), amastatin, captopril and phosphoramidon, inhibited the tail-flick response. The enk-induced inhibition was augmented by increasing the doses of the three PIs, with the maximum inhibition being attained at the doses of 10 nmol each. The enk-induced inhibition in rats pretreated with any combination of two PIs, however, were markedly smaller than that in rats pretreated with all three PIs, indicating that three kinds of enzymes all played important roles in the inactivation of enk. The inhibitory effect of enk on the tail-flick response in rats pretreated with the three PIs at doses of 10 nmol each was approximately tenfold higher than that of morphine. The relative anti-nociceptive potencies of enk and morphine were similar to the relative inhibitory potencies obtained previously with the isolated guinea pig ileum pretreated with the three PIs, indicating that the hydrolysis of the i.t.v. administered enk was largely prevented by the three PIs. However, the magnitude of the enk-induced inhibition in rats pretreated s.c. with the three PIs indicated that the hydrolysis of enk injected i.t.v. was not largely prevented by the s.c. administration of three PIs at doses up to 10 micromol each/kg.

Topics: Animals; Anti-Bacterial Agents; Area Under Curve; Captopril; Dose-Response Relationship, Drug; Drug Therapy, Combination; Enkephalin, Methionine; Glycopeptides; Injections, Intraventricular; Injections, Subcutaneous; Male; Naloxone; Naltrexone; Narcotic Antagonists; Nociceptors; Pain; Pain Measurement; Peptides; Protease Inhibitors; Rats; Rats, Wistar

Topics: Adenosine; Analgesics; Analgesics, Opioid; Anesthetics, Local; Dose-Response Relationship, Drug; Drug Administration Schedule; Forecasting; Humans; Infusions, Intravenous; Injections, Intravenous; Lidocaine; Naloxone; Narcotic Antagonists; Nociceptors; Pain; Pain Measurement; Phentolamine; Receptors, N-Methyl-D-Aspartate; Reflex Sympathetic Dystrophy; Sympatholytics; Treatment Outcome

Acute high-frequency (60/s) high-intensity (2,100-2,300 microA) stimulation of the mesial, caudal and inferior portion of the centromedian thalamic region within or close to the parafascicular nucleus produced a sharp, intense, cramp-like painful response localized to the face and shoulder (medial stimulation) or arm and hand (lateral stimulation) contralateral to the stimulation site in 4 intractable epileptic patients in whom depth electrodes had been implanted as a part of a neuroaugmentive procedure for seizure control. This thalamic induced painful response was always accompanied by objective clinical signs (facial gesticulation and contraction of the corresponding muscles) during thalamic stimulation and significant increments in EEG, EKG and respiratory frequencies and EMG muscular tonus from 10 s before to 10 s after thalamic stimulation. Opioid agonists (fentanyl 5.0 microg/kg) and antagonists (naloxone 3.5 microg/kg) were administered to induce and regulate a state of neuroleptanalgesia used for the subcutaneous internalization of the chronic stimulation systems. Under these conditions, we observed that fentanyl greatly attenuated and naloxone increased the intensity of the painful response, as well as the EEG, somatic and vegetative parameters evaluating such a painful response. Differences were significant when one compares the changes in response to electrical stimulation in EEG, EKG, respiration and EMG after the administration of fentanyl (decrease p = 0.001) and naloxone (increase p = 0.01) compared to those obtained after the administration of saline or no drugs during baseline recordings. These data suggest that this thalamic induced painful response is mediated by inhibition or activation of the morphine receptors of the thalamic cells primarily related to the pain process.

Topics: Adult; Analgesics, Opioid; Electric Stimulation Therapy; Electrocardiography; Electroencephalography; Electromyography; Epilepsy; Female; Fentanyl; Humans; Male; Naloxone; Narcotic Antagonists; Pain; Stereotaxic Techniques; Thalamus

There has been no previous demonstration of opioid tolerance and dependence with respect to the propulsive and contractile activities of the gut in vivo. In the experiments described herein, morphine was administered continuously (1 mg/kg/hr s.c., 72 hr) and/or by bolus injection (2 mg/kg) and intestinal motility and transit were evaluated in unanesthetized rats. Tolerance in intestinal motility (contractions) and propulsion (transit) was measured in two ways, i.e., by measuring the time required for motility and propulsion to return to control values and by measuring the loss of effectiveness of bolus morphine administered to animals receiving continuous infusion of the opiate. The dose of morphine chosen for continuous administration (1 mg/kg/hr s.c. via Alzet minipumps) was based on the dose at which morphine inhibited intestinal propulsion by 50%. Morphine (1 mg/kg/hr) decreased the frequency of contractions in, and propulsion along, the small bowel and colon and produced mild antinociception. The frequency of duodenal and colonic contractions returned to normal within 13 to 16 hr. After 24 hr of morphine treatment, the inhibitory effects of bolus doses of morphine on motility and transit were diminished; the effects were eventually lost (48 hr). Similarly, the antinociceptive effects of bolus doses of morphine were diminished by 18 hr and lost by 24 hr. Naloxone (0.1 mg/kg s.c.) given to morphine-tolerant animals (72 hr) resulted in an increase in the frequency and amplitude of contractions in the colon, an increase in the propulsive activity of the small intestine and colon and diarrhea. These results provide direct demonstration of opioid tolerance and dependence of contractile and propulsive activity in the rat intestine in vivo.

Topics: Animals; Colon; Drug Tolerance; Duodenum; Gastrointestinal Motility; Gastrointestinal Transit; Infusions, Parenteral; Injections, Subcutaneous; Male; Morphine; Morphine Dependence; Muscle, Smooth; Naloxone; Pain; Rats; Rats, Sprague-Dawley; Stereotyped Behavior

Injection of dilute formalin into the hindpaw produces brief (phase 1) and persistent (phase 2) nociceptive responses in the rat. We recently reported that ongoing peripheral nerve input is required for the expression of behavioral and cardiovascular responses during phase 2. Here we evaluated the contribution of central and peripheral sensitization mechanisms, generated during phase 1, to the magnitude and temporal profile of phase 2. During phase 1, we administered analgesic doses of an ultrashort-acting opioid, remifentanil (i.v. administration from 0-5 min after 5.0% formalin injection), or anesthetic concentrations of halothane (2.1%). Inhibition of phase 1 did not reduce the magnitude of flinching and cardiovascular responses during phase 2, but it did delay their onset and/or termination. Longer remifentanil infusions (0-15 or 0-30 min) produced even longer delays (up to 30 min) in the onset and termination of flinching during phase 2; however, when remifentanil was administered during the early part of phase 2 (15-30 or 15-45 min), it did not prolong the time to termination of phase 2. Continuous infusion (10 mg/kg/hr i.v.) of a peripherally acting opiate antagonist, naloxone methiodide, did not reduce the antinociception produced by remifentanil during phase 1 but almost completely reversed the delay in the onset and termination of phase 2. We conclude that central sensitization mechanisms during phase 1 do not influence the magnitude of phase 2. We also hypothesize that remifentanil interacts with peripheral opioid receptors to impede the formalin-evoked synthesis and/or release of proinflammatory compounds during phase 1 and thus delay phase 2.

Topics: Analgesics, Opioid; Analysis of Variance; Anesthesia, Inhalation; Animals; Blood Pressure; Formaldehyde; Halothane; Heart Rate; Injections, Intravenous; Male; Naloxone; Pain; Piperidines; Quaternary Ammonium Compounds; Rats; Rats, Sprague-Dawley; Remifentanil; Time Factors

Paracetamol at the dose of 400 mg/kg i.p. displayed antinociceptive activity in the hot-plate test and the formalin test. Moreover, it induced a significant increase in brain serotonin (5-HT) concentration and a reduction in the number of 5-HT2 receptors in cortical membranes. Pretreatment with naloxone abolished this antinociceptive activity both in the hot-plate test and in the first phase of the formalin test without affecting the serum concentration of paracetamol. At the same time, naloxone prevented the increase in 5-HT concentration in the central nervous system and the reduction in 5-HT2 receptors in cortical membranes. Competition experiments demonstrated that paracetamol possesses affinity for [3H]naloxone binding sites. The action of morphine on nociception and on the serotonergic system was similar to that of paracetamol; all morphine-induced effects were blocked by naloxone. These data provide further evidence for a central antinociceptive effect of paracetamol and support the hypothesis that paracetamol exerts its antinociceptive activity through the serotonergic system. Moreover, our results point to the relationship between serotonergic and opiatergic systems in the antinociceptive activity of paracetamol.

Topics: Acetaminophen; Animals; Cerebral Cortex; Formaldehyde; Hot Temperature; Ketanserin; Kinetics; Male; Morphine; Motor Activity; Naloxone; Pain; Pons; Rats; Rats, Wistar; Receptors, Serotonin; Serotonin; Stereotyped Behavior

Peritoneal irritation in rats induced by i.p. administration of acetic acid produces abdominal contractions reflecting visceral pain, and gastrointestinal ileus characterized by inhibition of gastric emptying and small intestine transit. In this study, gastric emptying (GE) and intestinal transit, calculated by the geometric center (GC) method, were estimated using a test meal labeled with 51Cr-EDTA. Visceral pain was assessed by counting abdominal contractions. Acetic acid produced abdominal contractions (80.8 +/- 3.3) and inhibition of GE (-54%) and GC (-63%) during the test-period. The kappa-opioid receptor agonists, CI-977 (+/-)-U-50,488H, (+/-)-bremazocine, PD-117,302, (-)-cyclazocine, and U-69,583, reversed abdominal contractions and inhibitions of gastrointestinal transit in a dose-related manner. The mu-opioid receptor agonists and potent analgesics, morphine and fentanyl did not restore normal gastric emptying and intestinal transit. These data suggest that selective kappa-opioid receptor agonists might be used to treat abdominal pain associated with motility and transit impairment during postoperative ileus.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Acetic Acid; Analgesics; Animals; Benzofurans; Benzomorphans; Cyclazocine; Fentanyl; Gastric Emptying; Intestinal Pseudo-Obstruction; Male; Morphine; Naloxone; Naltrexone; Narcotic Antagonists; Pain; Peritoneum; Pyrroles; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa; Receptors, Opioid, mu; Thiophenes

The opioid antagonist, naloxone, produces equivocal effects on the magnitude of nociceptive responses in several animal models of persistent pain, including the formalin test. Hindpaw injection of dilute formalin produces not only inflammation but also phasic (Phase 1) and persistent (Phase 2) behavioral and cardiovascular nociceptive responses in the rat. To test the hypothesis that endogenous opioid systems contribute to the magnitude of responses to intraplantar formalin injection, we evaluated the effects of continuous naloxone administration (0.01-100 mg/kg per h, i.v.) on formalin-evoked hindpaw inflammation, on behavioral indices of pain, flinching and licking pain behavior, and on changes in mean arterial pressure and heart rate. We report that naloxone, at doses less than 100 mg/kg per h, did not change any formalin-evoked response. Although the 100 mg/kg per h dose significantly decreased these responses, it also produced muscle rigidity and profound bradycardia. We conclude that endogenous opioids do not significantly modulate the nociceptive processing induced by subcutaneous formalin.

Topics: Animals; Behavior, Animal; Blood Pressure; Formaldehyde; Heart Rate; Hemodynamics; Inflammation; Infusions, Intravenous; Injections, Subcutaneous; Male; Naloxone; Narcotic Antagonists; Pain; Rats; Rats, Sprague-Dawley

Social conflict between mice produces analgesia in the attacked mouse. Both the magnitude and type (opioid or nonopioid) of this analgesia have been related to attack intensity and strain of mouse. In the present study low intensity social conflict (7 bites) did not produce analgesia, whereas high intensity - 30 and 60 bites - interactions produced, respectively, short-lasting (5 min) and very short-lasting (1 min) analgesia in Swiss albino mice, when compared with nonaggressive interaction (0 bite). The 30 bites aggressive interaction induced analgesia (AIIA) was not affected by IP injection of either naloxone (5.0 and 7.5 mg/kg) or diazepam (0.5, 1.0, 2.0 and 4.0 mg/kg). However, this attack-induced analgesia was reduced after IP administration of the 5-HT1A agonists, gepirone (0.3 and 3.0 mg/kg) and BAY R 1531 (0.01 mg/kg). These results indicate that the analgesia induced by 30 bites social conflict in Swiss albino mice does not involve opioid and GABA-benzodiazepine (GABA-BZD) mechanisms. In addition, they suggest that high-intensity social conflict activates serotonergic pain modulatory systems that act through 5-HT1A receptors.

Topics: Analgesia; Analgesics, Opioid; Analysis of Variance; Animals; Conflict, Psychological; Diazepam; Indoles; Male; Mice; Morphine; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Pyrimidines; Receptors, Serotonin; Serotonin Receptor Agonists

The effects of inhalation anesthetics, nitrous oxide (N2O) and halothane, on the expression of c-Fos protein evoked by formalin injection were studied in the spinal cord in the rat. The expression of c-Fos protein was detected by immunocytochemistry following the injection of formalin (5%, 100 microliters) into the plantar surface of the left hindpaw. After 15 min of halothane (F) anesthesia, the anesthetics was switched to 40% or 70% of N2O, 0.5% or 1.5% of F or room air (for control) immediately following the formalin injection. Two hours later the rats were sacrificed and perfused. Sections of the L4 level of spinal cord were immunostained with anti c-Fos antibody. We counted the number of Fos-like immunoreactive (FLI) cells in every specific lamina as follows: superficial layer (laminae I and II), nucleus proprius (laminae III and IV), neck of the dorsal horn (laminae V and VI) and ventral gray (laminae VII-X). Then we compared the results of each category of sample. Both N2O and halothane suppressed the expression of c-Fos in the neck of the dorsal horn and ventral gray in a dose-dependent manner, but no effects were seen at the superficial layer or nucleus proprius. Suppression of c-Fos expression was greater under N2O than halothane anesthesia. This finding suggests that N2O had a stronger analgesic effect than halothane. The current study indicates that inhalation anesthetics do not act equally on every kind of spinal neurons. Both N2O and halothane have effects on spinal neurons in the deeper layers but not on the neurons existed in laminae I-II, some of which directly receive noxious inputs. Pretreatment with 2 mg/kg of naloxone, which completely reversed the effects of morphine, did not alter the effect of 70%N2O, suggesting that the analgesic effect of N2O is not mediated by an intrinsic opioid mechanism at the spinal cord level.

Topics: Analgesia; Anesthetics, Inhalation; Animals; Formaldehyde; Halothane; Hindlimb; Male; Naloxone; Narcotic Antagonists; Narcotics; Neurons; Nitrous Oxide; Pain; Proto-Oncogene Proteins c-fos; Rats; Rats, Wistar; Spinal Cord

The magnitude of tolerance and dependence is defined in part by agonist concentration and duration of receptor exposure. Therefore, in the face of continued exposure to an opioid agonist, periodic reduction in opiate receptor occupancy should reduce tolerance. Alternately, we have shown that reversal of opiate agonist action yields increased glutamate release and NMDA-antagonist studies indicated that this release may lead to an exacerbation of tolerance. To address this issue, we observed the effect of transient daily antagonism by naloxone of otherwise continuous opioid receptor exposure on morphine tolerance development. Rats with intrathecal (i.t.) catheters and osmotic minipumps were assigned to one of the following 7-day infusion/treatment groups: group A: i.t. morphine (20 nmol/h) with daily subcutaneous (s.c.) injection of naloxone 0.6 mg/kg, group B: i.t. morphine (20 nmol/h) with daily s.c. saline, group C: i.t. saline (1 microl/h) with daily s.c. injection of naloxone 0.6 mg/kg, or, group D: i.t. saline (1 microl/h) with daily s.c. saline. Hot plate response latency was measured daily before and after the s.c. injection. The infusion was discontinued on day 7 and on day 8 the response of the rat to a probe dose of i.t. morphine (60 nmol) given as a bolus was observed. Elevated hot plate latencies were observed for groups A and B on day 1 of infusion and this declined over the following 3-4-day interval. Group B approached baseline, but by day 5 group A showed a mild hyperalgesia prior to each naloxone injection. Groups C and D showed no change in baseline latency. On day 8, 24 h after termination of morphine infusion, the magnitude of the analgesic response to the probe i.t. morphine was: group D = group C > group B > group A (P < 0.05, 1-way ANOVA). Thus, in contrast to the expectation that tolerance would be reduced by periodic blockade of opiate receptor occupancy, rats that had daily transient receptor antagonism showed a greater tolerance than rats with simple continuous receptor occupancy. These results are, however, consistent with work showing that (i) naloxone will evoke spinal glutamate release in spinal morphine tolerant rats and (ii) spinal NMDA receptor antagonism ameliorates loss of opiate effect in this spinal infusion model.

Topics: Analgesics, Opioid; Animals; Drug Tolerance; Infusion Pumps; Injections, Spinal; Injections, Subcutaneous; Male; Morphine; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Rats; Rats, Sprague-Dawley; Time Factors

Previous reports have indicated that the implantation of adrenal medullary chromaffin cells into the spinal subarachnoid space can reduce both acute and chronic pain in several animal models. Recent findings suggest that acute and chronic pain alleviation may be mediated by distinct mechanisms. Since the formalin response is composed of an acute and tonic phase which can be pharmacologically distinguished, the ability of adrenal medullary implants to alter these responses was assessed. In rats with adrenal medullary transplants, both phases of the formalin response were attenuated, in contrast to control implanted animals. Suppression of the acute phase by adrenal medullary implants was reversed by the opiate antagonist naloxone, and partially reversed by the alpha-adrenergic antagonist phentolamine, suggesting that opioid peptides and catecholamines released by the implanted chromaffin cells contribute to the observed antinociception. However, neither antagonist altered the antinociceptive effects of adrenal medullary implants on the tonic phase of the formalin response. These results indicate that adrenal medullary implants in the spinal subarachnoid space alleviate acute and tonic pain via distinct pharmacologic mechanisms.

Topics: Adrenal Medulla; Adrenergic alpha-Antagonists; Animals; Foot; Formaldehyde; Injections; Male; Naloxone; Narcotic Antagonists; Pain; Palliative Care; Phentolamine; Rats; Rats, Sprague-Dawley; Spinal Cord; Subarachnoid Space

A new series of 4,6-diaryl pyridazines substituted in the 3-position by arylpiperazinyl moieties was synthesized and evaluated for analgesic activity. Five out of the nine tested compounds possessed significant antinociceptive effects in the phenylbenzoquinone-induced writhing test (PBQ test) with ED50 values ranging from 26.0 to 37.7 mg/kg ip. The most active derivatives 2a, 2d and 2h had a low toxicity (LD50 > 800 mg/kg ip) but showed some sedative and neurotoxic effects from the dose of 50 mg/kg ip. The three selected pyridazines were devoid of activity in the hot-plate test. However, analgesic activity of 2d and 2h was significantly reversed by naloxone in the PBQ test. Administered at the low dose of 5 mg/kg ip, 2h greatly potentiated the antinociceptive response induced by morphine (0.15 mg/kg sc). In addition, analgesic effects of 2h (2.5 mg/kg ip) were also potentiated by 5-hydroxytryptophan combined with carbidopa. These results suggest that pyridazine 2h induces analgesia, which is mediated via both opioid and serotonergic mechanisms.

Topics: Acetaminophen; Analgesics, Non-Narcotic; Analgesics, Opioid; Animals; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Benzoquinones; Dipyrone; Dose-Response Relationship, Drug; Drug Design; Drug Interactions; Injections, Intraperitoneal; Male; Mice; Morphine; Motor Activity; Naloxone; Narcotic Antagonists; Neurotoxins; Pain; Pyrazolones; Pyridazines; Receptors, Opioid; Reference Standards; Selective Serotonin Reuptake Inhibitors; Structure-Activity Relationship; Trazodone

The ability of the selective cholecystokinin(B) (CCK(B)) receptor antagonist L-365,260 (0.2 mg/kg s.c.) to modulate the antinociceptive action of relatively low doses of systemic morphine (0.1, 0.3 and 1.0 mg/kg i.v.) was evaluated using a well established rat model of peripheral unilateral mononeuropathy. Behavioural tests based on both mechanical (vocalization threshold to paw pressure) and thermal (struggle latency after immersion of the paw into a cold (10 degrees C), warm (44 degrees C) or hot (46 degrees C) water bath) stimuli were used. Experiments were performed 2 weeks after the surgery when the pain-related behaviour has fully developed. We demonstrated a differential effect of L-365,260 depending both on the dose of morphine and the test used. Pretreatment with the CCK(B) receptor antagonist (0.2 mg/kg) inverted the ineffectiveness of the lowest dose (0.1 mg/kg i.v.) of morphine against the noxious (46 degrees C) thermal stimulus, and the effect of the combination was equal to that seen after the dose 0.3 mg/kg of morphine alone. Likewise, in the mechanical test, the already enhanced effect of this dose (0.1 mg/kg) of morphine on the nerve-injured paw was further increased (by 4-fold) after L-365,260 pretreatment. These effects were abolished by naloxone (0.01 mg/kg i.v.). However, the effects of the higher doses (0.3 and 1.0 mg/kg i.v.) of morphine against the mechanical or noxious thermal stimuli were not significantly enhanced by pretreatment with the CCK(B) receptor antagonist. Further, L-365,260 was found to be completely ineffective in modulating the responses to morphine at 10 degrees C and at 44 degrees C.

Topics: Analgesics; Animals; Benzodiazepinones; Cold Temperature; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Hot Temperature; Male; Morphine; Naloxone; Narcotic Antagonists; Pain; Phenylurea Compounds; Rats; Rats, Sprague-Dawley; Receptor, Cholecystokinin B; Receptors, Cholecystokinin; Sciatic Nerve; Stress, Mechanical; Vocalization, Animal

The development of tolerance and dependence to morphine injected onto the spinal cord was examined in a model of chronic pain following spinal cord injury in rats. Intrathecal morphine completely relieved the marked pain-like response of these rats to innocuous mechanical stimuli. The analgesic effect of morphine injected twice daily was, however, diminished within a few days. Tolerance to the antinociceptive effect of morphine assessed with the tail flick test also developed similarly in rats with chronic pain and in normal controls. Both groups exhibited similar signs of naloxone-precipitated withdrawal after 3 weeks of morphine treatment. The results suggest that the presence of chronic pain-like behavior did not prevent the development of morphine tolerance and dependence, even when morphine was used to treat the chronic pain itself.

Topics: Animals; Behavior, Animal; Chronic Disease; Drug Tolerance; Female; Hyperesthesia; Injections, Spinal; Morphine; Naloxone; Narcotic Antagonists; Pain; Rats; Rats, Sprague-Dawley; Reference Values; Spinal Cord Injuries; Substance Withdrawal Syndrome; Substance-Related Disorders

The present study was designed to investigate a role of the subnucleus reticularis dorsalis (SRD) in the analgesia produced by a low dose of naloxone during carrageenan-induced inflammation. Male Sprague-Dawley rats were divided into the following two groups: (1) rats with bilateral lesions of the SRD (n = 13) and 2) sham-operated rats (n = 24). In each group, effects of a low dose of naloxone (5 microg/kg, i.p.) on thermal nociception were examined 4 h, 7 and 28 days after the induction of unilateral inflammation. Carrageenan (6 mg in 0.15 ml saline) was injected subcutaneously into the plantar surface of the left hindpaw. The analgesic effect was assessed by prolongation of the paw withdrawal latency (PWL) to heating. Prior to carrageenan injection, a low dose of naloxone did not prolong PWLs in either group. Four hours after carrageenan, a low dose of naloxone produced a prolongation of PWLs in both sham-operated and SRD-lesioned rats. Seven days after carrageenan, naloxone failed to produce analgesia in the SRD-lesioned rats but did produce analgesia in the sham-operated rats. At 28 days, a low dose of naloxone induced hyperalgesia in the inflamed paw of both groups, whereas naloxone was ineffective in the contralateral non-inflamed paw. These results suggest that the SRD plays a role in naloxone-induced analgesia during the subacute phase of inflammation (e.g. 7 days after induction of inflammation).

Topics: Analgesia; Animals; Carrageenan; Male; Medulla Oblongata; Naloxone; Narcotic Antagonists; Neuritis; Nociceptors; Pain; Rats; Rats, Sprague-Dawley; Reticular Formation

Cutaneous stimulation with CO2 laser pulses activates small diameter sensory afferents and evokes a pain-related potential best recorded from the vertex (Cz) of humans. We report here the first successful recording of pain-related laser evoked potentials (LEPs) from awake monkeys. Laser pulses with stimulus intensities adjusted to the lowest level giving reproducible cerebral responses were delivered to the shaved tail of three awake African green monkeys. The proximal and distal tail were stimulated to calculate the conduction velocity of the activated fibers. The effects of subcutaneous injections of morphine and cocaine on the LEPs were evaluated. The results indicate that reproducible LEPs, with a morphology similar to those obtained from humans, can be recorded from the awake monkey. The calculated conduction velocity of the activated fibers averaged 8.7 m/s, which is in the range of A delta fibers. Following subcutaneous morphine injections, the LEPs disappeared and were quickly restored to their baseline amplitude following administration of naloxone. Cocaine administered subcutaneously led to a significant attenuation of LEP amplitudes without producing behavioral sedation. These findings suggest that the LEPs recorded from monkeys represent analgesic-sensitive, nociceptive-related potentials similar to those recorded from humans.

Topics: Anesthetics, Local; Animals; Behavior, Animal; Chlorocebus aethiops; Cocaine; Evoked Potentials; Lasers; Male; Morphine; Movement; Naloxone; Narcotic Antagonists; Narcotics; Neural Conduction; Pain; Pain Measurement; Tail; Time Factors

Acute superfusion of nerve growth factor (NGF; 1-100 ng/ml) through a naive rat spinal cord preparation did not alter basal or electrically evoked release of substance P-like immunoreactivity (SP-LI). In contrast, neurotrophin-3 (NT-3; 1-100 ng/ml), although not modifying SP-LI basal outflow, dose-dependently inhibited the electrically evoked, but not capsaicin (10 nM)-induced, release of the peptide. This NT-3 (10 ng/ml)-induced inhibition persisted even in the presence of 100 ng/ml NGF in the perfusion fluid and was still significant when the evoked release of SP-LI was enhanced by a prolonged in vivo treatment with NGF. Co-superfusion with naloxone (0.1 microM), but not CGP 36742 (100 microM), a GABAB antagonist, prevented NT-3 (10 ng/ml) inhibition of SP-LI release. Basal and electrically evoked release of SP-LI from the rat spinal cord in vitro was not modified 24 hr after single systemic injection of either NGF (1 mg/kg) or NT-3 (10 mg/kg). At these time intervals from administration, NGF had induced thermal and mechanical hyperalgesia in the rat hindpaw, and NT-3 had induced mechanical, but not thermal, hypoalgesia. NT-3 administered six times over a 2 week period (at 1 mg/kg) did not alter thermal threshold but significantly reduced electrically evoked release of SP-LI from the spinal cord. An identical treatment regimen with 1 mg/kg NGF induced a significant increase in evoked release of SP-LI. However, this was not associated with a significant hyperalgesia. Although finding that NGF-induced hyperalgesia does not clearly correlate with changes in the release of SP-LI in the spinal cord, this study shows that NT-3 is an inhibitor of SP-LI release and suggests that this mechanism may be responsible for NT-3-induced antinociception.

Topics: Analgesics; Animals; Capsaicin; Dose-Response Relationship, Drug; Drug Interactions; Evoked Potentials; GABA Antagonists; GABA-B Receptor Antagonists; Hot Temperature; Hyperalgesia; Hypesthesia; Injections, Subcutaneous; Male; Naloxone; Narcotic Antagonists; Nerve Growth Factors; Neurotrophin 3; Organophosphorus Compounds; Pain; Pain Threshold; Perfusion; Pressure; Rats; Rats, Wistar; Secretory Rate; Single-Blind Method; Spinal Cord; Substance P

This study investigates the antinociception caused by intradermal (i.d) or intracerebroventricular (i.c.v.) injection of the capsaicin receptor antagonist capsazepine (CPZ), and ruthenium red (RR) (a cation-selective antagonist coupled to vanilloid receptor of capsaicin), on the chemical nociception caused by i.d. injection of formalin (FM) and capsaicin (CAP) into the mouse paw. The i.d. injection of either CPZ or RR in association with FM or CAP, inhibited the early phase, and to a lesser extent the late phase, of the FM, as well as CAP-induced nociception. Given i.c.v., both CPZ and RR caused discrete antinociception in the FM (both phases), while producing graded inhibition of CAP. The actions of CPZ and RR were insensitive to i.p. injection of naloxone (5 mg/kg). These results indicate that i.d. injection of CPZ and RR produce marked antinociception in chemical models of neurogenic pain induced by CAP and FM in mice. However, administered by supraspinal site, both CPZ and RR were inactive in inhibiting FM, but prevented, in a graded manner, CAP-induced algesic response, suggesting the participation of distinct mechanisms in the nociception induced by FM and CAP. Thus, vanilloid selective antagonists seem to be useful tools for investigating the nociception elicited by CAP and FM.

Topics: Analgesics; Animals; Capsaicin; Dose-Response Relationship, Drug; Formaldehyde; Injections, Intradermal; Injections, Intraventricular; Male; Mice; Naloxone; Pain; Ruthenium Red

Two 3,8 diazabicyclo (3.2.1.) octane derivates, namely DBO 17 and DBO 11, were studied for the opioid-like activity. In the rat brain membrane preparation binding studies, DBO 17 and DBO 11 showed a high affinity and selectivity for the mu opioid receptor (Ki's: 5.1 and 25 nM, respectively). DBO 17 and DBO 11 inhibited the nociceptive response in the hot-plate test of mice with ED50 values of 0.16 mg/kg and 0.44 mg/kg, respectively. The antinociceptive action of both DBO 17 and DBO 11 was blocked by naloxone. Tolerance to the antinociceptive action of DBO 17 and DBO 11 was present after 13 and 7 days of repeated treatment, respectively. Both DBO 17 and DBO 11 were ineffective in morphine-tolerant mice and vice versa. Chronic treatments (three times daily for seven consecutive days) of DBO 17 and DBO 11 induced a naloxone-precipitated withdrawal syndrome in DBO 17 treated mice similar to that in morphine treated mice, whereas in DBO 11 treated mice abstinence signs were virtually absent. These results indicate an interesting pharmacological profile that suggests these compounds as possible new candidates for the clinical treatment of pain.

Topics: Analgesia; Analgesics; Analgesics, Opioid; Animals; Aza Compounds; Brain; Bridged Bicyclo Compounds; Drug Tolerance; Male; Mice; Naloxone; Narcotic Antagonists; Pain; Rats; Rats, Sprague-Dawley; Receptors, Opioid, mu

Pain modulating neurons of the rostral ventromedial medulla (RVM) include three physiologically distinct classes of neurons in intact, anesthetized animals: and cells that change their activity before the onset of withdrawal reflexes and cells, which have activity unrelated to withdrawal reflexes. A previous in vitro intracellular study demonstrated that the RVM contains two types of neurons that are distinguished by their action-potential characteristics. The present in vivo intracellular study examined whether these intracellularly recorded action-potential characteristics are correlated with the physiological response properties of RVM neurons recorded. RVM neurons exhibited two distinct types of action potentials in vivo. Fast-spike (FS) neurons (n = 30) had short-duration action potentials (0.27 +/- 0.02 (SE) ms at half amplitude) and biphasic afterhyperpolarizations with a characteristic rapid overshooting spike repolarization. Slow-spike (SS) neurons (n = 25) had longer duration action potentials (0.44 +/- 0.02 ms at half-amplitude) due to a slower-spike repolarization rate and monophasic afterhyperpolarization. and cell classes included both FS and SS neurons. FS and neurons had an early onset response to noxious heat stimulation. SS and cells showed a delayed onset response to noxious heat. cells (n = 13) were all SS cells. Among the SS neurons, only cells had action potentials longer than 0. 45 ms (n = 9). FS and SS neurons were intermingled throughout the RVM. The majority of intracellularly labeled cells (n = 15) had fusiform somata with two to five fine caliber primary dendrites and a predominantly mediolateral orientation of the long axis of their dendritic tree. All labeled FS cells (n = 5) had large, multipolar somata with four to nine large caliber primary dendrites. The present study defines in vivo membrane and morphological characteristics of RVM neurons that correlate with physiological differences and may be used for identification of nociceptive modulatory RVM neurons in slice preparations.

Topics: Action Potentials; Analgesics, Opioid; Animals; Injections, Intravenous; Medulla Oblongata; Morphine; Naloxone; Narcotic Antagonists; Neurons; Pain; Rats; Rats, Sprague-Dawley

The effects of cutaneous noxious heat stimuli and intrathecal administration of morphine on the oxidation current of 5-hydroxytryptamine (serotonin: 5-HT) in the nucleus raphe magnus (NRM) were examined in anesthetized rats. An oxidation current of 5-HT was seen at 320-340 mV using differential normal pulse voltammetry with nafion-coated carbon fiber electrodes. The signal was decreased by 28.5 +/- 5.7 and by 12.7 +/- 4.1% after cutaneous noxious heat stimuli of 52 and 45 degrees C, respectively. These decreases lasted for 5-10 min. Non-noxious stimuli (37 degrees C) did not affect the 5-HT signal. Intrathecal administration of morphine (2.5, 5.0, 10.0 and 15.0 microg) in the absence of cutaneous stimulation did not change the signal significantly. However, low doses of morphine (2.5 or 5.0 microg, i.t.) potentiated the decrease in the 5-HT signal induced by noxious stimuli, and high doses (10.0 or 15.0 microg, i.t.) attenuated it. Both effects of morphine at low and high doses were antagonized by naloxone (0.5 mg/kg, i.p.). These results indicate that the intrathecal administration of morphine affects the cutaneous noxious heat stimulus-induced decrease of serotonin release in the NRM.

Topics: Animals; Electrochemistry; Hot Temperature; Hydroxyindoleacetic Acid; Injections, Spinal; Male; Morphine; Naloxone; Pain; Raphe Nuclei; Rats; Rats, Wistar; Reaction Time; Serotonin; Spinal Cord; Uric Acid

To clarify the properties of BL-2401 ((+/-)-3-[2-benzyl-3-(propionylthio) propionyl]amino-5-methylbenzoic acid), a novel enkephalinase inhibitor, we examined its antinociceptive and antidepressant-like activities after oral administration, along with their association with endogenous opioid systems. BL-2401 produced an antinociceptive effect after oral administration in the mouse phenylbenzoquinone writhing test (ED50: 12.4 mg/kg) and the rat acetic acid writhing test (ED50: 55.8 mg/kg), the antinociceptive effect being antagonized by naloxone hydrochloride. BL-2401 also relieved arthritis-induced hyperalgesia in rats. In the mouse hot-plate and tail pressure tests, BL-2401 showed significant but modest antinociception at higher doses (200 and 400 mg/kg). In addition, BL-2401 (100 mg/kg) produced a naloxone-reversible antidepressant-like effect in the mouse forced swimming test. As for the mechanism of the action, the active metabolite of BL-2401, BL-2240 ((+/-)-3-(2-benzyl-3-mercaptopropionyl) amino-5-methylbenzoic acid), selectively inhibited enkephalinase in vitro (IC50: 5.2 nM). Oral administration of BL-2401 to mice significantly inhibited the enkephalinase activity in the striatum and also potentiated the antinociceptive effect of (D-Ala2,Met5)-enkephalin given intracisternally. These findings indicate that BL-2401 is an orally active enkephalinase inhibitor and may produce antinociceptive and antidepressant-like effects in association with endogenous opioid systems.

Topics: Administration, Oral; Analgesics; Analgesics, Opioid; Animals; Antidepressive Agents; Benzoates; Benzoquinones; Corpus Striatum; Curcumin; Dose-Response Relationship, Drug; Drug Synergism; Enkephalin, Methionine; Female; Hyperalgesia; Male; Mice; Naloxone; Narcotic Antagonists; Narcotics; Neprilysin; Pain; Pain Measurement; Rats; Rats, Sprague-Dawley; Rats, Wistar; Sulfhydryl Compounds; Swimming

The present study was performed to explore the effects of intrathecal administration of calcitonin gene-related peptide8-37 (CGRP(8-37)) on the hindpaw withdrawal latency (HWL) to pressure in rats with one thermally injured hindpaw. Furthermore, the interaction of CGRP(8-37)and naloxone was studied. Thermal injury was performed by dipping the left paw into 60 degrees C for 20 s. This induced a significant increase in the volume of the left hindpaw (P<0.001) and significant bilateral decreases of the latency of hindpaw withdrawal response to mechanical stimulation (Left: P<0.001; right: P<0.05). Intrathecal administration of 10, 20 and 40 nmol of CGRP(8-37), but not of 1 or 5 nmol, induced a significant bilateral increase in HWLs (P<0.001). The effect of CGRP(8-37) was partly reversed by intrathecal injection of naloxone at a dose of 32 and 64 microg respectively. Using radioimmunoassay, we found a significant bilateral increase in the concentration of CGRP-like immunoreactivity in the perfusate of both hindpaws 24 h after unilateral thermal injury (left: P< 0.001; right: P< 0.05). There was also an increase in the amount of CGRP-like immunoreactivity in the cerebrospinal fluid (P< 0.001), but not in plasma. The results indicate that CGRP plays a role in the transmission of nociceptive information in the spinal cord of thermally injured rats. Furthermore, our findings suggest that opioids can modulate CGRP-related effects in the spinal cord.

Topics: Animals; Antibody Specificity; Burns; Calcitonin Gene-Related Peptide; Edema; Extracellular Space; Hot Temperature; Inflammation; Injections, Spinal; Male; Miotics; Naloxone; Narcotic Antagonists; Nociceptors; Pain; Peptide Fragments; Physical Stimulation; Pressure; Radioimmunoassay; Rats; Rats, Sprague-Dawley; Reaction Time; Reflex; Spinal Cord

There are controversial reports on the effect of diabetes on the pain threshold. We used male Wistar rats to see the effect of streptozotocin induced diabetes on the tail flick, vocalisation and vocalisation after discharge responses. These represent the spinal, lower brain stem and hypothalamic responses respectively. The effect of morphine in these parameters was studied for both the control and diabetic group. In diabetic rats, the pain threshold was increased. However, this increase was not significant. Morphine produced significant analgesia after thirty minutes for tail flick and vocalisation responses and after fifteen minutes for after discharge in the control group. The antinociceptive effect of morphine was delayed and reduced for all three pain threshold confirming the antagonistic action of glucose on opiate receptors.

Topics: Analgesics, Opioid; Animals; Diabetes Mellitus, Experimental; Male; Morphine; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Rats; Rats, Wistar; Receptors, Opioid, delta; Streptozocin

In the same mice in which the intracerebroventricular (i.c.v.) administration of antisense oligodeoxyribonucleotide (oligo) directed against the Gi2alpha (but not Gi1alpha, Gi3alpha or G(s)alpha) G-protein subunits attenuated i.c.v. morphine-induced antinociception in the tail-flick test, none of the oligos altered naloxone-precipitated jumping (acute dependence). Likewise, none of the oligos significantly altered morphine-induced constipation. Hence, i.c.v. morphine-induced antinociception might be preferentially mediated via transduction pathway(s) different from constipation or acute dependence, offering novel opportunities for drug discovery.

Topics: Analgesics, Opioid; Animals; Base Sequence; Cerebral Ventricles; Constipation; GTP-Binding Proteins; Injections, Intraventricular; Kinetics; Male; Mice; Mice, Inbred Strains; Molecular Sequence Data; Morphine; Morphine Dependence; Naloxone; Oligonucleotides, Antisense; Pain; Reaction Time

The present experiments explored the role of endogenous opioids in the behavioral response to a formalin-induced nociceptive stimulus in the rat. Flinching was taken as a measure of the intensity of the nociceptive stimulus after the administration of formalin into the dorsal surface of the paw of control animals, or in animals receiving i.p. administration of receptor-selective doses of opioid antagonists including naloxone, naltrindole (delta opioid antagonist), nor-binaltorphimine (kappa opioid antagonist) or beta-funaltrexamine (mu opioid antagonist). Additionally, antisera to [Leu5]enkephalin, [Met5]enkephalin and dynorphin A (1-13) (dynorphin) were administered intrathecally before formalin to explore the contribution of endogenous opioids in modulation of the flinching response. Formalin-induced flinching was increased significantly by naloxone, and receptor selective doses of naltrindole and nor-binaltorphimine, but not beta-funaltrexamine. Additionally, antisera to [Leu5]enkephalin and dynorphin also resulted in a significant increase in formalin-induced flinching, whereas antisera to [Met5]enkephalin had no effect. On the basis of significant increases in formalin-induced flinching produced by 1) receptor-selective doses of delta and kappa, but not mu, opioid antagonists and 2) antisera to [Leu5]enkephalin and dynorphin A, but not [Met5]enkephalin, these data suggest the presence of an opioid inhibitory tone which acts to limit the intensity of the pain signal. This tone appears to be mediated via activation of delta and kappa receptors, possibly by a [Leu5]enkephalin- and dynorphin-like substance, respectively.

Topics: Animals; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalins; Formaldehyde; Immune Sera; Male; Naloxone; Naltrexone; Narcotic Antagonists; Opioid Peptides; Pain; Rats; Rats, Sprague-Dawley; Receptors, Opioid, delta; Receptors, Opioid, kappa

A physiological role for beta-endorphin in endogenous pain inhibition was investigated by targeted mutagenesis of the proopiomelanocortin gene in mouse embryonic stem cells. The tyrosine codon at position 179 of the proopiomelanocortin gene was converted to a premature translational stop codon. The resulting transgenic mice display no overt developmental or behavioral alterations and have a normally functioning hypothalamic-pituitary-adrenal axis. Homozygous transgenic mice with a selective deficiency of beta-endorphin exhibit normal analgesia in response to morphine, indicating the presence of functional mu-opiate receptors. However, these mice lack the opioid (naloxone reversible) analgesia induced by mild swim stress. Mutant mice also display significantly greater nonopioid analgesia in response to cold water swim stress compared with controls and display paradoxical naloxone-induced analgesia. These changes may reflect compensatory upregulation of alternative pain inhibitory mechanisms.

Topics: Amino Acid Sequence; Analgesia; Analgesics, Opioid; Animals; Base Sequence; beta-Endorphin; Circadian Rhythm; Codon; DNA Primers; Female; Hypothalamo-Hypophyseal System; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Molecular Sequence Data; Morphine; Mutagenesis, Site-Directed; Naloxone; Pain; Pituitary-Adrenal System; Polymerase Chain Reaction; Pro-Opiomelanocortin; Protein Biosynthesis; Sex Characteristics; Stem Cells; Stress, Psychological; Tyrosine

Immune cell-derived opioid peptides can activate opioid receptors on peripheral sensory nerves to inhibit inflammatory pain. The intrinsic mechanisms triggering this neuroimmune interaction are unknown. This study investigates the involvement of endogenous corticotropin-releasing factor (CRF) and interleukin-1beta (IL-1). A specific stress paradigm, cold water swim (CWS), produces potent opioid receptor-specific antinociception in inflamed paws of rats. This effect is dose-dependently attenuated by intraplantar but not by intravenous alpha-helical CRF. IL-1 receptor antagonist is ineffective. Similarly, local injection of antiserum against CRF, but not to IL-1, dose-dependently reverses this effect. Intravenous anti-CRF is only inhibitory at 10(4)-fold higher concentrations and intravenous CRF does not produce analgesia. Pretreatment of inflamed paws with an 18-mer 3'-3'-end inverted CRF-antisense oligodeoxynucleotide abolishes CWS-induced antinociception. The same treatment significantly reduces the amount of CRF extracted from inflamed paws and the number of CRF-immunostained cells without affecting gross inflammatory signs. A mismatch oligodeoxynucleotide alters neither the CWS effect nor CRF immunoreactivity. These findings identify locally expressed CRF as the predominant agent to trigger opioid release within inflamed tissue. Endogenous IL-1, circulating CRF or antiinflammatory effects, are not involved. Thus, an intact immune system plays an essential role in pain control, which is important for the understanding of pain in immunosuppressed patients with cancer or AIDS.

Topics: Analgesics, Opioid; Animals; Base Sequence; Corticotropin-Releasing Hormone; Immunohistochemistry; Inflammation; Interleukin-1; Male; Molecular Sequence Data; Naloxone; Oligonucleotides, Antisense; Pain; Radioimmunoassay; Rats; Rats, Wistar

The dried aqueous extract of leaves of Buddleia cordata (loganiaceae) and its main flavonoid glycoside, linarin, have been evaluated for analgesic and antipyretic effects in mice and rats, respectively. Both the extract and linarin exerted significant and dose-dependent analgesic and antipyretic activities, the first being obtained against a chemical stimulus (writhing a test in mice) and the second being obtained by a pyretogenic stimulus (yeast-induced hyperthermia test). Furthermore, the response of the animals in the hot plate test was modified by linarin and an aqueous extract. These activities were similar to that showed by morphine sulfate (MS) and they were inhibited by naxolone pretreatment, a specific morphinic antagonist compound. These findings lead to the conclusion that the aqueous extract and linarin exert central analgesic properties. On the other hand, linarin was shown to be responsible for the antipyretic activity of this species.

Topics: Analgesics; Analgesics, Non-Narcotic; Animals; Fever; Glycosides; Male; Mice; Mice, Inbred Strains; Morphine; Naloxone; Pain; Plant Extracts; Plants, Medicinal; Rats; Rats, Wistar

We examined the antinociceptive effect of smilaxin B administered intracerebroventricularly (i.c.v.) in ICR mice. The tail-flick test was used as an analgesic assay. Smilaxin B showed a strong antinociceptive effect in a dose-dependent manner. Sulfated cholecystokinin (CCK-8s, 0.5 ng), muscimol (50ng), or MK-801 [(+/-)-5-methyl-10, 11-dihydro-5H-dibenzo [a,d]cyclohepten-5, 10-imine maleate, 1 microgram] injected i.c.v. significantly reduced inhibition of the tail-flick response induced by smilaxin B administered i.c.v. However, naloxone (2 microgram), baclofen (10 ng), or CNQX (6-cyano-7- nitroquinoxaline-2,3-dione, 0.5 microgram) injected i.c.v. did not affect inhibition of the tail-flick response induced by similaxin B administered i.c.v. The intrathecal (i.t.) injection of yohimbine (20 micrograms), but not methysergide (20 micrograms) and naloxone (2 microgram), significantly attenuated inhibition of the tail-flick response. induced by smilaxin B administered i.c.v. Our results suggest that GABAA or NMDA receptors but not opioid, GABAB, and non-NMDA receptors located at the supraspinal level may play important roles in the production of antinociception induced by smilaxin B administered supraspinally. Furthermore, smilaxin B administered supraspinally. may produce its antinociception by activating descending noradrenergic- but not opioidergic- and serotonergic-neurons.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Baclofen; Cerebral Ventricles; Dizocilpine Maleate; Glycosides; Injections, Intraventricular; Injections, Spinal; Male; Methysergide; Mice; Mice, Inbred ICR; Muscimol; Naloxone; Pain; Sincalide; Spinal Cord; Spirostans; Yohimbine

Antinociceptive and antitussive effects of morphine were studied in DA-bg/bg (Beige) rats. Intraperitoneal administration of morphine (10 mg/kg) produced a marked antinociceptive effect, in the tail-flick test, in Beige rats and DA rats, a progenitor strain rats. There was no significant difference in the peak antinociceptive effect of morphine between Beige rats and DA rats. The antinociceptive effect of morphine in both Beige rats and DA rats was significantly reduced following pretreatment with a low dose (0.3 mg/kg, i.p.) of naloxone or naltrexonazine (1 mg/kg, s.c.), a selective mu 1-opioid receptor antagonist. Morphine suppressed coughs dose dependently at doses between 0.3-3 mg/kg, i.p., in Beige rats and between 0.1-1.0 mg/kg, i.p., in DA rats. The antitussive potency of morphine in Beige rats was less than that in DA rats. The antitussive effect of morphine was significantly antagonized by pretreatment with naloxone (0.3 mg/kg, i.p.) in both Beige rats and DA rats. However, pretreatment with naltrexonazine (1 mg/kg, s.c.), a selective mu 1-opioid receptor antagonist, had no effect on the antitussive effect of morphine. These results suggest that Beige rats are hyporesponsive to the mu 2-opioid receptor-mediated antitussive effect, but not to the mu 1-opioid receptor-mediated antinociceptive effect.

Topics: Analgesics, Opioid; Animals; Capsaicin; Cough; Female; Male; Morphine; Naloxone; Naltrexone; Pain; Rats; Rats, Inbred Strains; Species Specificity

In previous studies, we reported that supraspinally administered DAMGO, a mu-opioid agonist, produces a dose-related, naloxone-reversible inhibition of formalin-evoked pain behaviors and spinal cord Fos-like immunoreactivity (FLI) in the rat spinal cord. Although these results support the hypothesis that activation of supraspinal mu-opioid receptors produces antinociception by increasing the activity of bulbospinal inhibitory pathways, other studies suggest that supraspinal morphine decreases rather than increases descending inhibitory control. In the present study, we specifically examined the effect of intracerebroventricular (i.c.v.) injection of morphine in the rat. Supraspinal morphine produced a dose-related, naloxone-reversible inhibition of both formalin-evoked behaviors nd spinal cord FLI. Although the magnitude of the antinociception produced by i.c.v. morphine in the formalin test was significantly correlated with the numbers of FLI neurons in the spinal cord, the lowest dose of i.c.v. morphine tested (0.70 nmol) produced a significant reduction of FLI in the superficial laminae without producing behavioral antinociception, which is consistent with our hypothesis that noxious stimulus-evoked Fos expression in the superficial laminae is a poor predictor of the magnitude of pain behavior. These data support the hypothesis that the antinociceptive effects of supraspinally administered morphine result from an increase in descending inhibitory control.

Topics: Analgesics; Analgesics, Opioid; Animals; Area Under Curve; Behavior, Animal; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalins; Immunohistochemistry; Injections, Intraventricular; Male; Morphine; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Physical Stimulation; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Spinal Cord

The rostral ventromedial medulla is a critical relay for midbrain regions, including the periaqueductal gray and nucleus cuneiformis, that control nociception at the spinal cord. Opioid-containing neurons and terminals are concentrated in both the periaqueductal gray and the rostral ventromedial medulla in the rat. However, the function of endogenous opioid peptides within the medulla in pain modulation is unclear. In this study, bicuculline (30-50 ng) or morphine (5 micrograms) microinjected into the periaqueductal gray inhibited the tail-flick reflex and the firing of on-cells (cells that increase firing just before tail flick) in the medulla. Iontophoretically applied naloxone (20 or 30 nA), which blocked the inhibition of on-cell firing induced by iontophoresis of morphine (20 or 30 nA), consistently reduced the on-cell inhibition produced by bicuculline or morphine microinjected into the periaqueductal gray. Naloxone did not reduce the inhibition of on-cell firing induced by iontophoretically applied clonidine (10 or 20 nA), an alpha 2 adrenoceptor agonist. The firing of off-cells (cells that pause in firing just prior to tail-flick) in the medulla was increased by bicuculline applied in the periaqueductal gray and was not affected by naloxone. The present results suggest that when activation of neurons in the periaqueductal gray produces antinociception, endogenous opioid peptides are released in the rostral ventromedial medulla and selectively inhibit on-cells, which presumably have a facilitating action on spinal nociceptive transmission. This action is proposed to be critical for the behavioral antinociception induced by bicuculline or morphine in the periaqueductal gray.

Topics: Animals; Bicuculline; Brain Mapping; Enkephalins; Evoked Potentials; Male; Medulla Oblongata; Morphine; Naloxone; Nerve Endings; Neurons; Pain; Periaqueductal Gray; Rats; Rats, Sprague-Dawley; Reflex

This study examined the contribution of endogenous opioids to the antinociception produced by microinjection of the GABAA receptor antagonist, bicuculline, into the rat midbrain ventrolateral periaqueductal gray region. Microinjection of bicuculline (40 ng/0.4 microliter) into the periaqueductal gray produced robust antinociception as measured by the tail-flick latency to noxious heat. This antinociception was partially reversed by intravenous administration of the non-selective opioid antagonist naloxone hydrochloride (1 and 5 mg/kg), indicating that endogenous opioid release is necessary for this effect. To determine whether opioid release in the rostral ventromedial medulla, a major projection target of the periaqueductal gray, contributes to this effect, we microinjected another opioid antagonist, naltrexone, into the rostral ventromedial medulla. Naltrexone in the rostral ventromedial medulla (5 and 10 micrograms/microliter) significantly attenuated bicuculline antinociception elicited from the periaqueductal gray. Cys2, tyr3, orn5, pen7-amide (26.5 nmol), a selective mu-opioid receptor antagonist, also reversed the antinociception when microinjected into the rostral ventromedial medulla. Microinjections of naltrexone (10 micrograms/microliter) or cys2, tyr3, orn5, pen7-amide at sites in the medulla dorsal to the rostral ventromedial medulla were ineffective. None of the antagonists altered baseline tail-flick latencies. These results support the hypothesis that a population of periaqueductal gray neurons produces antinociception through a mu-opioid receptor-mediated action of endogenous opioids in the rostral ventromedial medulla. Thus, two opioid-sensitive pain-modulating brainstem sites are linked by an endogenous opioid synapse in the rostral ventromedial medulla.

Topics: Animals; Bicuculline; Brain Mapping; GABA Antagonists; Male; Medulla Oblongata; Mesencephalon; Microinjections; Models, Neurological; Naloxone; Naltrexone; Narcotic Antagonists; Pain; Periaqueductal Gray; Rats; Rats, Sprague-Dawley; Receptors, Opioid, mu; Somatostatin; Spinal Cord; Time Factors

The antinociceptive effect of dipyrone, a nonsteroidal and inflammatory drug, was studied in a series of experiment employing tail-flick and hot-place models and the abdominal constrictor test. The drug was given via intracerebroventricular (i.c.v.), intrathecal (i.t.) or subcutaneous (s.c.) routes. Dipyrone exhibited no analgesic activity in the tail-flick and hotplate tests while it inhibited the number of stretches in a dose-dependent manner. The antinociceptive effect of dipyrone administered by the i.c.v. and i.t. routes was almost complete reversed by naloxone treatment. The same procedure attenuated but not completely inhibited the dipyrone action induced by s.c. administration. Histopathological examination revealed that i.t. dipyrone application produces no significant lesion in the spinal cord. The results suggest that dipyrone may exert a central antinociceptive action reversed by naloxone.

Topics: Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Dipyrone; Dose-Response Relationship, Drug; Female; Injections, Intraventricular; Injections, Spinal; Injections, Subcutaneous; Male; Mice; Naloxone; Narcotic Antagonists; Pain; Spinal Cord Injuries

Opioid overdose is rarely the primary cause of altered mental status in cancer patients receiving opioid therapy. The inappropriate administration of naloxone to reverse an abnormal mental status can cause severe withdrawal symptoms and pain. To illustrate this problem, we report the case of a patient inappropriately treated with naloxone and the results of a retrospective review of the medical records of 15 consecutive patients with cancer treated with naloxone in the emergency department over a 5-month period. We offer guidelines for a more thoughtful approach to the management of patients with cancer who present with encephalopathy.

Topics: Aged; Humans; Male; Naloxone; Narcotic Antagonists; Neoplasms; Pain; Substance Withdrawal Syndrome

A heptadecapeptide (orphanin FQ or nociceptin) was recently identified as an endogenous ligand for the orphan opioid-like receptor. Here we report that intrathecal orphanin FQ produces dose-dependent depression of a spinal nociceptive flexor reflex in the rat. Furthermore, administration of orphanin FQ in rats with intrathecal catheters produced behavioural antinociception in the tail flick test with no signs of sedation or motor impairment. The reflex depressive effect of orphanin FQ was not reversed by antagonists of opioidergic, alpha 2-adrenergic and GABA-A receptors. Thus, orphanin FQ may suppress nociceptive input at the spinal level through an novel mechanism. Orphanin FQ or agonists of its receptor may represent novel analgesics for pain conditions which are not responsive to existing pharmacological therapy.

Topics: Adrenergic alpha-Antagonists; Adrenergic beta-2 Receptor Antagonists; Analysis of Variance; Animals; Bicuculline; Electromyography; Electroshock; Female; GABA-A Receptor Antagonists; Imidazoles; Injections, Spinal; Muscle, Skeletal; Naloxone; Narcotic Antagonists; Nerve Fibers; Nociceptin; Opioid Peptides; Pain; Rats; Rats, Sprague-Dawley; Receptors, Opioid; Spinal Cord; Sural Nerve

The aim of the present study was to evaluate the action of the descending modulation system from the locus coeruleus (LC) in a rat model of unilateral hyperalgesic inflammation. Unilateral hindlimb inflammation was produced by a subcutaneous injection of carrageenan (6 mg in 0.15 ml saline). One week before testing, rats received bilateral lesions of the LC using anodal current. Nociception was assessed by measuring withdrawal of the paw from a noxious thermal stimulus. Four hours after carrageenan injection, paw withdrawal latencies (PWLs) in the inflamed paw of the LC-lesioned rats were significantly shorter than those of the sham-operated rats. This difference in PWL between the two groups was not observed at 7 days, whereas edema and hyperalgesia still remained in the inflamed paw. At 4 h, systemic naloxone produced a further decrease of the PWL in the LC-lesioned rats but not in the sham-operated rats. These results suggest that inflammation-induced activation of the descending modulation system from the LC occurs in only the acute phase of inflammation and that a decrease in the extent of the development of hyperalgesia in the acute phase of inflammation might depend on the interaction between the descending modulation system from the LC and the opioid inhibitory system.

Topics: Analysis of Variance; Animals; Carrageenan; Disease Models, Animal; Efferent Pathways; Endorphins; Hindlimb; Hyperalgesia; Inflammation; Locus Coeruleus; Male; Naloxone; Pain; Rats; Rats, Sprague-Dawley

Naloxone has been reported to affect pain and locomotor activity differently depending on the dose. The objective of the present investigation was to study the effects of low and high (6 micrograms and 3 mg/kg, s.c.) doses of naloxone (Nx) on formalin-induced pain (tonic pain) and spontaneous motor activity and any correlation between them. The experiments were conducted on adult male Wistar rats. Tonic pain and spontaneous motor activity were recorded by the formalin test and video monitoring respectively. An increase in spontaneous motor activity (locomotion, movements and distance) was observed following formalin injection as compared to basal activity (P < 0.05). Low dose of Nx reduced the pain intensity and also the spontaneous motor activity during the later phase (after 15 min of formalin injection) (P < 0.05). High dose of Nx on the other hand increased the pain intensity but still reduced motor activity (P < 0.05). Both doses of Nx initially produced hyperalgesia (5 min peak). The bidirectional effects of Nx on formalin pain were dissociated from the spontaneous motor behavior of rats. A direct correlation could not be established between pain intensity and spontaneous motor activity.

Topics: Animals; Behavior, Animal; Dose-Response Relationship, Drug; Formaldehyde; Male; Motor Activity; Naloxone; Narcotic Antagonists; Nociceptors; Pain; Rats; Rats, Wistar

Neuropathic pain states are accompanied by increased sensitivity to both noxious and non-noxious sensory stimuli, characterized as hyperalgesia and allodynia, respectively. In animal models of neuropathic pain, the presence of hyperalgesia and allodynia are accompanied by neuroplastic changes including increased spinal levels of substance P, cholecystokinin (CCK), and dynorphin. N-Methyl-D-aspartate (NMDA) receptors appear to be involved in maintaining the central sensitivity which contributes to neuropathic pain. In addition to its opioid activities, dynorphin has been suggested to act at the NMDA receptor complex. In an attempt to mimic the increased levels of spinal dynorphin seen in animal models of neuropathic pain, rats received a single intrathecal (i.t.) injection of dynorphin A(1-17), dynorphin A(1-13), dynorphin A(2-17) or dynorphin A(2-13) through indwelling catheters. Tactile allodynia was determined by measuring response threshold to probing with von Frey filaments. Dynorphin A(1-17) administration evoked significant and long-lasting tactile allodynia (i.e. > 60 days). Likewise, the i.t. administration of dynorphin A(1-13) or dynorphin A(2-17) or dynorphin A(2-13) also produced long-lasting tactile allodynia. Intrathecal pretreatment, but not post-treatment, with MK-801 prevented dynorphin A(1-17)-induced development of allodynia; i.t. administration of MK-801 alone had no effect on responses to tactile stimuli. In contrast, i.t. pretreatment with naloxone did not affect the development of tactile allodynia induced by dynorphin A(1-17) or alter sensory threshold when given alone. These results demonstrate that a single dose of dynorphin A, or its des-Tyr fragments, produces long-lasting allodynia which may be irreversible in the rat. Further, this effect appears to be mediated through activation of NMDA, rather than opioid, receptors. While the precise mechanisms underlying the development and maintenance of the allodynia is unclear, it seems possible that dynorphin may produce changes in the spinal cord, which may contribute to the development of signs reminiscent of a "neuropathic' state. Given that levels of dynorphin are elevated following nerve injury, it seems reasonable to speculate that dynorphin may have a pathologically relevant role in neuropathic pain states.

Topics: Animals; Chronic Disease; Dizocilpine Maleate; Dynorphins; Excitatory Amino Acid Antagonists; Injections, Spinal; Male; Naloxone; Narcotic Antagonists; Pain; Peptide Fragments; Peripheral Nervous System Diseases; Rats; Rats, Sprague-Dawley; Sensory Thresholds

The sites in the rat hypothalamus where microinjection of morphine (5 micrograms/0.5 microliters) or electrical stimulation depresses the tail withdrawal reflex to noxious heating of the skin were examined. Among other hypothalamic sites found to be sensitive to morphine or to an electrical stimulus, the posterior part of the lateral hypothalamic area (LHA) was the only portion of the hypothalamus that was strongly sensitive to both manipulations. A 15-sec period of 35 microA sine-wave stimulation of the LHA significantly increased the latency of the tail reflex for periods up to 30 min. The effects of intraperitoneal administration of antagonists to opioids (naloxone), 5-hydroxytryptamine (methysergide), noradrenaline (phenoxybenzamine), dopamine (haloperidol), and acetylcholine (atropine and mecamylamine) on the antinociceptive effects of LHA stimulation were also examined. Naloxone, methysergide, and atropine (all given at doses of 0.5 and 1.0 mg/kg) attenuated the effects of LHA stimulation in a dose-dependent manner. Phenoxybenzamine but not haloperidol (both at the dose of 1.0 mg/kg), was also effective but dose-dependent curves could not be constructed. Mecamylamine (1.0 mg/kg) reduced the duration but not the peak effect of stimulating the LHA. We conclude that antagonism at the level of opioid, serotonergic, adrenergic, and muscarinic cholinergic receptors, but not dopamine or nicotinic cholinergic receptors, reduces the antinociceptive effects of LHA stimulation. This may imply that antinociception evoked from the LHA depends on the activation of descending pathways that relay in the mesencephalic periaqueductal gray matter and then in the nucleus raphe magnus and/or nucleus reticularis paragigantocellularis.

Topics: Adrenergic alpha-Antagonists; Analgesia; Analgesics, Opioid; Animals; Atropine; Dopamine Antagonists; Electric Stimulation; Haloperidol; Hypothalamic Area, Lateral; Male; Mecamylamine; Methysergide; Morphine; Muscarinic Antagonists; Naloxone; Narcotic Antagonists; Nicotinic Antagonists; Pain; Phenoxybenzamine; Rats; Rats, Wistar; Serotonin Antagonists

Physiological experiments were run to examine the effects of noxious thermal stimulation of one hindpaw on the tail-flick reflex in the lightly anesthetized rat. Male Sprague-Dawley rats were anesthetized with an i.p. injection of a mixture of Na-pentobarbital (20 mg/kg) and chloral hydrate (120 mg/kg). After baseline readings were taken in the tail-flick test, either a non-noxious or a noxious stimulus was applied which consisted of immersion of one hindpaw in water at 40, 45, 50 or 55 degrees C for 1.5 min. After immersion, tail-flick readings were taken at 3-min intervals for at least 16 min. Paw immersion in water at 55 degrees C induced an antinociceptive response, consisting of an increase in the reaction time, at 0.5 min after immersion. Recovery to baseline levels occurred over the next 3-6 min. Immersion at lower temperatures provoked smaller antinociceptive responses, except at 40 degrees C, where readings remained around the baseline values. The increase in reaction time in response to immersion at 55 degrees C was attenuated or blocked by the novel, nonpeptide substance P (NK-1) receptor antagonist, CP-96,345, administered s.c. 30 or 60 min, respectively, prior to paw immersion. Similar injection of CP-96,344, the inactive stereoisomer, had no effect on the response, while another NK-1 receptor antagonist, CP-99,994, also attenuated the antinociceptive effect of the immersion. The increase in reaction time induced by immersion at 55 degrees C was absent in animals treated neonatally with capsaicin.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Capsaicin; Endorphins; Hindlimb; Hot Temperature; Immersion; Male; Naloxone; Neurokinin-1 Receptor Antagonists; Nociceptors; Pain; Pain Measurement; Rats; Rats, Sprague-Dawley; Substance P

An aqueous fraction and dioclein (5,2',5'-trihydroxy-6,7-dimethoxyflavanone) obtained from the ethanolic extract of the Dioclea grandiflora were tested for their analgesic effect in mice and rats employing acetic-induced writhing and tail flick tests, respectively. When administered intraperitoneally the two agents exhibited significant analgesic effects. The activity of both dioclein and aqueous fraction apparently involves an opiate-like mechanism, since their analgesic action was attenuated by naloxone pretreatment.

Topics: Acetates; Acetic Acid; Analgesics; Animals; Chemical Fractionation; Dose-Response Relationship, Drug; Drug Interactions; Ethanol; Flavanones; Flavonoids; Injections, Intraperitoneal; Male; Mice; Naloxone; Pain; Plant Extracts; Random Allocation; Rats; Rats, Wistar

The effect of opioid peptides on corticofugal modulation of nociceptive response in thalamic ventrobasal nucleus (VB) produced by cortical sensorimotor area II (Sm II) was observed. Single unit activities of VB neurons were extracellularly recorded by glass microelectrodes. The results showed that the nociceptive responses of VB neurons were attenuated at 0-7.5 minutes after stimulating Sm II (n = 14, P < 0.05). The inhibitory effect of stimulation of Sm II was reduced after ventriculer microinjection of 20ul of naloxone (n = 9), while marked inhibition was shown at 0-2.5 minutes after stimulating Sm II in the saline control group (n = 9, P < 0.05). There was a statistical difference at 0-2.5 minutes after stimulating Sm II between the two groups (P < 0.05). These studies suggest that opioid peptides might be involved in corticofugal modulation of pain.

Topics: Animals; Down-Regulation; Injections, Intraventricular; Naloxone; Neurons; Nociceptors; Opioid Peptides; Pain; Rats; Rats, Wistar; Somatosensory Cortex; Thalamic Nuclei

Abnormal sensory hyperexcitability consequent to peripheral injury most likely involves activation of N-methyl-D-aspartate (NMDA) receptors in the spinal cord. This activation may lead to a cascade of neuroplastic events resulting in the exaggeration of sensory responses and the persistence of pathological pain states. Recent studies in our laboratory have demonstrated that the transplantation of adrenal medullary cells into the spinal subarachnoid space can alleviate pathological pain symptoms, possibly by reducing spinal hyperexcitability. The purpose of this study was to assess spinal NMDA activation-induced hypersensitivity to noxious and innocuous stimuli, and determine whether adrenal medullary transplants can intervene favorably to reduce these responses. Animals with either adrenal medullary or control transplants were injected intrathecally with several doses of NMDA, and responses to sensory stimuli were determined over time. NMDA at all doses tested (1-50 nmol) produced significant thermal and mechanical hyperalgesia and tactile allodynia in control transplanted animals, with peak severity at 30 min post-injection. In contrast, both the severity and duration of these exaggerated sensory responses were markedly reduced in animals with adrenal medullary transplants. To assess a possible contribution of released opioid peptides and catecholamines from the transplanted chromaffin cells, animals were pretreated with opiate antagonist naloxone or alpha-adrenergic antagonist phentolamine. While naloxone was ineffective, the phentolamine partially attenuated, but did not completely abolish, the antinociceptive effects of the transplants. The results of these studies demonstrate that adrenal medullary grafts can reduce hypersensitivity responses to NMDA-mediated activation via alpha-adrenergic modulation in addition to other neuroprotective mechanisms.

Topics: Adrenal Medulla; Animals; Dose-Response Relationship, Drug; Hot Temperature; Hyperalgesia; Injections, Spinal; Male; N-Methylaspartate; Naloxone; Nociceptors; Pain; Phentolamine; Physical Stimulation; Rats; Rats, Sprague-Dawley; Spinal Cord

The analgesic effects of the non-steroidal anti-inflammatory drugs (NSAIDs) flunixin and dipyrone were assessed in healthy sheep with no pre-existing inflammation, and in sheep with a chronic inflammatory lesion, using a mechanical noxious stimulus. Saline and dexamethasone were given as controls. Blood taken from healthy sheep after NSAID administration was assayed for thromboxane B2 (TxB2) to compare the ability of these drugs to inhibit cyclo-oxygenase. Both flunixin and dipyrone produced a small but statistically significant rise in pain thresholds (18% and 21% of maximum possible effect respectively) in the healthy sheep which peaked at 30 min and had returned to pre-drug values by 2-3 h. In the lame sheep a similar effect occurred but the response was smaller, much more variable and tended to be prolonged. Saline and dexamethasone had no effect on thresholds over 6 h in either group of sheep. The rise in thresholds was prevented by pre-treatment with naloxone (an opioid antagonist) or atipamezole (an alpha 2-adrenergic antagonist) in the healthy sheep. Naloxone and atipamezole had no effect on thresholds when given alone to healthy sheep. Both NSAIDs inhibited the production of TxB2 to a similar extent. These results indicate that central mechanisms may be involved in NSAID analgesia.

Topics: Adrenergic alpha-Antagonists; Analgesia; Animals; Anti-Inflammatory Agents, Non-Steroidal; Clonixin; Dipyrone; Double-Blind Method; Drug Interactions; Female; Foot Rot; Imidazoles; Injections, Intravenous; Lameness, Animal; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Random Allocation; Sheep; Sheep Diseases; Thromboxane B2

Studies in mice and rats have shown that antinociception produced by intrathecal (i.t.) administration of opioids can be partially inhibited by intracerebroventricular (i.c.v.) administration of naloxone. In this study we tested the hypothesis that this inhibition by i.c.v. naloxone results from antagonism of supraspinal endogenous opioid-mediated antinociception produced by the action of i.t. opioids on an ascending antinociceptive pathway. In rats lightly anesthetized with urethane/alpha-chloralose, i.t. DAMGO, i.t. lidocaine, or spinal transection at T5-T6 all attenuated the trigeminal jaw opening reflex (JOR) (i.e., were antinociceptive), an effect that was antagonized in each case by i.c.v. naloxone. These findings support the suggestion that there exists a pathway that ascends from the spinal cord to a supraspinal site that tonically inhibits antinociception mediated by supraspinal opioids. When activity in this ascending pathway is suppressed (e.g., by i.t. opioids or local anesthetics or by spinal cord transection), antinociception mediated by supraspinal opioids is disinhibited. To determine the supraspinal site(s) at which endogenous opioid-dependent antinociception is evoked by i.t. opioids, we microinjected naloxone methiodide into several supraspinal sites. Microinjection of naloxone methiodide into nucleus accumbens but not into the rostral ventral medulla (RVM) or the periaqueductal gray matter (PAG) antagonized the suppression of the JOR produced by i.t. DAMGO or lidocaine. The possibility that this ascending pathway may represent a source of spinal input to mesolimbic circuitry involved in setting the state of sensorimotor reactivity to noxious stimuli is discussed.

Topics: Analgesics; Animals; Brain Stem; Cerebral Ventricles; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalins; Injections, Intraventricular; Injections, Spinal; Lidocaine; Male; Mice; Microinjections; Models, Neurological; Naloxone; Pain; Rats; Rats, Sprague-Dawley; Reflex; Spinal Cord; Synapses; Trigeminal Nerve

We analysed the effects of morphine microinjections (0.2 microliter) into the subnucleus oralis (SNO), i.e. the rostral division of the spinal trigeminal nucleus, on the formalin test adapted for orofacial pain. Duration of rubbing following an injection (50 microliters) of formalin solution (1.5%) in the right upper lip of the rat was measured. Compared to microinjections of saline (NaCl, 0.9%) used as control, 90 and 180 nmol microliter-1 of morphine solution in the SNO significantly curtailed rubbing. This effect was dose-dependent, reversed by naloxone, and also site-specific to the SNO since no effect was observed after microinjection of morphine into areas adjacent to the SNO. These results are further evidence for the involvement of the SNO in perioral nociceptive mechanisms.

Topics: Animals; Dose-Response Relationship, Drug; Formaldehyde; Male; Microinjections; Morphine; Naloxone; Pain; Rats; Rats, Sprague-Dawley; Trigeminal Nucleus, Spinal

Systemically administered local anesthetics are known to provide analgesia in a variety of pain states; however, the site of action and the mechanism by which these effects are produced remain in question. In the present study, the effects of low (subblocking for nerve conduction) concentrations of lidocaine on a spinal cord nociceptive potential were studied. Spinal cords were removed from neonatal rats and maintained in vitro. Lumbar dorsal and ipsilateral ventral roots were attached to suction electrodes for stimulation and recording, respectively. Following a stabilization period (60-120 min) with control measurements, each preparation was exposed to a single concentration of lidocaine (30-60 min) then returned to control perfusate for recovery (60-120 min). Data were digitized and integrals computed for both monosynaptic and slow ventral root potentials (VRP). Low concentrations of lidocaine produced a selective reduction in the magnitude of the slow-VRP. At lidocaine concentrations of 1-10 micrograms/ml (3.6-36 microM), the slow-VRP was reduced from 79% to 36% of control. Recovery to pre-exposure control levels was slow and sometimes not complete after 60-120 min in drug-free perfusate. The monosynaptic component of the VRP was unaffected by lidocaine at any concentration, suggesting that the depression of the slow-VRP cannot be attributed to simple conduction block. The addition of naloxone 0.1 microM to the perfusate had minimal effect on lidocaine-induced depression. Although resembling the selective effects of morphine, the antinociceptive effects of lidocaine do not appear to be primarily mediated through opiate receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Butylamines; Female; In Vitro Techniques; Lidocaine; Male; Naloxone; Pain; Rats; Rats, Sprague-Dawley; Spinal Cord; Tetrodotoxin

2-Amino-5-tert-butyl-2-oxazoline (ATBO, 2) was synthetized from 3,3-dimethyl-2-iodobutyl isocyanate via N-(3,3-dimethyl-2-iodobutyl) urea (1). The structures of compounds 1 and 2 are based on analytical and spectroscopic data. Compound 2 induced in rats and mice a peripheral antinociceptive effect through both spinal and supraspinal mechanisms. ATBO did not impair motor coordination or activity of the experimental animals.

Topics: Acetates; Acetic Acid; Animals; Anti-Inflammatory Agents, Non-Steroidal; Dose-Response Relationship, Drug; Male; Methimazole; Mice; Morphine; Motor Activity; Naloxone; Oxazoles; Pain; Pain Measurement; Postural Balance; Rats; Rats, Wistar

Antinociceptive effects of systemically or locally administered opioid mu, kappa and delta agonists were evaluated in a rat model of visceral pain. Resiniferatoxin (RTX, 3 nmol), a capsaicin-like mutant, produced abdominally directed grooming behavior after direct administration into the urinary bladder (intravesical, Lves.) by indwelling cannula. Systemic (s.c. or i.p.) pretreatment with the mu agonists morphine or [D-Ala2, NMePhe4, Gly-ol]enkephalin (Damgo), the kappa agonists trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl] benzeneacetamide (U50,488) or [5R-(5,7,8-beta)]-N-methyl-N-[7-(1-pyrrolidinyl)1-oxaspiro[4,5]dec - 8-yl]-4-benzofuranacetamide (CI-977), or the nonpeptidic delta agonist (+/-)-4-((alpha-R*)-alpha-((2S*,5R(*)-4-Allyl-2,5-dimethyl-1- piperazinyl)-3-hydroxybenzyl)-N, N-diethylbenzamide (BW373U86) dose-dependently decreased RTX-induced abdominal licking; such antinociception was selectively blocked by the appropriate receptor-selective antagonists beta-funaltrexamine (mu), nor-binaltorphimine (kappa) and naltrindole (delta). Local (i.ves.) BW373U86, [D-Ala2,Glu4]deltorphin (DELT II) and Cl-977 also significantly decreased RTX-induced licking. Intracerabroventricular quaternary naloxone partially blocked the effects of systemic morphine, but not that of CI-977 or BW373U86. Intraperitoneal quaternary naloxone blocked the effect of local and systemic BW373U86 but not that of local or systemic CI-977; systemic morphine was partially blocked. Thus, systemic mu, kappa and delta agonists all produced antinociception against a novel visceral chemical stimulus in the rat. Local CI-977 also produced antinociception, but the only compound clearly acting at peripheral opioid receptors was BW373U86, a delta agonist. This study suggests that opioid delta receptors may be present on bladder nociceptive afferents and may be activated for production of peripheral analgesia.

Topics: Analgesics, Opioid; Animals; Diterpenes; Drug Administration Routes; Female; Grooming; Naloxone; Narcotic Antagonists; Pain; Rats; Rats, Sprague-Dawley; Receptors, Opioid; Viscera

The spiking activity of single units and their corresponding mass activity in the rostral ventromedial medulla (RVM) was recorded simultaneously in rats that were either awake or anesthetized with pentobarbital or ketamine. Autocorrelograms and cross-correlograms were calculated to illustrate the distribution of interspike intervals under each of these conditions. The spontaneous activity in both anesthetized groups, but not the awake group, displayed a low incidence for short intervals (about 1-36 ms) between spikes. However, this low incidence of short interspike intervals was found in some awake rats following the administration of subanesthetic dosages of ketamine, pentobarbital, or morphine. The occurrences, or lack of occurrences of these short interspike intervals may be a marker for the anesthetized state of the rat. A basal spiking pattern, as illustrated by three different types of correlograms, was observed, and these basal patterns did not usually change after the administration of morphine to awake or anesthetized rats, even though the cells became excited or inhibited. Cross-correlograms revealed that the synapses between "on" and "off" cells might sometimes be inhibitory, while at other times they might be excitatory; however, cells of the same class mainly shared excitatory connections. In summary, ketamine and pentobarbital do alter the firing patterns of individual neurons in the RVM, but, no matter what state the rat is in, the activity of individual RVM neurons is strongly related to the activity of other neurons in the local network.

Topics: Action Potentials; Analgesics, Opioid; Animals; Data Interpretation, Statistical; Drug Combinations; Ketamine; Male; Medulla Oblongata; Morphine; Naloxone; Pain; Pentobarbital; Rats; Reference Values

We have characterised pressor responses to stimulation of the ureter in anaesthetised rats (n = 20) as a model of acute visceral pain. The left ureter was cannulated close to the bladder and graded stimuli applied (5-90 mmHg, 30 s). The threshold was approximately 25 mmHg. Suprathreshold pressures evoked responses proportional to the stimulus intensity, which were little altered when stimulation of the kidney was prevented by ligation of the ureteric-pelvic junction. The stimulus response curve was dose-dependently attenuated by morphine (1-3 mg kg-1 i.v.), in a naloxone reversible manner. The characteristics of the responses observed correlate well with pain sensation in man and with the properties of ureteric primary afferent neurones in animals.

Topics: Analgesics, Opioid; Anesthesia; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Kidney Pelvis; Morphine; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Pain Threshold; Pressure; Rats; Rats, Wistar; Ureter

The effects of intraperitoneal (I.P.), intracerebroventricular (ICV) and intrathecal (IT) opiates were studied in the rat neuropathic pain model of Kim and Chung. Dose dependent reduction of allodynia was observed after I.P. and ICV morphine, but not after IT morphine, IT or ICV c[D-pen2 D-pen5]enkephalin (DPDPE) (delta agonist), or IT or ICV U50488H (kappa agonist). The effects of ICV morphine were blocked by I.P. naloxone, but not by IT methysergide, phentolamine or 8-sulfophenyltheophylline. Catalepsy (immobility) was observed after IT, ICV and IT morphine but this was not reliably associated with a reduction of allodynia. I.P. and ICV morphine may thus reduce tactile allodynia via supraspinal, but not spinal, mu opioid receptors.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Analgesics, Opioid; Animals; Enkephalin, D-Penicillamine (2,5)-; Enkephalins; Injections, Intraperitoneal; Injections, Intraventricular; Injections, Spinal; Morphine; Motor Activity; Naloxone; Narcotic Antagonists; Pain; Peripheral Nerve Injuries; Pyrrolidines; Rats; Rats, Sprague-Dawley

Neuropeptide FF (NPFF) is a mammalian FMRFamide-like octapeptide with antiopioid properties that inhibits morphine-induced analgesia but also produces hyperalgesia. In the present study, a series of three experiments was carried out to investigate the interactions between opioid receptor stimulation and antiopioid systems. First, by using in vitro superfusion system with rat spinal cord slices, we showed that morphine stimulated NPFF release in a dose-dependent manner. The stimulating effect which was observed with morphine concentrations as low as 100 fM reached a maximum at 0.1 nM, then decreased and was ineffective at 10 microM. The morphine-induced release of NPFF was abolished by naloxone (1 microM) but unaltered by tetrodotoxin. Second, by an in vivo approach, we showed that a single heroin administration (2.5 mg/kg, s.c.) elicited in 30 min a drastic drop (38%) in spinal NPFF content. In a third experiment, we evaluated the capacity of naloxone in revealing an antiopioid component associated with opioid receptor stimulation. The administration of naloxone (1 mg/kg, s.c..) 25 min following that of heroin (2.5 mg/kg, s.c.) not only abolished the heroin-induced increase of tail-flick latency, but also lowered it under the basal value by 30%. These results indicate that opioid receptor stimulation activates both pain inhibitory and pain facilitatory systems in which NPFF may play a significant role and that opiate-induced analgesia is always partly masked.

Topics: Animals; Heroin; In Vitro Techniques; Male; Morphine; Naloxone; Narcotic Antagonists; Neuropeptides; Oligopeptides; Pain; Rats; Rats, Sprague-Dawley; Reaction Time; Receptors, Opioid; Spinal Cord; Tetrodotoxin

The adjuvant arthritic rat model has been utilized for the study of chronic pain, as polyarthritic rats present a variety of symptoms similar to those seen in human chronic pain conditions. In particular, hyperventilatory responses are notable in both and may more accurately reflect basal ongoing pain than do evoked noxious stimuli. To assess whether adrenal medullary transplants in the spinal subarachnoid space can alleviate basal arthritic pain, respiratory parameters were determined using whole body plesthmography in polyarthritic rats. Arthritis was induced by inoculation with an intradermal injection of complete Freund's adjuvant. Steady-state ventilation was monitored at weekly intervals in arthritic animals with adrenal medullary or control striated muscle transplants. Results revealed that adjuvant arthritis produced significant hyperventilation in animals with control transplants, as indicated by increased tidal volumes and minute ventilation, which paralleled the progression of the inflammatory process. In contrast, this hyperventilation was eliminated by adrenal medullary transplants. A role for catecholamines and opioid peptides released from the transplants was suggested by the reversal of these effects with phentolamine and naloxone. In addition, the retardation in weight gain normally observed in polyarthritic animals was markedly attenuated by adrenal medullary, but not control transplants. These findings indicate that adrenal medullary transplants in the spinal subarachnoid space can alleviate basal chronic pain as assessed in adjuvant arthritis.

Topics: Adrenal Medulla; Adrenergic alpha-Antagonists; Animals; Arthritis, Experimental; Catecholamines; Chronic Disease; Hyperventilation; Naloxone; Narcotic Antagonists; Opioid Peptides; Pain; Pain Management; Phentolamine; Rats; Rats, Sprague-Dawley; Respiratory Mechanics; Subarachnoid Space; Weight Gain

We have previously reported that repetitive, noxious colorectal distention (CRD) induces c-Fos in the lumbosacral spinal cord. This study examined the effects of the analgesics morphine and tramadol on c-Fos expression resulting from noxious CRD in the rat. Pre-treatment (30 min or 1 min, i.v.) with morphine (1.25 mg/kg-5.0 mg/kg) or tramadol (1 mg/kg-20 mg/kg) dose-dependently attenuated c-Fos expression to CRD in all areas of the L6-S1 spinal gray matter. The highest dose of morphine was equipotent to the highest dose of tramadol. Repetitive dosing (1/4 of the greatest dose every 30 min) was as effective as a single bolus dose for both drugs. The visceromotor response to CRD was dose-dependently attenuated by tramadol and was reversed by naloxone. However, the dose of tramadol that eliminated the visceromotor response (7% of control) reduced the c-Fos expression to 47% of control. These results demonstrate that these two analgesics attenuate immediate-early gene expression and the visceromotor response to a noxious visceral stimulus and suggest that complete attenuation of c-Fos expression is not necessary for these compounds to produce analgesia to a noxious visceral stimulus.

Topics: Analgesics, Opioid; Animals; Behavior, Animal; Colon; Dose-Response Relationship, Drug; Electromyography; Gene Expression; Genes, fos; Male; Morphine; Naloxone; Narcotic Antagonists; Pain; Physical Stimulation; Rats; Rats, Sprague-Dawley; Rectum; Spinal Cord; Tramadol

Substance P, a putative neurotransmitter or neuromodulator of nociception or pain in the spinal cord, exhibits both antinociceptive and hyperalgesic properties. Investigators have shown that the N-terminal metabolite of substance P, substance P(1-7), produces naloxone-reversible antinociception when given supraspinally and systemically in mice and hyperalgesia when injected intrathecally in rats. The goal of our investigation was to identify the receptors mediating these actions of substance P(1-7) at the initial site of release of substance P, i.e. in the spinal cord. Thirty minutes after intrathecal injection, substance P(1-7) produced naloxone-reversible antinociception in a dose-dependent manner in the abdominal stretch assay. When administered with naloxone, substance P(1-7) produced hyperalgesia 5 and 10 min after injection, which was inhibited by dizocilpine (MK-801), a phencyclidine ligand and non-competitive antagonist of N-methyl-D-aspartate. Antinociception was inhibited by the mu-selective opioid antagonist beta-funaltrexamine, but not by the mu 1-selective opioid antagonist naloxonazine or the delta-selective antagonist naltrindole, indicating a mu 2-opioid receptor-mediated effect. These findings suggest that the N-terminal portion of substance P may modulate nociception or pain, as demonstrated in the acetic acid abdominal stretch (writhing) assay, via activation of two different receptor systems. Substance P(1-7)-induced hyperalgesia is mediated by a phencyclidine-sensitive mechanism and antinociception involves activity at mu-opioid, most likely mu 2, receptors.

Topics: Animals; Biological Assay; Disease Models, Animal; Dizocilpine Maleate; Hyperalgesia; Injections, Spinal; Injections, Subcutaneous; Male; Mice; Naloxone; Naltrexone; Narcotic Antagonists; Pain; Peptide Fragments; Phencyclidine; Receptors, Opioid, mu; Spinal Cord; Substance P

Acute inflammation of the sigmoid wall was induced by perendoscopic injection of formalin (50 microliters, 5%) under brief anesthesia in rats. The procedure was followed by behavioral patterns that significantly differed from those in animals injected with isotonic saline instead of formalin. Analysis of the formalin-induced behaviors allowed for the calculation of a pain score that evolved in a biphasic manner along the 3 h of test. The score was dose-dependently reduced by morphine (0.5-4 mg/kg), and the analgesic effect of the largest morphine dose was abolished by naloxone (2.4 mg/kg). These results suggest that formalin into the sigmoid colon is a new model of visceral pain, presumably through direct irritation at injection site and/or localized acute inflammation of the intestinal wall.

Topics: Acute Disease; Animals; Colitis; Disease Models, Animal; Female; Formaldehyde; Morphine; Naloxone; Pain; Pain Measurement; Palliative Care; Rats; Rats, Sprague-Dawley; Sodium Chloride; Viscera

Fedotozine has been shown to act on gastrointestinal sensitivity through peripheral kappa-opioid receptors. The present study investigated the action of fedotozine and reference compounds, morphine and (+/-)-U-50,488H, on duodenal pain in anesthetized rats. The noxious stimulus was produced by duodenal distension (100 mm Hg; 30 s). Fedotozine (1-5 mg/kg i.v.) produced a dose-dependent inhibition of the cardiovascular reflex induced by duodenal distension (ED50 = 1.87 mg/kg) but had no effect at doses up to 300 micrograms/rat by either intracerebroventricular (i.c.v.) or intrathecal routes (i.t.). The mu-opioid receptor agonist, morphine, was active by both i.v. (ED50 = 0.62 mg/kg) and i.c.v. routes (ED50 = 2.17 micrograms/rat) as was the kappa-opioid receptor agonist, (+/-)-U-50,488H (trans-(+/-)-3,4-dichloro-N-methyl-N-(2-[1- pyrrolidinyl]cyclohexyl)benzeneacetamide) (ED50 = 0.25 mg/kg and 149 micrograms/rat for i.v. and i.c.v. routes, respectively). The selective kappa-opioid receptor antagonist, nor-binaltorphimine (10 mg/kg s.c.), abolished the response to fedotozine (5 mg/kg i.v.) and (+/-)-U-50,488H (2 mg/kg i.v.) but not that to morphine (1 mg/kg i.v.). In contrast, naloxone (30 micrograms/kg i.v.) blocked the response to morphine (1 mg/kg i.v.) but not that to fedotozine (5 mg/kg i.v.) or (+/-)-U-50,488H (2 mg/kg i.v.). It is concluded that the antinociceptive effects of fedotozine on duodenal pain are mediated by peripheral kappa-opioid receptors.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Animals; Benzyl Compounds; Blood Pressure; Dose-Response Relationship, Drug; Duodenum; Injections, Intravenous; Injections, Intraventricular; Male; Morphine; Naloxone; Naltrexone; Pain; Propylamines; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa; Reflex

Pain associated-anxiety induced by formalin, which resulted in a significant delay in the development of tolerance to morphine antinociception, failed to prevent the development of physical dependence as evidenced by naloxone challenge. Dependence also developed in mice rendered tolerant to morphine. Thus, the development of morphine dependence was observed in the absence and presence of tolerance to morphine antinociception; Our results further confirm the dissociation of opioid tolerance and dependence in the animal model of experimental pain/anxiety.

Topics: Analgesia; Animals; Anxiety; Disease Models, Animal; Drug Tolerance; Formaldehyde; Injections, Intraperitoneal; Injections, Subcutaneous; Male; Mice; Morphine; Morphine Dependence; Naloxone; Pain; Pain Threshold

This work describes a method for performing direct intrathecal (i.t.) injections in rats without introducing a spinal catheter. Its ease of use in awake animals yields rapid and reproducible results with no sign of motor impairment. The quality of each injection was ensured by the observation of an injection-induced tail-flick. A 10-microL injection of methylene blue was well localized yielding a very limited diffusion along the spinal cord. The method was validated by demonstrating that morphine (i.t.) had a marked antinociceptive effect and that naloxone (i.t.) blocked the effect of systemic (s.c.) morphine in mononeuropathic rat.

Topics: Administration, Cutaneous; Animals; Injections, Spinal; Male; Methylene Blue; Morphine; Naloxone; Pain; Rats; Rats, Sprague-Dawley

Topics: Analgesics, Opioid; Documentation; Female; Humans; Male; Naloxone; Nursing Assessment; Pain; Respiratory Insufficiency; Risk Factors

The effects were investigated of cysteamine--a well known somatostatin depletor--on the pain induced by chemical stimuli in mice. Cysteamine injected intraperitoneally 4 h before the test at doses of 50 and 100 mg/kg reduced the second phase of the licking response which was induced by formalin injected into the hind paw. Furthermore, cysteamine administered at the doses of 10, 50 and 100 mg/kg reduced the writhing induced by acetic acid. Naloxone, yohimbine and CGP 35348 administered in cysteamine-pretreated animals were not able to change the cysteamine antinociceptive effects in the formalin test. Intrathecally injected somatostatin was able to revert the cysteamine antinociceptive effects in the second phase of the formalin test and in the writhing test, whereas intracerebroventricularly injected somatostatin reduced the antinociceptive effects induced by cysteamine in the second phase of the formalin test. Intrathecally injected cyclo(7-aminoheptanoyl-Phe-D-Trp-Lys-Thr[Bzl])--a reported somatostatin antagonist--increased cysteamine antinociceptive effects in the second phase of the formalin test and in the writhing test. These results suggest that somatostatin is involved in the effects of cysteamine on the nociceptive threshold.

Topics: Amino Acid Sequence; Animals; Cysteamine; Drug Interactions; Locomotion; Male; Mice; Molecular Sequence Data; Naloxone; Organophosphorus Compounds; Pain; Somatostatin; Yohimbine

Local analgesic effects of exogenous opioid agonists are particularly prominent in painful inflammatory conditions and are mediated by opioid receptors on peripheral sensory nerves. The endogenous ligands of these receptors, opioid peptides, have been demonstrated in resident immune cells within inflamed tissue of animals and humans. Here we examine in vivo and in vitro whether interleukin 1 beta (IL-1) or corticotropin-releasing factor (CRF) is capable of releasing these endogenous opioids and inhibiting pain. When injected into inflamed rat paws (but not intravenously), IL-1 and CRF produce antinociception, which is reversible by IL-1 receptor antagonist and alpha-helical CRF, respectively, and by the immunosuppressant cyclosporine A. In vivo administration of antibodies against opioid peptides indicates that the effects of IL-1 and CRF are mediated by beta-endorphin and, in addition, by dynorphin A and [Met]enkephalin, respectively. Correspondingly, IL-1 effects are inhibited by mu-, delta-, and kappa-opioid antagonists, whereas CRF effects are attenuated by all except a kappa-antagonist. Finally, IL-1 and CRF produce acute release of immunoreactive beta-endorphin in cell suspensions freshly prepared from inflamed lymph nodes. This effect is reversible by IL-1 receptor antagonist and alpha-helical CRF, respectively. These findings suggest that IL-1 and CRF activate their receptors on immune cells to release opioids that subsequently occupy multiple opioid receptors on sensory nerves and result in antinociception. beta-Endorphin, mu- and delta-opioid receptors play a major role, but IL-1 and CRF appear to differentially release additional opioid peptides.

Topics: Analysis of Variance; Animals; Antibodies; beta-Endorphin; Corticotropin-Releasing Hormone; Cyclosporine; Dose-Response Relationship, Drug; Dynorphins; Endorphins; Enkephalin, Leucine; Enkephalin, Methionine; Humans; Inflammation; Injections; Interleukin-1; Male; Naloxone; Pain; Rats; Rats, Wistar; Recombinant Proteins; Regression Analysis; Somatostatin

The prevailing view is that supraspinal mu opioid-mediated antinociception in mice is mediated via the mu 1 subtype. The purpose of the present study was to determine if the highly mu-selective compound etonitazene could produce supraspinal (intracerebroventricular; i.c.v.) antinociception in CXBK mice, which are deficient in brain mu1, but not mu2, opioid receptors. CXBK or normal Crl:CD-1 (ICR)BR mice were administered graded doses of etonitazene i.c.v. and 15 min later antinociception was assessed by a standard radiant-heat or 55 degrees C water tail-flick test. Etonitazene produced dose-related antinociception that was blocked by naloxone and by beta-FNA (demonstrating a mu opioid mechanism), but not by either ICI-174,864 or naltrindole (demonstrating the lack of involvement of delta opioid receptors). These findings suggest that mu2 opioid receptors are important contributors to opioid-induced supraspinal antinociception in mice.

Topics: Animals; Benzimidazoles; Cerebral Ventricles; Dose-Response Relationship, Drug; Enkephalin, Leucine; Hot Temperature; Injections, Intraventricular; Injections, Subcutaneous; Male; Mice; Mice, Inbred ICR; Mice, Mutant Strains; Naloxone; Naltrexone; Narcotic Antagonists; Pain; Receptors, Opioid, mu; Spinal Cord

alpha 2 Agonists are powerful analgesics after spinal delivery. The current work characterizes the dose-dependent antinociception and effects upon respiratory function of dexmedetomidine after intrathecal, epidural, intravenous, and intracisternal delivery in chronically prepared dogs.. Dogs were prepared with chronic tracheostomies and trained to perform rebreathing studies. These animals were then prepared with chronic lumbar intrathecal, epidural, or intracisternal catheters.. A rapid dose-dependent increase in the thermal skin twitch response latency and paw withdrawal to mechanical pinch was observed after intrathecal, epidural, and intravenous dexmedetomidine (dose required to reach 50% of maximal effect for skin twitch = 1.8, 10, and 15 micrograms, respectively) but not after intracisternal dexmedetomidine (> 15 microgram), with the maximally effective dose lasting approximately 90 min. The spinal effect was unaccompanied by effects upon behavioral alertness, motor function, or changes in CO2 response. In contrast, intravenous dexmedetomidine (1-10 micrograms/kg) resulted in a dose-dependent sedation and a significant reduction in heart rate and respiratory rate and a diminished response to increased CO2, these effects lasting approximately 2 h. Intracisternal administration of up to 15 micrograms had no effect upon the nociceptive threshold, and CO2 response, and failed to result in a significant reduction in alertness. All of the effects of dexmedetomidine were antagonized by the alpha 2-antagonist atipamezole (30-300 micrograms/kg, intravenous), but not by the opioid antagonist naloxone (30 micrograms/kg, intravenous), while atipamezole did not reverse the antinociceptive or respiratory depressant actions of intravenous sufentanil (50 micrograms), effects which were reversible by naloxone.. Dexmedetomidine, acting through an alpha 2-receptor, produces a powerful antinociceptive effect, mediated at the spinal level, while systemic redistribution of the drug leads to a hypnotic state with significant cardiorespiratory effects.

Topics: Adrenergic alpha-Agonists; Adrenergic alpha-Antagonists; Anesthesia, Epidural; Anesthesia, Spinal; Animals; Body Temperature; Carbon Dioxide; Dogs; Dose-Response Relationship, Drug; Forelimb; Heart Rate; Hindlimb; Imidazoles; Infusions, Intravenous; Infusions, Parenteral; Medetomidine; Motor Activity; Naloxone; Pain; Receptors, Adrenergic, alpha-2; Respiration

We have recently developed a rat model of chronic pain states after spinal cord injury. Thus, after severe, but incomplete, ischemic spinal cord injury, some rats chronically exhibited responses indicative of pain to innocuous mechanical stimuli (allodynia) in the rostral dermatomes involving the injured spinal segments. These responses have some characteristics in common with chronic central pain in patients with spinal cord injury. We now report that systemic CI988, a specific antagonist of the cholecystokinin (CCK) type B receptor, effectively relieved the allodynia-like symptom, an effect that was reversed by the opioid receptor antagonist naloxone. Furthermore, in rats which did not develop the allodynia-like symptom after spinal cord lesion, systemic naloxone induced typical allodynia. In contrast, naloxone failed to produce allodynia in normal animals. It is thus suggested that the abnormal sensory processing initiated by spinal cord ischemic lesion is under tonic opioidergic control and dysfunction of this control by the upregulated endogenous CCK system is responsible for the development of painful sensations in these rats.

Topics: Animals; Anti-Anxiety Agents; Behavior, Animal; Cholecystokinin; Chronic Disease; Diazepam; Endorphins; Female; Indoles; Meglumine; Naloxone; Pain; Pain Measurement; Pain Threshold; Rats; Rats, Sprague-Dawley; Receptors, Cholecystokinin; Spinal Cord Injuries; Vocalization, Animal

This work studies the antinociceptive effect of a sustained (7 day) release dosage form of vapreotide, a peptidic analogue of somatostatin, in rats submitted to a nociceptive mechanical stimulus (paw pressure). One intramuscular injection (0.6 mg/animal) induced a significant antinociceptive effect for 7 complete days with a maximal increase in vocalization thresholds of 68 +/- 5% and a plateau of activity during the first 4 days. This action was totally inhibited by naloxone (1 mg kg-1, s.c.) injected 24 h or 6 days after vapreotide, suggesting an opioidergic involvement throughout the antinociceptive effect. These findings suggest potential interest in human therapy.

Topics: Analgesics; Animals; Delayed-Action Preparations; Injections, Intramuscular; Male; Naloxone; Pain; Pain Measurement; Rats; Rats, Sprague-Dawley; Receptors, Opioid; Somatostatin; Time Factors

Intracerebroventricular (i.c.v.) administration to mice of IgGs raised against alpha subunits of Gi2 or Gx/z transducer proteins lessened the activation of low Km GTPase induced by morphine, DAMGO and DADLE in P2 membranes from mouse periaqueductal grey matter (PAG). In mice injected with anti Gi2 alpha, DADLE, DPDPE and [D-Ala2] Deltorphin II, but not beta-endorphin-(1-31), antagonized the analgesic activity of morphine. Conversely, following anti Gx/z alpha, morphine antagonized the antinociceptive potency of DADLE. It is concluded that opioids display diverse efficacy at mu-Gi2 and mu-Gx/z complexes to produce supraspinal analgesia in mice.

Topics: Amino Acid Sequence; Analgesia; Analgesics, Opioid; Animals; Cell Membrane; Cerebral Ventricles; Endorphins; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, D-Penicillamine (2,5)-; Enkephalin, Leucine-2-Alanine; Enkephalins; GTP Phosphohydrolases; GTP-Binding Proteins; Immunoglobulin G; Injections, Intraventricular; Kinetics; Male; Mice; Molecular Sequence Data; Morphine; Naloxone; Pain; Peptide Fragments; Receptors, Opioid, mu; Signal Transduction

Recent data have suggested that adrenal medullary tissue allografts in the spinal cord subarachnoid space, by releasing catecholamines and opioid peptides, attenuate responses to various acute noxious stimuli and chronic pain-related behaviors. However, the application of this approach is limited by the low availability of allogeneic donor material. Alternatively, chromaffin cells from xenogeneic sources such as the bovine adrenal medulla are plentiful and simple to extract. The goal of this study was to evaluate the potential for bovine chromaffin cell xenografts in the rat spinal subarachnoid space to alleviate chronic pain. This was assessed in an animal model of neuropathic pain induced by loose ligation of the sciatic nerve, which resulted in allodynia, hyperalgesia, and skin temperature abnormalities. Two weeks after nerve injury, animals were implanted with either isolated bovine chromaffin cells or control bovine adrenal fibroblasts in the spinal subarachnoid space at the level of lumbar enlargement and immunosuppressed with cyclosporine A. In animals with chromaffin cell implants, but not fibroblast implants, both cold allodynia and thermal hyperalgesia were markedly reduced or eliminated as early as 1 week following implantation and hind paw skin temperature asymmetry was also normalized. These beneficial effects were maintained without decrement or apparent tolerance for the 9 week course of the symptomology. The analgesic effects of chromaffin cell grafts were partially attenuated following i.t. injection of naloxone and phentolamine separately and in combination, suggesting involvement of spinal opioid and alpha-adrenergic receptors. Following termination of behavioral studies, immunocytochemical analysis revealed robust survival of chromaffin cells in the implants. These results demonstrate that chromaffin cell xenografts may be effective in alleviating pain of neurogenic origin.

Topics: Adrenal Medulla; Animals; Body Temperature; Cattle; Chromaffin System; Cold Temperature; Hindlimb; Male; Naloxone; Pain; Peripheral Nervous System Diseases; Phentolamine; Rats; Rats, Sprague-Dawley; Spinal Cord; Subarachnoid Space

This study was undertaken to examine the role of morphine in modulation of nociception in visceral and somatic pain tests at the level of the spinal cord, using neurophysiological and behavioural reflex assays. In the neurophysiological study, we recorded extracellularly the activity of the single viscero-somatic convergent neurons of the spinal dorsal horn, which was evoked by the colorectal distention (80 mmHg) of noxious visceral stimulation and the radiant heat (51 degrees C) of noxious somatic stimulation, in decerebrated, spinally transected cats. Spinally administered morphine (200 micrograms) produced significant suppression of noxiously evoked activity by both stimuli in a time-dependent manner. In addition, intravenously administered naloxone reversed the suppressive effects of morphine. In the behavioral reflex study, colorectal distension threshold and tail-flick latency were measured in rats chronically implanted with lumbar intrathecal catheter. Intrathecally administered morphine significantly elevated the colorectal distension threshold and prolonged the tail-flick latency in a time- and dose-dependent manner. The results of the present study demonstrated that spinal morphine was capable of suppressing the evoked activity of the viscero-somatic convergent neurons, resulting in suppression visceral and somatic pain behavioral reflexes.

Topics: Afferent Pathways; Animals; Behavior, Animal; Cats; Colon; Evoked Potentials; Female; Foot; Injections, Spinal; Male; Morphine; Naloxone; Neurons; Pain; Rats; Rats, Sprague-Dawley; Rectum; Sensory Thresholds; Skin; Spinal Cord; Viscera

The purpose of this study was to examine whether adenosine or serotonin is involved in mediation of the antinociception produced by norepinephrine at the spinal cord level. Aminophylline, an adenosine receptor antagonist and naloxone given intrathecally (i.t.) were used to test the antinociception produced by i.t. norepinephrine, serotonin, morphine or the adenosine receptor agonist 5'-N-ethylcarboxamidoadenosine (NECA) by using the tail-flick assay in rats. It was observed that (1) aminophylline blocked the antinociception produced by norepinephrine, but exhibited no effect on the antinociception produced by serotonin, (2) aminophylline blocked the antinociception produced by morphine similarly to naloxone, (3) aminophylline blocked the antinociception produced by NECA and (4) naloxone failed to block the antinociception produced by NECA and serotonin. The results suggest that adenosine is involved in mediation of the norepinephrine-produced antinociception at the spinal level and that norepinephrine and adenosine may act in a sequential manner in norepinephrine-induced antinociception.

Topics: Adenosine; Adenosine-5'-(N-ethylcarboxamide); Aminophylline; Animals; Female; Male; Morphine; Naloxone; Norepinephrine; Pain; Purinergic P1 Receptor Agonists; Rats; Rats, Wistar; Serotonin; Spinal Cord; Time Factors

The effects of intrathecally (IT) administered naloxone (Nal) on the antinociception produced by IT norepinephrine (NE), serotonin (5-HT), or morphine (Mor) were observed and compared in rats using the tail-flick (TF) assay. The results show that: a) NE, 5-HT, and Mor in doses of 1 nmol, 240 nmol, and 0.5 nmol, respectively, produce similar increases in amplitude and time in TF latency (TFL); b) Nal treatment of 240 and 360 nmol has no effects on TFL; c) the antinociception produced by NE (1 nmol) can be blocked by Nal (240 nmol); d) antinociception produced by Mor (0.5 nmol) can also be blocked by Nal (240 nmol); e) 240 nmol of Nal does not affect the 5-HT (120 nmol)-produced antinociception, while 360 nmol of Nal show a delayed blockade to the 5-HT (120 nmol)-produced antinociception. The results suggest that endogenous opiate-like substances may be involved in both NE- or 5-HT-produced antinociception at the spinal level, and these effects may be mediated through different types of opiate receptors.

Topics: Animals; Dose-Response Relationship, Drug; Female; Injections, Spinal; Male; Morphine; Naloxone; Norepinephrine; Pain; Rats; Rats, Wistar; Reflex; Serotonin; Spinal Cord; Time Factors

RB101 (N-((R,S)-2-benzyl-3[(S)(2-amino-4-methylthio)butyl dithio]-1-ox-opropyl)-L-phenylalanine benzyl ester) is a recently developed full inhibitor of the enkephalin-catabolizing enzymes able to cross the blood-brain barrier, whereas RB38A ((R)-3-(N-hydroxycarboxamido-2-benzylpropanoyl)-L-phenylalanine) is as potent as RB101 but almost unable to enter the brain. In this study, we have investigated the effects of systemic administration of morphine, RB101 and RB38A on nociception induced by pressure on inflamed peripheral tissues. Antinociceptive test was performed between 4 and 5 days after injection into the rat left hindpaw of Freund's complete adjuvant to produce localized inflammation. Morphine (1, 2 and 4 mg/kg, i.v.) induced antinociception in inflamed paws at all the doses used, and only at the highest dose in non-inflamed paws. RB101 (10 and 20 mg/kg, i.v.) induced an antinociceptive response only in the inflamed paws. RB38A, also induced an antinociceptive effect in the inflamed paws, but only at the highest dose (20 mg/kg, i.v.). The responses induced by morphine and the inhibitors of enkephalin catabolism were antagonized by the systemic administration of naloxone (1 mg/kg) or methylnaloxonium (2 mg/kg) which acts essentially outside the brain. Central injection (i.c.v.) of methylnaloxonium (2 micrograms) blocked the effect of morphine only in non-inflamed paws, and slightly decreased the response induced by RB101 on inflamed paws. These results indicate that the endogenous opioid peptides, probably enkephalins, are important in the peripheral control of nociception from inflamed tissues.

Topics: Analgesics; Animals; Disulfides; Enkephalins; Hydroxamic Acids; Inflammation; Injections, Intraventricular; Male; Morphine; Naloxone; Narcotic Antagonists; Neprilysin; Pain; Pain Measurement; Phenylalanine; Quaternary Ammonium Compounds; Rats; Rats, Sprague-Dawley

The general and sexual activity of food restricted male broiler breeder poultry was assessed for evidence of behavioural changes associated with musculoskeletal lesions. The activity and fertility of male birds given betamethasone (an anti-inflammatory steroid) or saline were compared in a two-period crossover experiment. Behavioural changes occurred and the birds' mating activity and fertility were decreased when they were given the steroid, but these effects were not associated with the presence of lesions. In a second experiment, there were no differences in sexual motivation between birds either with or without leg disorders. The birds were trained to walk down an alley for their food and the speed of walking was compared in a two-period crossover experiment. Betamethasone decreased their walking speed in period one and the carryover effect was significant in period two. Naloxone decreased the walking speed of birds with lesions more than of those without lesions. This effect was taken as evidence for analgesia by endogenous opioids and may help to explain the lack of response of the birds to the analgesic agent. The evidence that these food restricted male broiler breeder birds experienced pain was equivocal.

Topics: Animals; Betamethasone; Body Weight; Chickens; Cross-Over Studies; Food Deprivation; Male; Musculoskeletal Diseases; Naloxone; Organ Size; Pain; Poultry Diseases; Sexual Behavior, Animal; Testis

Topics: Acupuncture Analgesia; Animals; Hyperalgesia; Male; Naloxone; Pain; Pain Measurement; Rats; Rats, Wistar; Sciatic Nerve

The pharmacological properties of a structurally novel kappa-opioid receptor agonist, (3R)-3-(1-pyrrolidinylmethyl)-4-[(1S)-5,6-dichloro-1-indancarbo nyl]- tetrahydro-1,4-thiazine hydrochloride (R-84760), were examined. In an opioid receptor binding assay with a guinea pig brain membrane fraction, R-84760 showed a 5 times higher affinity for the kappa-opioid receptor than CI-977, the most potent reference kappa-opioid receptor agonist, and selectivity of R-84760 for the kappa-opioid receptor was higher than that of U-69593, a highly selective kappa-opioid receptor agonist. R-84760 was functionally 2.5 times more potent than CI-977 as a kappa-opioid receptor agonist in rabbit vas deferens. Subcutaneously administered R-84760 had an antinociceptive effect in the phenylquinone writhing test in mice and its potency was 5-846 times higher than those of CI-977, U-50488, morphine, pentazocine and butorphanol. On oral administration, R-84760 was 20-2077 times more potent than the same reference drugs. The antinociceptive effect of R-84760 was not antagonized by naloxone in a dose at which naloxone antagonized the effect of morphine, but on the other hand nor-binaltorphimine antagonized the effect of R-84760 at a dose which did not affect the effect of morphine. R-84760 and the reference kappa-opioid receptor agonists produced sedative and diuretic effects in mice with the same order of potency as for the antinociceptive effect. Tolerance to the antinociceptive effect of R-84760 barely developed, and naloxone-induced jumping tests for morphine-like physical dependence of R-84760 gave negative results.

Topics: Amino Acid Sequence; Analgesics, Opioid; Animals; Benzoquinones; Binding, Competitive; Diuretics; Drug Tolerance; Guinea Pigs; In Vitro Techniques; Male; Mice; Mice, Inbred Strains; Molecular Sequence Data; Naloxone; Pain; Postural Balance; Pyrrolidines; Rabbits; Receptors, Opioid, kappa; Substance-Related Disorders; Thiazines; Vas Deferens

We assessed the effect of naloxonazine, a selective mu 1-opioid receptor antagonist, on antinociception produced by intrathecal or intracerebroventricular injections of morphine in streptozotocin-induced diabetic mice. The antinociceptive effect of morphine (10 micrograms), administered i.c.v., was significantly less in diabetic mice than in non-diabetic mice. The antinociceptive effect of i.c.v. morphine was significantly reduced in both diabetic and non-diabetic mice following pretreatment with naloxonazine. There were no significant differences in the antinociceptive effect of morphine (1 microgram, i.t.) in diabetic and non-diabetic mice. Furthermore, naloxonazine had no significant effect on the antinociceptive effect of i.t. morphine in either diabetic or non-diabetic mice. On the other hand, the antinociceptive effects of i.c.v. and i.t. morphine were significantly reduced following pretreatment with beta-funaltrexamine, a selective mu-opioid receptor antagonist, in both diabetic and non-diabetic mice. In conclusion, mice with diabetes are selectively hyporesponsive to supraspinal mu 1-opioid receptor-mediated antinociception, but are normally responsive to activation of spinal mu 2-opioid receptors.

Topics: Analgesics; Animals; Diabetes Mellitus, Experimental; Injections, Intraventricular; Injections, Spinal; Male; Mice; Mice, Inbred ICR; Morphine; Naloxone; Naltrexone; Narcotic Antagonists; Pain; Pain Measurement; Receptors, Opioid, mu; Spinal Cord

Preemptive treatment with a combination of inhalation anesthesia plus intrathecal morphine has been shown to inhibit development of hyperalgesia that follows subcutaneous (SC) formalin injection in rats. Using a similar paradigm, this study sought to determine whether moderate doses of opioids, administered systemically, could inhibit development of a hyperalgesic state.. Flinches per minute were observed 1 and 5 min after formalin injection (phase 1) and at 5-min intervals for the remainder of 1 h (phase 2) for five groups of rats. All animals received isoflurane 1% during and for 6 min after formalin injection. Groups 1 and 2 received SC alfentanil 200 micrograms/kg or normal saline, respectively, before formalin and 0.5 mg/kg naloxone SC 6 min after formalin. Groups 3 and 4 received SC morphine 20 mg/kg or SC normal saline, respectively, before formalin and SC naloxone 0.5 mg/kg plus naltrexone 0.5 mg/kg after formalin. Group 5 received normal saline at both injection times.. Phase 2 activity was nearly identical for the three control groups. Total phase 2 activity for group 1 (alfentanil) was 16% less than control (not significant, P > 0.05). Total phase 2 activity for group 3 (morphine) was almost identical to control.. Administration of 1% isoflurane plus systemic opioids, administered in doses that produce profound analgesia in standard analgesic testing paradigms, do not produce the significant suppression of subsequent hyperalgesia that has been reported with inhalation anesthesia plus intrathecal opioids.

Topics: Alfentanil; Animals; Drug Administration Schedule; Formaldehyde; Hot Temperature; Hyperalgesia; Injections, Subcutaneous; Isoflurane; Male; Morphine; Naloxone; Pain; Rats; Rats, Sprague-Dawley; Spine; Time Factors

The mechanisms underlying the antinociception induced by morphine or U-50,488H (trans-(+-)-3,4-dichloro-N-methyl-N-(2-[1-pyrrolidinyl]- cyclohexyl)benzeneacetamide) against painful colonic distension were examined in anaesthetized rats. The respective ED50 values for morphine and U-50,488H were 0.34 and 0.35 mg/kg for the i.v. route, and 1.68 and 167 micrograms/rat for the i.c.v. route. Morphine was active by the intrathecal route (ED50 = 7.8 micrograms) whereas U-50,488H had no effect at doses up to 100 micrograms/rat. The morphine response was selectively antagonized by naloxone (30 micrograms/kg i.v.) whereas that of U-50,488H was blocked by nor-binaltorphimine (10 mg/kg s.c.). Bilateral vagotomy abolished the response to morphine at 0.35 mg/kg i.v. and reduced by 41.3% that to 1 mg/kg morphine, but had no effect on that to U-50,488H or i.c.v. morphine (10 micrograms/rat). It is concluded that peripheral mu- and kappa-opioid receptors may produce antinociception for colonic pain and that vagal integrity is required for mu-opioid but not kappa-opioid peripheral antinociception.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Animals; Blood Pressure; Colon; Injections, Intraventricular; Injections, Spinal; Male; Morphine; Naloxone; Naltrexone; Neurons, Afferent; Pain; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa; Receptors, Opioid, mu; Reflex; Vagotomy; Vagus Nerve

The expression of Fos, Jun and Krox-24 proteins was investigated in spinal cord neurons of the rat 2, 4 and 8 h following noxious thermal stimulation of one hind-paw and pre-treatment with morphine. The number of neurons expressing c-Fos, c-Jun, Jun B and Krox-24 were maximal after 2 h and thereafter declined. The number of Fos B and Jun D immunoreactive neurons increased constantly for up to 8 h with Jun D showing expression above baseline only after 4 h following stimulation. Intravenous application of morphine (5 and 10 mg/kg) 20 min before noxious heat stimulation decreased the expression of all six proteins at any time-point with a predilective effect on neurons of deeper laminae of the dorsal horn. The suppressive effects of morphine were more pronounced with the higher dose of morphine and completely reversed by intravenous naloxone (1 and 10 mg/kg). The temporospatial patterns of expression following morphine were similar to those seen without morphine, but in a much smaller number of neurons and with a shorter time-course. However, despite the high dose of morphine and continuous halothane anaesthesia during the whole experimental procedures, a considerable number of neurons expressing the various genes remained in all laminae of the spinal cord. At 2 h following noxious heat stimulation morphine had decreased the number of labelled neurons for c-Fos, Fos B, Krox-24, c-Jun and Jun B to 30-60% of control levels in laminae I-II and to 10-30% in laminae III-VII,X of the spinal cord. At 4 h the level of reduction had further increased while Jun D was only moderately reduced to 75% in all laminae of the spinal cord. Eight hours following noxious heat plus morphine application we did not detect noxious evoked immunoreactivity for c-Fos, Krox-24, c-Jun and Jun B, while there was residual labelling for Fos B in the superficial dorsal horn and for Jun D in laminae I-VII and X of the spinal cord. The different temporospatial pattern of immediate early gene expression in neurons of the spinal cord dorsal horn following noxious stimulation suggest that variable transcription complexes may interact with DNA regulatory sequences and could thus activate alternative secondary response genes, even under protection of a high dosage of morphine applied before noxious stimulation.

Topics: Animals; Dose-Response Relationship, Drug; Gene Expression; Hot Temperature; Immediate-Early Proteins; Immunohistochemistry; Male; Morphine; Naloxone; Neurons; Pain; Physical Stimulation; Rats; Rats, Sprague-Dawley; Spinal Cord; Time Factors

Expression of the immediate-early genes (IEG) c-FOS, NGF1-A and c-JUN was induced by noxious thermal stimulation in neurons of the rat spinal cord dorsal horn. Intravenous injection of Kelatorphan (5, 10 and 20 mg/kg), an inhibitor of multiple enkephalin-degrading enzymes, 20 min before noxious stimulation reduced the overall number of dorsal horn neurons expressing c-FOS and NGF1-A by up to 20-30%. While c-FOS expression was suppressed in superficial and deep laminae of the spinal cord, NGF1-A and c-JUN was only suppressed in superficial laminae. Morphine (5, 7.5 and 10 mg/kg) produced a dose-dependent reduction of c-FOS expression by up to 70% only when injected before noxious stimulation. Morphine injected 10 min after the noxious treatment was virtually ineffective. The depressant effect of Kelatorphan and morphine could be prevented by prior application of the opioid antagonist naloxone. Naloxone itself slightly increased the overall number of c-FOS-positive neurons in all laminae of the spinal cord. The present data support the existence of a tonic release of endogenous opioid peptides at the spinal level and show that inhibition of their peptidase-induced degradation modulates IEG expression in dorsal horn neurons of the rat. The finding that opioid agonists were ineffective when applied after stimulation underline the necessity of pre-emptive analgesia to prevent long-term activity-dependent changes in spinal cord neurons.

Topics: Analgesics; Animals; Dipeptides; Dose-Response Relationship, Drug; Gene Expression; Genes, Immediate-Early; Hot Temperature; Immunohistochemistry; Male; Morphine; Naloxone; Neurons; Pain; Physical Stimulation; Rats; Rats, Sprague-Dawley; Spinal Cord

The purpose of this study is to investigate the effect of hyperventilation on the spinal pain modulating system by using naloxone. Under enflurane anaesthesia, cats were prepared with midcollicular decerebration and lumbar laminectomy. The spinal cord was transected at T12-L1. WDR cells, responding primarily to noxious peripheral stimuli, were sampled with a microelectrode at the depth of 2,000 microns from the cord dorsum. Following the control period, ventilation was adjusted to produce hypocapnia of PCO2 20-25 mmHg. After activities of WDR cells were well suppressed, naloxone 0.1 mg.kg-1 was given intravenously. Changes of firings of WDR cells were investigated. Returning to normocapnia, recovery of firings was followed. Hypocapnia of PCO2 20-25 mmHg significantly suppressed the activities of WDR cells. Naloxone significantly antagonized the suppressive effects of hyperventilation upon the activity of WDR cell. Our results suggest that the hyperventilation has suppressive effects on single-unit activity of WDR cell and the mechanisms of those suppressive effects are related to pain modulating system by endogenous opiates.

Topics: Action Potentials; Animals; Cats; Decerebrate State; Evoked Potentials; Female; Hyperventilation; Male; Naloxone; Pain; Spinal Cord

Topics: Animals; Drug Therapy, Combination; Humans; Naloxone; Pain; Tilidine

The effects of cold water swim stress (CWSS) on the nociceptive responses to i.t. administered substance P (SP) and somatostatin (SST) were examined. Male ICR mice, weighing about 30 g, were forced to swim in water at 20 degrees C for 3 min. In unstressed mice, i.t. injection of SP (0.1 nmol) and SST (1 nmol), respectively, produced nociceptive-related behaviors. Although CWSS had no effect on the intensity of the SP-induced nociceptive responses, CWSS significantly reduced the intensity of the SST-induced nociceptive responses. The effect of CWSS on the SST-induced nociceptive responses was blocked by naloxone (5 mg/kg, s.c.) and naltrindole (1 mg/kg, s.c.), a selective delta-opioid receptor antagonist, but not by beta-funaltrexamine (20 mg/kg, s.c.), a selective mu-opioid receptor antagonist. These results indicate that CWSS may selectively reduce the SST-induced nociceptive responses primarily through delta-opioid receptors.

Topics: Animals; Cold Temperature; Male; Mice; Mice, Inbred ICR; Naloxone; Pain; Receptors, Opioid, delta; Somatostatin; Stress, Physiological; Substance P; Swimming

The non-peptide NK-1 receptor antagonist, CP 96,345, has been evaluated for antinociceptive activity in two chemical pain models in the mouse. CP 96,345, injected intrathecally (i.t.) 5 min prior to 2.0% formalin, produced significant antinociception in both the early and late phases of the formalin-induced paw licking procedure. Antinociception could also be observed during the late phase by treatment with CP 96,345 after formalin. In the capsaicin (CAP) test, i.t. injection of CP 96,345 produced a dose-dependent reduction of the paw-licking response at doses much less than antinociceptive doses in the formalin test. Naloxone did not affect antinociception in either test. CP 96,345 evoked a reversible deficit in motor performance as assayed by the rotarod test. The results indicate that i.t. CP 96,345 is antinociceptive in the capsaicin test at doses showing no overt behavioural effects but there is an overlap in doses producing antinociceptive and motor effects in the formalin test.

Topics: Analgesics; Animals; Biphenyl Compounds; Capsaicin; Dose-Response Relationship, Drug; Formaldehyde; Hypnotics and Sedatives; Injections, Spinal; Male; Mice; Mice, Inbred Strains; Naloxone; Pain; Pain Measurement; Postural Balance; Receptors, Neurokinin-2; Receptors, Neurotransmitter; Substance P

Topics: Analgesics; Analysis of Variance; Animals; Brain; Cell Membrane; Injections, Spinal; Male; Mice; Mice, Inbred Strains; Naloxone; Pain; Receptors, Opioid; Spinal Cord; Substance P

The antinociceptive effect of substance P- and substance P-(6-11) analogues containing D-histidine (D-His) in position 9 was examined in mice in the formalin and capsaicin tests. [D-Arg1,D-Trp7,9,Leu11]substance P (spantide) was used as reference drug. Intrathecal injections of the [D-His9]substance P and substance P-(6-11) analogues at 4.0 nmol resulted in no significant antinociception as measured in the 2.0% formalin test, although spantide was antinociceptive in the early and late phases. The early response induced by 0.0625% formalin was reduced significantly by the [D-His9]substance P and substance P-(6-11) analogues at 4.0 nmol, which were less potent than spantide. The antinociception induced by spantide and a few analogues of substance P and substance P-(6-11) containing D-His was reversed significantly by pretreatment with 2 mg/kg naloxone, an opioid antagonist. The nociceptive response to capsaicin was inhibited significantly by lower doses (2.0 nmol) of the analogues. The antinociception evoked by the analogues was not reversed by naloxone in the capsaicin test. Co-injection of the [D-His9]substance P and substance P-(6-11) analogues at 2.0 nmol selectively decreased substance P-induced licking, biting and scratching without affecting the behavioural responses to NK2 and NK3 receptor agonists. Spantide non-selectively inhibited the behavioural responses produced by not only substance P, but also neurokinin A, D-septide, neurokinin B and eledoisin. The data show that the capsaicin test may be a better method for evaluating neurokinin antagonists than the formalin test.

Topics: Analgesics; Animals; Capsaicin; Drug Interactions; Formaldehyde; Injections, Spinal; Male; Mice; Naloxone; Pain; Substance P

The possible influence of painful stimulation and morphine analgesia on hypothalamic met-enkephalin levels, and the possible correlation between this biochemical parameter and animal behaviour was studied. The results indicate that both painful stimulation and morphine treatment induce an increase in hypothalamic metenkephalin. On the other hand, naloxone did not cause any variation. In animals submitted to painful stimulus, morphine treatment induced a decrease in hypothalamic met-enkephalin levels. Finally, when both morphine and naloxone were administrated before nociceptive stimulation, much higher levels were measured. There was no correlation between the level of hypothalamic met-enkephalin and the pain rating.

Topics: Animals; Enkephalin, Methionine; Formaldehyde; Hypothalamus; Male; Morphine; Naloxone; Pain; Rats; Rats, Wistar; Stimulation, Chemical

The antinociceptive effects of various i.v. doses (2.5, 3.75, 5, 10, 15 and 20 mg/kg) of a prodrug mixed inhibitor of enkephalin degrading enzymes, PC 12, were tested in normal and Freund's adjuvant-induced arthritic rats, using vocalization thresholds to paw pressure as a nociceptive test. In normal animals, PC 12 produced a dose-dependent antinociceptive effect over the 2.5-15 mg/kg range, but the time-course of the response was shorter with the dose of 20 mg/kg. In arthritic rats, PC 12 had no significant effect at 2.5 mg/kg, but induced a highly significant dose-dependent antinociceptive action with 3.5 and 5 mg/kg, which decreased with the highest doses. The antinociceptive effect of PC 12 (10 mg/kg i.v.) was prevented by naloxone (0.5 mg/kg i.v.) in the two categories of rats, providing evidence for the involvement of opioid receptors. These results are discussed in relation with the increased level of endogenous opioid substances in the spinal dorsal horn of arthritic rats and the nociceptive test used.

Topics: Aminopeptidases; Analgesics; Animals; Arthritis, Experimental; CD13 Antigens; Dose-Response Relationship, Drug; Enkephalins; Glycine; Male; Naloxone; Neprilysin; Pain; Pain Measurement; Prodrugs; Rats; Rats, Sprague-Dawley; Vocalization, Animal

We examined the ability of the alpha 2-adrenoceptor agonist, ST-91, microinjected into the medullary dorsal horn (MDH), to diminish the sensory-discriminative features of noxious heat stimuli in awake behaving monkeys. Two monkeys performed a noxious thermal detection task and the time to detection of small increases in heat served as a measure of the perceived intensity of pain. ST-91 microinjected into the MDH (1.0, 3.0, 10.0 and 30.0 micrograms/0.4 microliter) produced dose-dependent increases in detection time to graded temperature increases (0.4-1.0 degrees C) from a noxious 46 degrees C base line. These dose-dependent effects were attenuated by the systemic administration of the alpha 2-adrenoceptor antagonist, idazoxan (2.0 mg/kg, i.m.), but not by the alpha 1-adrenoceptor antagonist, prazosin (0.5 mg/kg, i.m.) or the opioid-receptor antagonist, naloxone (0.5 mg/kg, i.m.). The effect of ST-91 on detection latency of thermal stimuli was not the result of alterations in attentional, motivational or motoric aspects of the monkeys' behavior, because detection of visual stimuli and non-noxious temperature coolings (36.0-34.5 degrees C) in a similar paradigm were not consistently altered. Microinjection of morphine (3.0 mg) into the MDH also increased detection latency of the noxious heat stimuli. Systemic administration of the opioid-receptor antagonist, naloxone (0.5 mg/kg), and the alpha 2-adrenoceptor antagonist, idazoxan (2.0 mg/kg, i.m.) attenuated these effects of morphine. In a separate experiment, morphine (5.0 micrograms) microinjected into the MDH induced facial scratching behavior. Idazoxan (2.0 mg/kg) was effective at attenuating this scratching behavior.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adrenergic alpha-Agonists; Adrenergic alpha-Antagonists; Adrenergic Antagonists; Animals; Behavior, Animal; Clonidine; Dioxanes; Electrophysiology; Hot Temperature; Idazoxan; Macaca fascicularis; Macaca mulatta; Male; Medulla Oblongata; Microinjections; Naloxone; Norepinephrine; Pain; Physical Stimulation; Receptors, Opioid

Intravenous (i.v.) administration of morphine produces a dose-dependent inhibition of the tail-flick (TF) reflex, depressor response, and bradycardia in the rat. Some of these effects depend on interactions of i.v. morphine with peripheral opioid receptors and the integrity of cervical vagal afferents. The present studies used the relatively specific mu, delta, and kappa opioid receptor agonists (DAGO, DPDPE or U-50,488H) and the relatively specific mu, delta, and kappa opioid receptor antagonists (beta-FNA, naloxonazine, naltrindole or nor-BNI) in either intact rats or rats with bilateral cervical vagotomy (CVAG) to delineate the vagal afferent/opioid-mediated components of these effects. I.v. administration of DAGO in intact rats produced a dose-dependent inhibition of the TF reflex, depressor response, and bradycardia virtually identical to those produced by i.v. morphine. All of these effects of either i.v. DAGO or i.v. morphine were significantly attenuated by either bilateral CVAG or pre-treatment with the mu 2 opioid receptor antagonist beta-FNA. Pre-treatment with the mu 1 opioid receptor antagonist naloxonazine affected i.v. DAGO-induced inhibition of the TF reflex and bradycardia, but had no significant effects on i.v. morphine-produced responses. I.v. administration of DPDPE produced a dose-dependent pressor response, but had no marked effects on the either the TF reflex or heart rate (HR). The pressor response was unaffected by either bilateral CVAG or pre-treatment with naltrindole, naloxone, hexamethonium, or bertylium. i.v. administration of U-50,488H produced a depressor response and bradycardia, but had no significant effect on the TF reflex. The depressor response and bradycardia produced by i.v. U-50,488H were unaffected by bilateral CVAG, but could be antagonized by pre-treatment with either nor-BNI or naloxone. These studies suggest that the vagal afferent-mediated antinociceptive and cardiovascular effects of i.v. morphine are primarily mediated by interactions with low affinity mu 2 opioid receptors.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analysis of Variance; Animals; Blood Pressure; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, D-Penicillamine (2,5)-; Enkephalins; Heart Rate; Hexamethonium; Hexamethonium Compounds; Indoles; Injections, Intravenous; Male; Morphinans; Morphine; Naloxone; Naltrexone; Narcotic Antagonists; Narcotics; Pain; Pyrrolidines; Rats; Rats, Sprague-Dawley; Reference Values; Time Factors; Vagotomy; Vagus Nerve

A peptide recently isolated from human and bovine brain, Tyr-W-MIF-1 (Tyr-Pro-Trp-Gly-NH2), was tested for its effects on nociception in the tail-flick test after intracerebroventricular injection in the rat. Tail-flick latencies were significantly increased with a rapid onset and remained significantly elevated for at least 50 min. Naloxone reversed the effect of the peptide, indicating opiate receptor involvement in the response. Met-enkephalin at the same dose produced only slight antinociception. Some animals showed 'barrel-rolling' behavior in addition to the analgesia; this behavior was unusually short-lived, not a prerequisite for the analgesia, and had no apparent persistent effects. The results show that, in addition to previously described opiate-like actions (binding to the mu-receptor and inhibition of electrically induced contractions of the guinea pig ileum), Tyr-W-MIF-1 is capable of inducing significant analgesia.

Topics: Amino Acid Sequence; Analgesics, Opioid; Animals; Injections, Intraventricular; Male; Molecular Sequence Data; Motor Activity; MSH Release-Inhibiting Hormone; Naloxone; Pain; Rats; Rats, Sprague-Dawley; Time Factors

The purpose of this study was to determine what effects leucine-enkephalin and D-Ala2-D-Leu5-enkephalin have on both the background and naturally evoked activity of thalamic nucleus submedius neurons responsive to mechanical cutaneous stimulation. Thirty-five neurons in the nucleus submedius were fully characterized during single-unit extracellular recordings as nociceptive, low-threshold mechanoreceptive (LTM) or unresponsive. Micropressure was used to apply the opioids. Eighteen neurons were inhibited; 13 of these were nociceptive and one was LTM. Six units were activated; two of these were nociceptive and three were LTM. The remaining 11 units were unaffected. Opioid responses were tested for antagonism by naloxone in 12 neurons; eight of these responses were antagonized by naloxone. Statistical analyses indicated that the effects of enkephalins on nociceptive neurons were selective for neuronal modality. The opioids also altered the response of some nociceptive neurons to receptive field stimulation. The presence of nociceptive neurons in the nucleus submedius that are selectively inhibited by opioids provides additional support for the involvement of submedius neurons in nociception. The results of this study suggest that this involvement is more than merely transmission of nociceptive input, since the opioids may be selectively modulating the type of information that is transmitted to the cortex.

Topics: Animals; Enkephalin, Leucine; Enkephalin, Leucine-2-Alanine; Evoked Potentials; Membrane Potentials; Micromanipulation; Naloxone; Neurons; Pain; Pressure; Rats; Rats, Sprague-Dawley; Stress, Mechanical; Thalamic Nuclei

The effect of taurine on nociception was investigated in adult male Swiss mice using the formalin and acetic acid tests. Taurine (50-200 mg/kg) injected sc into the animals (N = 6 per group) 30 min before formalin injection into the right hind paw reduced formalin-induced early phase (0-5 min) licking activity by 30-42%, but had no effect on the late phase (20-25 min) response. Writhing responses induced by acetic acid injected ip were also significantly inhibited by 49% and 56% by doses of 100 and 200 mg/kg taurine, respectively. In both tests taurine demonstrated antinociception which was significantly blocked by naloxone (1 mg/kg, sc, administered simultaneously with taurine). The naloxone-sensitive antinociceptive action of taurine was probably mediated via modulation of endogenous pain-regulatory systems that involve opioid peptides, neuropeptides like substance P and amino acids such as glutamate and aspartate.

Topics: Acetates; Animals; Formaldehyde; Male; Mice; Naloxone; Nociceptors; Pain; Pain Measurement; Reaction Time; Taurine

The kin selection theory predicts that individuals would behave differently toward one another, depending on their genetic relatedness. Proximate mechanisms have been postulated to exist helping the individual to discriminate what is good or bad for him. Opioids have been discovered to be involved in the mediation of reinforcement, in particular they underlay social emotion. In this study it is shown that pain sensitivity decreased in male mice interacting with siblings following 2 months of separation; this analgesic response was antagonized by naloxone administration. Interaction with unknown and unrelated subjects did not change the nociceptive threshold. These results suggest that interacting with kin is an adaptive situation reinforced, at the neural level, by the release of endogenous opioids.

Topics: Animals; Behavior, Animal; Brain; Emotions; Male; Naloxone; Narcotics; Pain; Rats; Reinforcement, Psychology; Sibling Relations

In an attempt to determine the opioid receptor class(es) which underly the two opposing effects of naloxone in models of persistent pain, we tested the action of the selective delta antagonist naltrindole, and that of the kappa antagonist MR-2266 on the bidirectional effect of systemic naloxone in arthritic rats. As a nociceptive test, we used the measure of the vocalization thresholds to paw pressure. The antagonists were administered at a dose (1 mg/kg i.v. naltrindole, 0.2 mg/kg i.v. MR-2266), without action per se but which prevents the analgesic effect of the delta agonist DTLET (3 mg/kg, i.v.) or the kappa agonist U-69,593 (1.5 mg/kg, i.v.) respectively, and does not influence the effect of morphine (1 mg/kg i.v.) or the mu agonist DAMGO (2 mg/kg, i.v.) in these animals. In arthritic rats injected with the delta antagonist, the paradoxical antinociceptive effect produced by 3 micrograms/kg i.v. naloxone was not significantly modified (maximal vocalization thresholds (% of control) were 146 +/- 9% versus 161 +/- 7% in the control group). By contrast, the hyperalgesic effect produced by 1 mg/kg i.v. naloxone was significantly reduced (maximal vocalization thresholds were 87 +/- 4% versus 69 +/- 5% in the control group). In rats injected with the kappa antagonist, the antinociceptive effect of the low dose of naloxone was almost abolished (mean vocalization thresholds were 115 +/- 3% versus 169 +/- 7%) whereas the hyperalgesic effect of naloxone 1 mg/kg i.v. was not significantly modified (mean vocalization thresholds = 70 +/- 3% and 65 +/- 3%, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Analysis of Variance; Animals; Arthritis; Benzomorphans; Dose-Response Relationship, Drug; Injections, Intravenous; Male; Naloxone; Naltrexone; Narcotic Antagonists; Nociceptors; Pain; Pain Threshold; Rats; Rats, Sprague-Dawley; Receptors, Opioid, delta; Receptors, Opioid, kappa; Vocalization, Animal

The effects of intracerebroventricular administration of the cholecystokinin (CCK) analogue, BDNL, and the selective CCK-B agonist, BC 264, were determined using the hot plate test in mice. BDNL (0.2 nmol and 0.5 nmol) increased the jump and the paw lick latencies. These effects were blocked by the CCK-A antagonist MK-329 (0.02 mg/kg), supporting the involvement of CCK-A receptors in CCK-induced analgesia. In contrast, the selective CCK-B agonist BC 264 produced, at one dose (2.5 nmol), a slight decrease in the lick latency that was only antagonized by the CCK-B antagonist. Naloxone, but not naltrindole, antagonized BDNL-induced analgesia. The results suggest that activation of CCK-A receptors by BDNL leads to antinociceptive responses indirectly mediated by stimulation of mu-opioid receptors by endogenous enkephalins.

Topics: Animals; Benzodiazepinones; Cerebral Ventricles; Cholecystokinin; Devazepide; Hot Temperature; Injections, Intraventricular; Male; Mice; Mice, Inbred Strains; Naloxone; Pain; Peptide Fragments; Phenylurea Compounds; Receptors, Cholecystokinin; Sincalide

The antinociceptive effects of centrally administered (i.c.v.) endothelin-1 (ET-1) and endothelin-3 (ET-3) were studied in mice by the use of 3 experimental procedures: hot plate, tail flick and acetic acid writhing tests. ET-1 (0.625-5 pmol/mouse) and ET-3 (2.5-25 pmol/mouse) produced statistically significant increase of the hot plate and tail flick latencies with duration of about 120 min. ET-3 showed weaker antinociceptive effect. ET-1 inhibited acetic acid-induced writhings with ED50 = 1.9 (1.1-2.7) pmol/mouse. With ET-3 a maximum effect of 45.2% suppression of the writhing response was achieved at 5 pmol/mouse. The antinociception due to ET-1 and ET-3 was not antagonized by naloxone and is thus independent of endogenous opioid release.

Topics: Analgesics; Animals; Cerebral Ventricles; Dose-Response Relationship, Drug; Endothelins; Injections, Intraventricular; Male; Mice; Mice, Inbred Strains; Naloxone; Pain; Pain Measurement

Repeated daily administration of the opiate receptor antagonist naloxone prior to hotplate tests provokes longer paw-lick latencies by attenuating the habituation of novelty-induced hypoalgesia. This hypoalgesia has been found to persist when pain tests are subsequently conducted following saline administration. The present experiments were conducted to determine whether the substrates mediating the hypoalgesia observed during naloxone and saline tests are similar or distinct. Neither the hypoalgesia observed during naloxone nor saline tests were affected by the induction of tolerance to the hypoalgesic effect of morphine, suggesting that both effects are mediated by nonopioid antinociceptive mechanisms. Previous work from our laboratory demonstrated that the hypoalgesia observed during naloxone tests is inhibited by clonidine, enhanced by yohimbine, and unaffected by prazosin and phentolamine. In the present article, we report a similar pattern of results for the hypoalgesia observed during saline tests. It is concluded that the substrates mediating both effects are similar. The results are discussed in relation to the possibility that an opioid substrate involved in habituative learning may be inhibitory on a nonopioid antinociceptive substrate.

Topics: Adrenergic alpha-1 Receptor Antagonists; Adrenergic alpha-2 Receptor Antagonists; Animals; Clonidine; Habituation, Psychophysiologic; Male; Morphine; Naloxone; Norepinephrine; Pain; Pain Measurement; Phentolamine; Rats; Rats, Wistar; Receptors, Adrenergic, alpha-1; Receptors, Adrenergic, alpha-2

Clinical studies have suggested that patients who take morphine for pain relief do not show a high degree of dependence. The present study examined the development of naloxone-precipitated withdrawal in rats receiving morphine in the presence or absence of formalin-induced pain. Morphine (10 mg/kg, i.p.) or saline was administered for 4 consecutive days 10 min after a subcutaneous injection of 50 microliters of 2.5% formalin or saline into the hind-paw. On the 5th day, rats were injected with naloxone (1 mg/kg, i.p.) and observed for signs of precipitated withdrawal (ptosis, teeth chattering and excretion/diarrhea). Naloxone-precipitated withdrawal symptoms were significantly greater in rats that received morphine in the absence of pain than in rats that received morphine in the presence of pain.

Topics: Animals; Behavior, Animal; Blepharoptosis; Diarrhea; Formaldehyde; Male; Morphine Dependence; Naloxone; Pain; Rats; Substance Withdrawal Syndrome

Naloxone is known to decrease, increase or have no effect on nociceptive thresholds. Here, using two commonly accepted pain-related behaviors (licking and flinching) associated with injection of noxious formalin into a hind paw in rats, naloxone (0.1-1 mg/kg s.c.) simultaneously decreases and increases nociceptive responding in the same animal. Licking, which is reduced by naloxone, is enhanced by low doses but attenuated by high doses of morphine. However, although licking initially increases with a rise in formalin concentration, at higher concentrations the time spent licking the injected paw actually declines. By contrast, flinching, which is enhanced by naloxone, is only antagonized by morphine and increases linearly with formalin concentration. Both actions of naloxone can be interpreted in terms of a leftward shift in the formalin concentration-response curves. This study demonstrates that naloxone can increase formalin-induced flinching while simultaneously decreasing licking behavior. These findings suggest that, on its own, an unexpected decrease in a single nociceptive index may be an inadequate criterion for demonstrating antinociception.

Topics: Animals; Behavior, Animal; Buprenorphine; Dose-Response Relationship, Drug; Formaldehyde; Injections, Subcutaneous; Male; Morphine; Naloxone; Pain; Rats; Rats, Sprague-Dawley

Two experiments examined the hypoalgesic effects that accrue from pairing exposure to a heat stressor with the opioid antagonist naloxone. Experiment 1 confirmed that rats given separate exposures to a heated floor and to naloxone are hypoalgesic when then tested on that floor. Further, the results confirmed that pairing the initial exposure to the heat stressor with naloxone resulted in a more profound hypoalgesic response. Experiment 2 provided new evidence for the hypoalgesic effects of separate exposures to the heat stressor and to naloxone, and for naloxone's enhancement of acquisition of the hypoalgesia, in rats tested for responsiveness to formalin. These results, therefore, demonstrate generalisability of the hypoalgesic effects across assays for acute and chronic pain.

Topics: Animals; Conditioning, Psychological; Hot Temperature; Male; Naloxone; Pain; Pain Measurement; Pain Threshold; Rats; Rats, Wistar; Time Factors

The present study is undertaken to investigate the effect of systemic morphine on neurons in the lateral reticular nucleus (LRN) using extracellular recording techniques. The spontaneous activities of 64 neurons in the LRN area were tested with morphine (3-5 mg/kg, IV). Morphine excited 23 and inhibited 28 neurons tested, and 13 neurons were not affected. Of the 28 neurons inhibited, 20 were identified as nociceptive and the remaining 6 were nonnociceptive. Of the 23 neurons excited by morphine, 18 were nociceptive and 5 were nonociceptive. Systemic naloxone (0.3-0.5 mg/kg) significantly reversed the morphine effect in 15 out of 19 neurons excited and 19 out of 20 neurons inhibited by morphine. Thirteen out of 64 neurons were further identified as reticulospinal neurons, of which four were excited and four were inhibited by morphine. The remaining five were not affected. The results demonstrate that a similar proportion of neurons in the LRN area were either excited or inhibited by systemic morphine, and the majority of them are nociceptive neurons. It is suggested that different types of neurons in the LRN area may have different functions in morphine analgesia.

Topics: Animals; Catheterization, Central Venous; Male; Medulla Oblongata; Morphine; Naloxone; Neurons; Pain; Rats; Rats, Sprague-Dawley

Recombinant human interleukin-1 alpha (rHu-IL-1 alpha) has been indicated to produce central antinociception in the mouse phenylquinone writhing test, the antinociception being unaffected by naloxone. Because interleukin-1 has been demonstrated to be a potent releaser of corticotropin-releasing factor (CRF) from the hypothalamus, we were interested to see whether CRF is involved in the antinociception induced by rHu-IL-1 alpha. In the present study, we examined this question using the mouse phenylquinone writhing test, in which mice were injected with various doses of CRF and/or alpha-helical CRF-(9-41), a CRF antagonist. CRF inhibited writhing responses after i.v. and intracisternal (i.c.) administration. The antinociception elicited by i.v. administered CRF was antagonized by i.v. injection, but not by i.c. injection, of alpha-helical CRF-(9-41). The antinociception elicited by i.e. administered CRF was antagonized by i.c. injection of alpha-helical CRF-(9-41) and s.c. treatment of opioid antagonists. rHu-IL-1 alpha-induced antinociception was attenuated by i.v. injection, but not by i.c. injection, of alpha-helical CRF-(9-41). These findings suggest that CRF possesses antinociceptive efficacy by both peripheral and central mechanisms, and that the antinociception induced by rHu-IL-1 alpha is mediated, at least in part, by the peripheral action of CRF.

Topics: Animals; Benzomorphans; Corticotropin-Releasing Hormone; Drug Interactions; Humans; Hypothalamus; Injections, Intravenous; Interleukin-1; Mice; Naloxone; Pain; Pain Measurement; Peptide Fragments; Recombinant Proteins

Three novel benzomorphans, (+)-N-benzylnormetazocine, (-)-deoxy-N-benzylnormetazocine, and (-)-deoxypentazocine were tested for their ability to produce circling behavior in rats following intranigral microinjections. Dose studies revealed the following rank order of potency: (-)-deoxypentazocine > (-)-deoxy-N-benzylnormetazocine > (+)-N-benzylnormetazocine. This rank order approximates that for affinities for sigma 2 receptors but not sigma 1 receptors. It is very unlikely that the effects of the (-)-deoxybenzomorphans were mediated by opiate receptors for the following reasons: (1) consistent with the known requirement for the phenolic hydroxyl group for opiate activity, both (-)-deoxy compounds showed very low affinity for opiate receptors; (2) naloxone (4 micrograms) co-administered with (-)-deoxy-N-benzylnormetazocine failed to reduce its efficacy; (3) both (-)-deoxy compounds failed to produce marked analgesic effects in the tail flick test following systemic injections of 20 mg/kg s.c. These finding suggest that sigma 2 receptors mediate the motor effects of sigma ligands in rats.

Topics: Animals; Benzomorphans; Cyclazocine; Male; Motor Activity; Naloxone; Narcotics; Pain; Phenols; Rats; Rats, Sprague-Dawley; Receptors, Opioid; Receptors, sigma; Rotation; Stereoisomerism

Repeated daily administration of the opiate receptor antagonist naloxone (10 mg/kg) attenuates the habituation of novelty-induced hypoalgesia. This effect can be reversed by the alpha 2-noradrenergic receptor agonist clonidine and enhanced by the alpha 2-antagonist yohimbine. The present experiments were conducted to provide further support for the importance of the alpha 2-receptor and determine the possible influence of the alpha 1-receptor. Naloxone's effect on novelty-induced hypoalgesia was not affected by pretreatment with the specific alpha 1-receptor antagonist prazosin (0.2-1.0 mg/kg, SC) or the nonselective alpha antagonist phentolamine (2.0-10.0 mg/kg). In a second series of experiments, it was found that the potentiation of naloxone's effect by yohimbine (2 mg/kg) was reversed by clonidine (0.1 mg/kg) but was not influenced by prazosin or phentolamine. These results suggest that the alpha 1-noradrenergic receptor subtype does not mediate the effect of naloxone on novelty-induced hypoalgesia. They also reinforce the importance of the alpha 2-receptor subtype in the mediation of this effect.

Topics: Animals; Clonidine; Drug Synergism; Habituation, Psychophysiologic; Male; Naloxone; Pain; Phentolamine; Prazosin; Rats; Rats, Wistar; Receptors, Adrenergic; Receptors, Adrenergic, alpha; Yohimbine

The effect of various doses of the selective delta agonist BUBU (Tyr-D-Ser(O-t-butyl)-Gly-Phe-Leu-Thr(O-t-butyl) on the vocalization threshold to paw pressure were compared in normal and arthritic rats, a suitable clinical model of chronic pain. In both group of rats, the intravenous administration of BUBU (6, 9, 12 mg/kg in normal and 1.5, 3, 6 mg/kg in arthritic rats) led to significant antinociceptive effects. The same dose of BUBU (6 mg/kg i.v.) produced a much more potent antinociceptive effect in arthritic than in normal rats, and a dose as low as 1.5 mg/kg produced a significant analgesic effect in the arthritic animal, whereas at 3 mg/kg BUBU was ineffective in normal rats. The analgesic effects of BUBU (9 mg/kg in normal and 3 mg/kg in arthritic rats) were completely prevented by the selective delta antagonist naltrindole (1 mg/kg i.v. a dose devoid of analgesic potency per se), while they were not affected by the selective mu antagonist naloxone (0.05 mg/kg i.v.). In addition, 3 mg/kg i.v. of BUBU remained effective in morphine tolerant arthritic rats. These results suggest that delta opioid receptor activation can modulate the transmission of cutaneous mechanical nociceptive information in rats, especially in inflammatory pain conditions.

Topics: Analgesics; Animals; Arthritis, Experimental; Drug Administration Schedule; Drug Interactions; Enkephalins; Male; Morphine; Naloxone; Naltrexone; Oligopeptides; Pain; Rats; Rats, Sprague-Dawley; Receptors, Opioid, delta; Reference Values; Vocalization, Animal

We have studied the effects of several opioid antagonists on a type of footshock stress-induced analgesia (FSIA) measured by the tail-flick test in male mice. Naloxone injected either subcutaneously (0.1-10 mg/kg) or intrathecally (1-20 micrograms) antagonized FSIA at higher doses than those that blocked a similar degree of analgesia induced by morphine. Intracerebroventricular (i.c.v.) naloxone (1-20 micrograms) did not modify the FSIA while antagonizing the i.c.v. morphine-induced analgesia. As a consequence, the antagonism of the FSIA by naloxone probably occurs at the level of the spinal cord and through receptors different than mu. The delta selective antagonist naltrindole (0.1-3 mg/kg s.c.) did not antagonize the analgesic effects of the stress. Nor-binaltorphimine, a kappa selective antagonist, blocked the FSIA when administered systemically (1-4 mg/kg i.p.) or locally (0.1-1 microgram i.t.). These results strongly suggest that spinal kappa opioid receptors are responsible for this type of endogenous analgesia.

Topics: Analgesia; Animals; Cerebral Ventricles; Electroshock; Injections, Intraventricular; Injections, Spinal; Male; Mice; Mice, Inbred Strains; Morphine; Naloxone; Naltrexone; Narcotic Antagonists; Pain; Receptors, Opioid, kappa; Spinal Cord; Stress, Psychological

This study evaluated the antinociceptive effects of systemically administered selective opioid agonists of mu (DAMGO), delta (BUBU) and kappa (U 69593) receptors on the vocalization threshold to paw pressure in a rat model of peripheral unilateral mononeuropathy produced by loose ligatures around the common sciatic nerve. DAMGO (0.5-2 mg/kg), BUBU (1.5-6 mg/kg) and U 69593 (0.75-3 mg/kg) injected intravenously (i.v.) produced a potent long-lasting antinociceptive effect on both hind paws. The effects on the lesioned paw were clearly and statistically more potent than for the non-lesioned paw. The selective antinociceptive effect of 2 mg/kg DAMGO, 3 mg/kg BUBU and 1.5 mg/kg U 69593 were completely prevented by prior administration of the appropriate antagonists: 0.1 mg/kg naloxone, 1 mg/kg naltrindole and 0.4 mg/kg MR 2266. The present data clearly show that an acute i.v. injection of these selective opioid agonists induces potent antinociceptive effects in a rat model of peripheral neuropathy. These data are discussed with regard to the classical view that there is opioid resistance in neuropathic pain.

Topics: Analgesics; Animals; Benzeneacetamides; Benzomorphans; Disease Models, Animal; Drug Interactions; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalins; Male; Naloxone; Naltrexone; Narcotic Antagonists; Oligopeptides; Pain; Pain Measurement; Pain Threshold; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Vocalization, Animal

A C-fibre reflex elicited by electrical stimulation within the receptive field of the sural nerve was recorded from the ipsilateral biceps femoris muscle in anaesthetized rats. Recruitment curves were built by varying the stimulus intensity from 0 to 50 mA and temporal evolution was studied by using a constant level of stimulation. At a constant level of stimulation, intrathecal administration of morphine resulted in a depressive effect on the C-fibre reflex in the 0.18-0.75 microgram range (ED50 = 0.2 microgram). Study of the recruitment curves showed that, in the 0.18-0.375 microgram range, morphine had little effect on the threshold, but induced significant decreases in the slopes. At doses above 0.75 microgram, morphine modified both the threshold and the slope of the recruitment curves. Systemic naloxone totally reversed these effects. It is concluded that intrathecal morphine not only produces a shift in the encoding functions of the spinal cord but also reduces the gain of these functions. It is suggested that this method is reliable for the pharmacological study of the spinal transmission of nociceptive signals.

Topics: Analysis of Variance; Animals; Autonomic Fibers, Postganglionic; Electric Stimulation; Electromyography; Injections, Spinal; Male; Morphine; Muscles; Naloxone; Pain; Rats; Rats, Sprague-Dawley; Reflex; Spinal Cord; Sural Nerve; Synaptic Transmission

In morphine-sensitive (s. c. 1.5 mg/kg) Wistar rats i.p. injection of 0.3 mg/kg naloxone either did not change nociception (tail-flick test) or induced hyperalgesia. In morphine-resistant rats 0.2-0.7 mg/kg naloxone injection induced analgetic effect but 1.0 mg/kg induced hyperalgesia. In morphine-sensitive rats chronic morphine administration induced the tolerance and naloxone injection evoked analgetic effect. Morphine inoculation just after naloxone analgesia was over induced analgetic effect. In morphine-resistant and -tolerant rats chronic naloxone administration induced gradual decrease and subsequent disappearance of its analgetic effect and subsequent morphine injections induced analgetic effect for some days. It is suggested that naloxone in morphine-resistant and -tolerant rats with high level of enkephalinase activity functions as its inhibitor. Chronic naloxone administration evoked progressive inhibition of enkephalinase activity that induced the morphine analgetic effect in morphine-resistant and -tolerant rats.

Topics: Analgesia; Animals; Drug Resistance; Drug Tolerance; Hyperalgesia; Male; Morphine; Naloxone; Neprilysin; Pain; Rats; Rats, Wistar; Reaction Time

1. Flavone, its methoxy derivatives and flavanone were synthesized by standard methods and were tested for analgesic activity in mice by employing acetic acid writhing and tail flick methods. 2. All the tested compounds except flavanone exhibited significant dose-dependent analgesic activity in both the assay models. Some of the compounds were found to involve opioid mechanisms in their analgesic effect. 3. A definite structure-activity relationship was observed in the analgesic activity of flavone derivatives as well as in their mechanism of action.

Topics: Analgesics; Animals; Dose-Response Relationship, Drug; Flavonoids; Male; Mice; Morphine; Naloxone; Pain; Structure-Activity Relationship

We had recently demonstrated that a subregion of the parabrachial area relays nociceptive information in the spino(trigemino)-ponto-amygdaloid pathway. The aim of the present study was to investigate, in halothane-anesthetized rats, the effect of i.v. administration of morphine on nociceptive specific neurons located in the parabrachial area with some cells being antidromically driven from the amygdala. Morphine induced a marked depression of responses elicited by noxious thermal stimuli (waterbath, 50 degrees C) dose relatedly (1, 3, 9 mg/kg) and naloxone reversibly, with an ED50 = 1.8 mg/kg. This effect of morphine probably not only reflects the direct action of this drug at the spinal level, but could also involve a direct action at the parabrachial level. These results could account at least in part for the effect of morphine on the emotional-affective aspects of pain.

Topics: Amygdala; Animals; Hot Temperature; Injections, Intravenous; Male; Morphine; Naloxone; Neural Pathways; Neurons; Pain; Pons; Rats; Rats, Sprague-Dawley; Trigeminal Nucleus, Spinal

A dilute solution of formalin (20 microliters of 10% formalin) was injected subcutaneously in the dorsal right hind paw of the naked mole-rat. The injection of the dilute formalin produced two periods of pain behaviour, the early (0-5 minutes) and the late phase (25-60 minutes). These were quantified as the total time spent licking the injected paw. Codeine phosphate (10, 25 or 50 mg kg-1) significantly reduced pain behaviour in both the early and late phase. Codeine administration also induced aggressive, hyperactive behaviour and motor impairment that was naloxone (2 mg kg-1) reversible. Naproxen (200 mg kg-1) and dexamethasone phosphate (30 mg kg-1) significantly reduced licking activity in the late phase only.

Topics: Animals; Behavior, Animal; Codeine; Dexamethasone; Dose-Response Relationship, Drug; Formaldehyde; Injections, Intraperitoneal; Injections, Subcutaneous; Muscle Rigidity; Naloxone; Naproxen; Pain; Rodentia

The aim of this study was to investigate whether the rostral ventromedial medulla (RVM) participates in the lifting of diffuse noxious inhibitory controls (DNIC) by systemic morphine. The effects of morphine (1 mg/kg i.v.) on DNIC were compared in sham-operated rats and animals with electrolytic lesions of the RVM performed one or three weeks earlier. The C-fibre-evoked responses of spinal dorsal horn convergent neurones were similar in the sham-operated and lesioned animals. DNIC acting on these responses were also similar in these groups. DNIC were similarly reduced naloxone reversibly following morphine injections in sham-operated animals and animals tested one week after lesioning of the RVM. In contrast, DNIC were not significantly altered by morphine in animals tested three weeks after lesioning. The lesions were similar in both groups of animals. This time-dependent attenuation of the effects of morphine indicates that the RVM is not directly involved in the reduction of DNIC induced by systemic morphine. However, it is suggested that lesions in this region can induce a reorganization of brainstem opioidergic systems.

Topics: Analgesics; Animals; Behavior, Animal; Electric Stimulation; Electrophysiology; Male; Medulla Oblongata; Morphine; Naloxone; Nerve Fibers; Pain; Rats; Rats, Sprague-Dawley