piperidines and Pain

Owing to its pharmacodynamic properties, especially the rapid onset and short duration of its action, the use of remifentanil in obstetric anesthesia, as well as in neonatology, might be increasingly used.. We conducted a systematic review to assess the efficacy and safety of remifentanil in preterm and term neonates. Outcomes of interest were neonatal adaptation after fetal exposure; neonatal pain, distress, and discomfort control during invasive procedures; and the occurrence of hemodynamic effects or respiratory depression induced by remifentanil infusion.. Given the different contexts of use, we have organized this work into three parts: (A) use of remifentanil for labor or cesarean section, with exposure of the fetus before birth, (B) brief use for neonatal procedural analgesia, and (C) prolonged use for sedation/analgesia of neonates. The bibliographic search was conducted based on keywords using electronic medical databases (DATABASE, Cochrane Library, PubMed, and EMBASE) from 1 January 2000 until 31 December 2022.. Twenty-two articles were included (10 in part A, 5 in part B and 7 in part C). Prospective, controlled, randomized, blinded, and intention-to-treat trials were retained. Neonates were well adapted after exposure to remifentanil in the fetal period. Pain, stress, and discomfort were controlled during a brief or prolonged invasive procedure when remifentanil was used for sedation/analgesia. The physiological parameters were stable and the procedures were straightforward. Chest wall rigidity appeared to be a common side effect, but this can be managed by slow and continuous infusion and by using the minimum effective dose.. Remifentanil appears to be effective and safe in the short term in preterm and full-term neonates. However, its safety is compromised by the risk of chest wall rigidity. It should be used in appropriate neonatal units and in the presence of physicians able to monitor its side effects. Long-term outcomes have not been evaluated, to our knowledge.

Topics: Analgesics, Opioid; Cesarean Section; Female; Fetus; Humans; Infant, Newborn; Pain; Piperidines; Pregnancy; Prospective Studies; Remifentanil

To compare improvement in pain and physical function for patients treated with baricitinib, adalimumab, tocilizumab and tofacitinib monotherapy from randomised, methotrexate (MTX)-controlled trials in conventional synthetic disease-modifying antirheumatic drugs (csDMARDs)/biologic (bDMARD)-naïve RA patients using matching-adjusted indirect comparisons (MAICs).. Data were from Phase III trials on patients receiving monotherapy baricitinib, tocilizumab, adalimumab, tofacitinib or MTX. Pain was assessed using a visual analogue scale (0-100 mm) and physical function using the Health Assessment Questionnaire-Disability Index (HAQ-DI). An MAIC based on treatment-arm matching, an MAIC with study-level matching and Bucher's method without matching compared change in outcomes between therapies. Matching variables included age, gender, baseline disease activity and baseline value of outcome measure.. With all methods, greater improvements were observed in pain and HAQ-DI at 6 months for baricitinib compared with adalimumab and tocilizumab (. Results suggest greater pain reduction and improved physical function for baricitinib monotherapy compared with tocilizumab and adalimumab monotherapy. No statistically significant differences in pain reduction and improved physical function were observed between baricitinib and tofacitinib with the MAIC analyses.

Topics: Adalimumab; Antibodies, Monoclonal, Humanized; Antirheumatic Agents; Arthritis, Rheumatoid; Azetidines; Biological Products; Clinical Trials, Phase III as Topic; Disability Evaluation; Humans; Methotrexate; Network Meta-Analysis; Pain; Pain Measurement; Piperidines; Purines; Pyrazoles; Pyrimidines; Randomized Controlled Trials as Topic; Sulfonamides; Treatment Outcome

Opioid-induced constipation (OIC) is a major side effect of opioid use. Centrally acting antagonists result in opioid withdrawal or worsening of pain and lead to use of peripherally acting mu-opioid receptor antagonists (PAMORAs). The required doses of the PAMORAs, methylnaltrexone and naloxegol, in the treatment of OIC are well established in chronic opioid users. OIC may occur after short duration of opioid treatment; the required doses of naloxone, naltrexone, and PAMORAs in opioid-naïve subjects (with no opioid use for at least 3 months) are unclear. The aim of this review was to evaluate the PAMORA dose required for opioid-naïve subjects to achieve similar beneficial effects on symptoms or valid surrogates to those observed in chronic opioid users.. A PubMed search of μ-opioid antagonists to counter μ-opioid effects included terms: naloxone, naltrexone, methylnaltrexone, alvimopan, and naloxegol, as well as OIC and colonic transit.. The approved dose of methylnaltrexone in chronic opioid users, 0.3 mg/kg subcutaneous (SQ), did not affect motility in opioid-naïve subjects. Trials investigating the required dose of alvimopan showed 0.5-1 mg dose was efficacious in treating OIC; a 10-fold higher dose (12 mg) of alvimopan is needed to block effects of codeine on small bowel and colonic transit in opioid-naïve subjects compared to chronic opioid users. Opioid-naïve users need 125 mg of naloxegol to reverse the effects of opioids on transit; this is in contrast to the 12.5 to 25 mg needed to treat OIC in chronic opioid users.. Opioid-naïve subjects require a higher dose of PAMORA than chronic opioid users to achieve μ-opioid antagonist effect.

Topics: Analgesics, Opioid; Constipation; Dose-Response Relationship, Drug; Gastrointestinal Agents; Humans; Morphinans; Narcotic Antagonists; Pain; Piperidines; Polyethylene Glycols; Receptors, Opioid, mu; Treatment Outcome

Sedation and analgesia are commonly required to relieve anxiety and pain in mechanically ventilated patients. Fentanyl and morphine are the most frequently used opioids. Remifentanil is a selective μ-opioid receptor that is metabolized by unspecific esterases and eliminated independently of liver or renal function. Remifentanil has a rapid onset and offset and a short context-sensitive half-life regardless of the duration of infusion, which may lead to reductions in weaning and extubation. We aimed to compare the efficacy and safety of remifentanil to that of other opioids in mechanically ventilated patients.. We conducted a search to identify relevant randomized controlled studies (RCTs) in the PubMed, Embase, Cochrane Library and SinoMed databases that had been published up to 31 December 2016. The results were analysed using weighted mean differences (WMDs) and 95% confidence intervals (CIs).. Twenty-three RCTs with 1905 patients were included. Remifentanil was associated with reductions in the duration of mechanical ventilation (mean difference -1.46; 95% CI -2.44 to -0.49), time to extubation after sedation cessation (mean difference -1.02; 95% CI -1.59 to -0.46), and ICU-LOS (mean difference -0.10; 95% CI -0.16 to -0.03). No significant differences were identified in hospital-LOS (mean difference -0.05; 95% CI -0.25 to 0.15), costs (mean difference -709.71; 95% CI -1590.98 to 171.55; I. Remifentanil seems to be associated with reductions in the duration of mechanical ventilation, time to extubation after cessation of sedation, and ICU-LOS. No significant differences were identified between remifentanil and other opioids in terms of hospital-LOS, costs, mortality or agitation.

Topics: Analgesics, Opioid; Humans; Hypnotics and Sedatives; Intensive Care Units; Pain; Piperidines; Remifentanil; Respiration, Artificial

Molecular hybridization is a recent strategy based on the covalent fusion of two or more pharmacophores to create a single molecule with multiple mechanisms of action, which represents an encouraging approach in the development of new drugs with potential therapeutic application in several pathologies. This review provides a comprehensive perspective of the most relevant advances in the development of hybrid molecules acting in the central nervous system. For instance, several opioid hybrids based on endogenous opioid peptides (e.g. enkephalins, deltorphins and endomorphins) have been developed, and γ-aminobutyric acid agonists have also been designed for neuropathic pain control. In addition, a number of hybrid compounds have also been synthesized and evaluated for their anticonvulsant activity and neurotoxicity, which may be further developed as potential antiepileptic drugs. Moreover, several hybrid compounds have also been designed for the treatment of neurodegenerative diseases focusing primarily on Alzheimer's disease by targeting the cholinergic neurotransmission, as acetylcholinesterase inhibitors, and the amyloid β-protein deposition. There are also studies addressing hybrid compounds including an antioxidant moiety, which can be potentially useful in Alzheimer's and Parkinson's diseases and other neurodegenerative disorders. Additionally, other research works have also shown promising hybrid molecules for depression, autism and cocaine addiction. Thus, the development of molecular hybrid compounds seems to be a promising strategy in the discovery of novel therapeutic drugs.

Topics: Analgesics; Central Nervous System Diseases; Choline; Donepezil; Epilepsy; gamma-Aminobutyric Acid; Humans; Indans; Opioid Peptides; Pain; Piperidines; Tacrine

Rocuronium bromide is a routinely used muscle relaxant in anaesthetic practice. Its use, however, is associated with intense pain on injection. While it is well established that rocuronium bromide injection causes pain in awake patients, anaesthetized patients also tend to show withdrawal movements of the limbs when this muscle relaxant is administered. Various strategies, both pharmacological and non-pharmacological, have been studied to reduce the incidence and severity of pain on rocuronium bromide injection. We wanted to find out which of the existing modalities was best to reduce pain on rocuronium injection.. The objectives of this review were to assess the ability of both pharmacological and non-pharmacological interventions to reduce or eliminate the pain that accompanies rocuronium bromide administration.. We searched the Cochrane Central Register of Controlled Trials (CENTRAL 2013, Issue 7), MEDLINE via Ovid SP (1966 to July 2013) and EMBASE via Ovid SP (1980 to July 2013). We also searched specific websites. We reran the searches in February 2015 and will deal with the 11 studies of interest found through this search when we update the review.. We included all randomized controlled trials (RCTs) that compared the use of any drug or a non-pharmacological method with control patients, or those receiving no treatment to reduce the severity of pain with rocuronium injection. Our primary outcome was pain on rocuronium bromide injection measured by a pain score assessment. Our secondary outcomes were rise in heart rate and blood pressure following administration of rocuronium and adverse events related to the interventions.. We used the standardized methods for conducting a systematic review as described in the Cochrane Handbook for Systematic Reviews of Interventions. Two authors independently extracted details of trial methodology and outcome data from reports of all trials considered eligible for inclusion. We made all analyses on an intention-to-treat basis. We used a fixed-effect model where there was no evidence of significant heterogeneity between studies and a random-effects model if heterogeneity was likely.. We included 66 studies with 7840 participants in the review, though most analyses were based on data from fewer participants. In total there are 17 studies awaiting classification. No studies were at a low risk of bias. We noted substantial statistical and clinical heterogeneity between trials. Most of the studies reported the primary outcome pain as assessed by verbal response from participants in an awake state but some trials reported withdrawal of the injected limb as a proxy for pain after induction of anaesthesia in response to rocuronium administration. Few studies reported adverse events and no study reported heart rate and blood pressure changes after administration of rocuronium. Lidocaine was the most commonly studied intervention drug, used in 29 trials with 2256 participants. The risk ratio (RR) of pain on injection if given lidocaine compared to placebo was 0.23 (95% confidence interval (CI) 0.17 to 0.31; I² = 65%, low quality of evidence). The RR of pain on injection if fentanyl and remifentanil were given compared to placebo was 0.42 (95% CI 0.26 to 0.70; I² = 79%, low quality of evidence) and (RR 0.10, 95% CI 0.04 to 0.26; I² = 74%, low quality of evidence), respectively. Pain on injection of intervention drugs was reported with the use of lidocaine and acetaminophen in one study. Cough was reported with the use of fentanyl (one study), remifentanil (five studies, low quality evidence) and alfentanil (one study). Breath holding and chest tightness were reported with the use of remifentanil in two studies (very low quality evidence) and one study (very low quality evidence), respectively. The overall rate of complications was low.. The evidence to suggest that the most commonly investigated pharmacological interventions reduce pain on injection of rocuronium is of low quality due to risk of bias and inconsistency. There is low or very low quality evidence for adverse events, due to risk of bias, inconsistency and imprecision of effect. We did not compare the various interventions with one another and so cannot comment on the superiority of one intervention over another. Complications were reported more often with use of opioids.

Topics: Acetaminophen; Adult; Analgesics, Opioid; Androstanols; Anesthetics, Local; Child; Fentanyl; Humans; Lidocaine; Neuromuscular Depolarizing Agents; Pain; Pain Measurement; Piperidines; Randomized Controlled Trials as Topic; Remifentanil; Rocuronium

The importance of voltage-gated calcium channels (VGCCs) in basic physiological processes such as cardiac and neurological function has generated intense interest in these proteins as targets of pharmacological intervention. N-type calcium channels are a subset of VGCCs distinguished by their physiology, pharmacology and significance to the pathology of chronic pain. Despite decades of investigation, only a single drug targeting N-type channel function has entered the marketplace. This review will summarize our current understanding of the biology, physiology and pharmacology of N-type calcium channels and the implication of these features for therapeutic intervention. From this basis of understanding, recent efforts to discover and develop peptide based and small molecule modulators of N-type calcium channel function will be discussed.

Topics: Amino Acid Sequence; Animals; Calcium Channels, N-Type; Drug Discovery; Humans; Indoles; Molecular Sequence Data; Pain; Peptides; Piperazines; Piperidines

Approximately 30 years ago, the myth that nervous system immaturity precluded neonates from pain perception and its negative effects was rejected. Neurobiologists further explored neurodevelopmental nociception. These observations strongly suggest that early pain experience contributes to neurodevelopmental outcome, pain thresholds, pain or stress-related behaviour and physiological responses in later life. Effective management of pain therefore remains an important indicator of the quality of care provided to neonates, not only from an ethical, but also from a short and long-term outcome perspective. Simultaneously, neonatal care itself has changed and data on neuro-apoptosis and impaired synaptogenesis following exposure to analgosedatives emerged. When developmental pharmacology concepts are applied to neonatal analgosedation, this means that this should be based on systematic assessment, followed by titrated administration of the most appropriate analgesic(s) with subsequent re-assessment to adapt treatment. This review will focus on the limitations of the available assessment tools, newly emerging analgosedatives in neonates to illustrate how these compounds can be integrated into the changing concepts of neonatal care.

Topics: Acetaminophen; Adrenergic alpha-2 Receptor Agonists; Analgesia; Analgesics, Opioid; Dexmedetomidine; Humans; Hypnotics and Sedatives; Infant, Newborn; Midazolam; Morphine; Pain; Pain Measurement; Piperidines; Propofol; Quality of Health Care; Remifentanil

Opioids play an important role in every aspect of modern anesthetic practice. Remifentanil is an ultra-short-acting opioid featuring a unique pharmacokinetic profile allowing clinical versatility and improved control of its action. In this review, we assess the pharmacology of remifentanil, its clinical uses as well as safety issues on its action on the major organ systems and in particular clinical settings.. A synthesis of evidence from a MEDLINE search for articles from 1993 to 2009 for available up-to-date information on remifentanil and its current applications and safety profile.. A synopsis of the unique pharmacokinetic properties of remifentanil and its action on major organ systems will provide insight on the safe and effective use of the drug in a variety of clinical settings.. Remifentanil is a valuable opioid in the armamentarium of the clinician, providing great clinical flexibility and safety but vigilance is required to avoid pitfalls.

Topics: Analgesics, Opioid; Animals; Cardiovascular Diseases; Humans; Pain; Piperidines; Remifentanil; Respiration Disorders

Excessive stimulation of NMDA receptors is involved in various CNS pathologies such as Parkinson's disease, acute and chronic pain and cerebral ischaemia. The use of NMDA antagonists as therapeutic agents has been restricted as a result of unwanted side effects including hallucinations and loss of co-ordination. NR2B subtype selective antagonists have previously shown a therapeutic effect without causing the side effects of broad spectrum NMDA antagonists. Considerable research has since been devoted to the development of orally bioavailable, selective NR2B antagonists and their applications in various neurological diseases. The improved therapeutic index of these compounds is expected to be the result of the subtype selectivity and cellular location of the NR2B receptors within the CNS. This review describes recent advances in the development of NR2B antagonists as well as their therapeutic applications.

Topics: Animals; Benzamidines; Brain Ischemia; Chemistry, Pharmaceutical; Excitatory Amino Acid Antagonists; Humans; Mice; Pain; Parkinson Disease; Piperidines; Rats; Receptors, N-Methyl-D-Aspartate; Structure-Activity Relationship

Timely and important studies are reviewed and commentaries provided by leading palliative care clinicians. Symptoms, interventions, and treatment-related adverse events addressed in this issue are management of Alzheimer's agitation with donepezil; needle-free lidocaine powder for minor painful procedures; psychostimulants in depression; anticoagulation for cancer-related venous thromboembolism; effect of waiting for acute pain treatment on risk of chronic pain; and an update on severe cutaneous reactions associated with medications.

Topics: Alzheimer Disease; Amphetamines; Anesthetics, Local; Anticoagulants; Antidepressive Agents; Depression; Donepezil; Drug Therapy; Drug-Related Side Effects and Adverse Reactions; Humans; Indans; Lidocaine; Nootropic Agents; Pain; Palliative Care; Phlebotomy; Piperidines; Prescription Drugs; Psychomotor Agitation; Randomized Controlled Trials as Topic; Sertraline; Stevens-Johnson Syndrome; Thromboembolism

N-methyl-D-aspartate receptors (NMDARs) are ion channels gated by glutamate, the major excitatory neurotransmitter in the mammalian central nervous system (CNS). They are widespread in the CNS and are involved in numerous physiological and pathological processes including synaptic plasticity, chronic pain and psychosis. Aberrant NMDAR activity also plays an important role in the neuronal loss associated with ischaemic insults and major degenerative disorders including Parkinson's and Alzheimer's disease. Agents that target and alter NMDAR function may, thus, have therapeutic benefit. Interestingly, NMDARs are endowed with multiple extracellular regulatory sites that recognize ions or small molecule ligands, some of which are likely to regulate receptor function in vivo. These allosteric sites, which differ from agonist-binding and channel-permeation sites, provide means to modulate, either positively or negatively, NMDAR activity. The present review focuses on allosteric modulation of NMDARs containing the NR2B subunit. Indeed, the NR2B subunit confers a particularly rich pharmacology with distinct recognition sites for exogenous and endogenous allosteric ligands. Moreover, NR2B-containing receptors, compared with other NMDAR subtypes, appear to contribute preferentially to pathological processes linked to overexcitation of glutamatergic pathways. The actions of extracellular H+, Mg2+, Zn2+, of polyamines and neurosteroids, and of the synthetic compounds ifenprodil and derivatives ('prodils') are presented. Particular emphasis is put upon the structural determinants and molecular mechanisms that underlie the effects exerted by these agents. A better understanding of how NR2B-containing NMDARs (and NMDARs in general) operate and how they can be modulated should help define new strategies to counteract the deleterious effects of dysregulated NMDAR activity.

Topics: Allosteric Regulation; Allosteric Site; Animals; Brain Diseases; Depressive Disorder, Major; Humans; Magnesium; Neurotransmitter Agents; Pain; Piperidines; Polyamines; Protein Subunits; Receptors, N-Methyl-D-Aspartate; Synaptic Transmission; Zinc

Topics: Amyloid beta-Peptides; Animals; Crystallography, X-Ray; Drug Design; Humans; Hypersensitivity; Inflammation; Intramolecular Oxidoreductases; Lipocalins; Molecular Chaperones; Muscular Dystrophies; Pain; Piperidines; Prostaglandin D2; Protein Conformation; Sleep

Over the past decade, there have been major advances in our understanding of the role of glutamate and N-methyl-d-aspartate (NMDA) receptors in several disorders of the central nervous system, including stroke, Parkinson's disease, Huntington's disease and chronic/neuropathic pain. In particular, NR2B subunit-containing NMDA receptors have been the focus of intense study from both a physiological and a pharmacological perspective, with several pharmaceutical companies developing NR2B subtype-selective antagonists for several glutamate-mediated diseases. Recent studies have shown the importance of NR2B subunits for NMDA receptor localization and endocytosis, and have suggested a role for NR2B-containing NMDA receptors in the underlying pathophysiology of neurodegenerative disorders such as Alzheimer's and Huntington's diseases. Anatomical, biochemical and pharmacological studies over the past five years have greatly added to our understanding of the role of NR2B subunit-containing NMDA receptors in chronic and neuropathic pain states, and have shown that NR2B-mediated analgesic effects might be supra- rather than intra-spinally mediated, and that phosphorylation of the NR2B subunit could be responsible for the initiation and maintenance of the central sensitization seen in neuropathic pain states. These data will hopefully provide the impetus for development of novel compounds that use multiple approaches to modulate the activity of NR2B subunit-containing NMDA receptors, thus bringing to fruition the promise of therapeutic efficacy utilizing this approach.

Topics: Animals; Brain Ischemia; Clinical Trials as Topic; Disease Models, Animal; Excitatory Amino Acid Antagonists; Glutamic Acid; Humans; Huntington Disease; Pain; Phenols; Piperidines; Protein Conformation; Receptors, N-Methyl-D-Aspartate

Guided by an understanding of signal transduction in pain-processing systems, high-efficacy 5-hydroxytryptamine (5HT)1A receptor activation, by means of F-13640, has been discovered as a new molecular mechanism of pain relief in laboratory animals, inducing two neuroadaptive phenomena. Firstly, this activation cooperates with nociceptive stimulation, paradoxically causing analgesia, and secondly, inverse tolerance develops so that the resulting analgesia grows rather than decays. As an apparent result of these novel neuroadaptive mechanisms, F-13640 exerts an analgesic action in rat models of acute, tonic and chronic nociceptive pain that is rivaled only by large doses of high-efficacy mu-opioid receptor agonists. In models of neuropathic allodynia of peripheral or central origin, chronic F-13640 administration causes an analgesia that surpasses that observed with morphine or other agents exemplifying other central nervous system drug mechanisms of pain relief (e.g., ketamine, imipramine and gabapentin). Indeed, F-13640 produces long-lasting, preemptive and, most remarkably, curative-like actions in neuropathic allodynia. Although awaiting proof-of-concept evidence in humans, high-efficacy 5-HT(1A) receptor activation may uniquely challenge the opioids for pain therapy.

Topics: Analgesics; Animals; Drug Tolerance; Humans; Ligands; Pain; Peripheral Nervous System Diseases; Piperidines; Pyridines; Receptor, Serotonin, 5-HT1A; Serotonin 5-HT1 Receptor Agonists; Serotonin 5-HT1 Receptor Antagonists; Signal Transduction

The clinical use of an intravenous opioid testing can help to predict whether opioids will be beneficial. The determination of individual opioid responsiveness justifies subsequent long-term opioid treatment and is generally recommended. An overview over current testing procedures is given with particular regard to choice of opioid, maximum dose, determination of endpoints and duration of testing and recovery. Remifentanil testing is a new approch and is studied in a randomized placebo-controlled cross-over study in 24 patients suffering from severe non-cancer pain. An ascending infusion of remifentanil and placebo respectively was titrated against endpoints. The testing allowed a disctinction between 11 opioid-responders and 13 non-responders. Complete recovery after end of infusion was rapid with a reach of baseline conditions after 25 min in all patients. Thus the complete remifentanil testing procedure required at utmost 1 h. In conclusion, remifentanil testing offers a more rapid procedure allowing the routine use in an ambulatory setting.

Topics: Analgesics, Opioid; Chronic Disease; Dose-Response Relationship, Drug; Endpoint Determination; Humans; Infusions, Intravenous; Pain; Piperidines; Remifentanil; Treatment Outcome

Remifentanil is a new, ultra-short acting opioid, which may be applied in several branches of anaesthesia. Data concerning pharmacokinetics and pharmacodynamics as well as review of references regarding practical use, combining this drug with other anaesthetics agents and side effects are given. Particular attention is paid to the usefulness of remifentanil to provide good control of haemodynamics and stress response during surgical procedures. Remifentanil also seems to be very effective in the intensive care setting and for pain control during various medical procedures.

Topics: Analgesics, Opioid; Humans; Pain; Piperidines; Remifentanil; Treatment Outcome

Topics: Anticonvulsants; Botulinum Toxins; Calcitonin Gene-Related Peptide; Central Nervous System; Clinical Trials as Topic; Drug Design; Fructose; Humans; Indoles; Meta-Analysis as Topic; Migraine Disorders; Pain; Piperidines; Pyrrolidines; Serotonin Receptor Agonists; Signal Transduction; Sumatriptan; Topiramate; Triazoles; Trigeminal Nerve; Tryptamines; Vasodilation

Recent advances have dramatically increased our understanding of cannabinoid pharmacology: the psychoactive constituents of Cannabis sativa have been isolated, synthetic cannabinoids described and an endocannabinoid system identified, together with its component receptors, ligands and their biochemistry. Strong laboratory evidence now underwrites anecdotal claims of cannabinoid analgesia in inflammatory and neuropathic pain. Sites of analgesic action have been identified in brain, spinal cord and the periphery, with the latter two presenting attractive targets for divorcing the analgesic and psychotrophic effects of cannabinoids. Clinical trials are now required, but are hindered by a paucity of cannabinoids of suitable bioavailability and therapeutic ratio.

Topics: Amides; Amidohydrolases; Analgesics; Animals; Arachidonic Acids; Benzoxazines; Brain; Camphanes; Cannabinoid Receptor Modulators; Cannabinoids; Cell Membrane; Clinical Trials as Topic; Disease Models, Animal; Drug Design; Drug Interactions; Endocannabinoids; Enzyme Inhibitors; Ethanolamines; Glycerides; Humans; Injections, Spinal; Molecular Structure; Morpholines; Naphthalenes; Pain; Palmitates; Palmitic Acids; Piperidines; Plant Extracts; Polyunsaturated Alkamides; Pyrazoles; Receptors, Cannabinoid; Receptors, Drug; Rimonabant; Spinal Cord

Epidural analgesia and spinal analgesia are the most effective techniques for relieving labour pain. Basically, local anaesthetics (i.e. bupivacaine) and opioids (i.e. fentanyl or sufentanil), especially when combined, produce excellent analgesia with minimal motor blockade. However, none of these agents is devoid of side-effects and analgesia remains sometimes imperfect, suggesting that new drugs would be welcome. Adrenalin and clonidine act on a2-adrenoceptors in the spinal cord and both have been found to improve analgesia. These two drugs have already been used in many patients and studies because the absence of neurotoxicity has been well documented. Clonidine looks more attractive, although sedation and hypotension limit its use. Other analgesic drugs are promising alternatives but are still at an experimental or very early clinical stage. Neostigmine and ketamine (without preservative) are not neurotoxic while midazolam neurotoxicity is still controversial. Intravenous remifentanil might prove useful when neuraxial analgesia is contraindicated.

Topics: Analgesia, Obstetrical; Analgesics, Non-Narcotic; Clonidine; Epinephrine; Female; Humans; Midazolam; Neostigmine; Obstetric Labor Complications; Pain; Piperidines; Pregnancy; Receptors, N-Methyl-D-Aspartate; Remifentanil

Topics: Animals; Benzamides; Brain; Kinetics; Neurokinin A; Pain; Piperidines; Receptors, Neurokinin-2; Respiratory Physiological Phenomena; Respiratory System

Topics: Acidosis; Androstanes; Anesthesia; Anesthesia, General; Anesthesia, Inhalation; Anesthesia, Obstetrical; Anesthetics; Anti-Bacterial Agents; Anxiety; Contraceptives, Oral; Female; Ferricyanides; Fever; Humans; Hypnotics and Sedatives; Hypotension; Ketones; Male; Neuromuscular Nondepolarizing Agents; Occupational Diseases; Pain; Piperidines; Pregnancy; Pregnanes; Steroids; Tranquilizing Agents

Topics: Analgesics; Analgesics, Non-Narcotic; Antipyretics; Biphenyl Compounds; Chemistry, Pharmaceutical; Heroin; Morphine; Nalorphine; Pain; Piperidines

To compare outcomes between two standard-of-care anesthesia regimens for operative laryngoscopy: general anesthesia with a neuromuscular blocking agent (NMBA) versus remifentanil and propofol (non-NMBA).. This was a prospective, single-blinded, randomized controlled trial at a tertiary care center. Patients were randomized to either anesthesia using rocuronium (NMBA) or with remifentanil/propofol infusion alone (non-NMBA). Intraoperative impressions, anesthesia data, and post-operative patient surveys were collected.. Sixty-one patients who underwent suspension laryngoscopy from 2020 to 2022 were included (25 female, 36 male, ranging 20-81 years). Thirty patients were enrolled in the NMBA arm and 31 patients in the non-NMBA arm. Heart rate and mean arterial pressure were higher in the NMBA (p < 0.01). Patients in the non-NMBA group were more likely to require vasopressors (p = 0.04, RR = 3.08 [0.86-11.05]). Surgeons were more frequently satisfied with conditions in the NMBA group (86.7%) compared to the non-NMBA group (58.1%, p < 0.01). Procedures were more likely to be paused due to movement in the non-NMBA group (45.1%) compared to the NMBA group (16.6%, p < 0.03, RR = 2.26 [1.02-4.99]). Patients in the non-NMBA group were more likely to endorse myalgia the week after surgery (44%) compared to the NMBA group (8.3%, p < 0.01) and reported higher average pain levels on a 0-10 pain scale (3.7) compared to the paralysis group (2.0).. Anesthesia with rocuronium was associated with better intraoperative conditions and postoperative pain compared to anesthesia with remifentanil/propofol. Remifentanil/propofol were associated with lower blood pressure and suppression of laryngoscopy-associated tachycardia.. 2 Laryngoscope, 133:2654-2664, 2023.

Topics: Androstanols; Anesthesia, General; Anesthetics, Intravenous; Female; Humans; Laryngoscopy; Male; Neuromuscular Nondepolarizing Agents; Pain; Piperidines; Propofol; Prospective Studies; Remifentanil; Rocuronium

Tofacitinib is an oral Janus kinase inhibitor for the treatment of psoriatic arthritis (PsA). This post hoc analysis assessed tofacitinib efficacy on enthesitis by baseline location and severity, and impact on disease activity and patient-reported outcomes (PROs), in patients with PsA.. Data were pooled from two phase 3 studies (NCT01877668/NCT01882439) in patients with PsA receiving tofacitinib 5 or 10 mg twice daily to month (M)6 or placebo to M3. Endpoints were: change from baseline in Leeds Enthesitis Index (LEI) or Spondyloarthritis Research Consortium of Canada Enthesitis Index (SPARCC); proportions of patients with enthesitis, relapsed enthesitis after resolution, de novo enthesitis, low disease activity (LDA) or remission (minimal disease activity/very low disease activity; Psoriatic Arthritis Disease Activity Score; Disease Activity Index for Psoriatic Arthritis, and Composite Psoriatic Disease Activity in Psoriatic Arthritis); and PROs (Functional Assessment of Chronic Illness Therapy-Fatigue [FACIT-F] total and arthritis pain Visual Analog Scale scores). Descriptive statistics were generated by visit and treatment. Change from baseline in PROs was evaluated by multivariate linear regression.. Seven hundred ten patients from two studies were included: 479 had LEI > 0; 545 had SPARCC > 0; and 136 had LEI = 0 and SPARCC = 0 at baseline. At baseline, among patients with LEI > 0 or SPARCC > 0, mean LEI and SPARCC across treatments and enthesitis locations/severities ranged from 1.0-4.4 and 1.3-9.4, respectively. Across several baseline enthesitis locations/severities, changes from baseline in LEI and SPARCC up to M3 were greater with tofacitinib (-2.0-0.4 and -3.5-0.2) vs placebo (-‍0.9-‍0.4 and -1.5-1.1). Enthesitis at M6 was more common in patients with greater baseline enthesitis severity. At M6, ≤ 40% of patients with baseline LEI > 0 or SPARCC > 0 whose enthesitis had resolved by M1/M3 experienced a relapse, and < 14% of patients with baseline LEI = 0 and SPARCC = 0 had de novo enthesitis. LDA/remission rates generally increased with tofacitinib over time. Baseline LEI location was significantly associated with change from baseline in arthritis pain score, while baseline SPARCC severity was significantly associated with change from baseline in FACIT-F total and arthritis pain scores.. Tofacitinib treatment resulted in improvements in enthesitis in patients with PsA, regardless of baseline location or severity.. NCT01877668;NCT01882439.

Topics: Arthritis, Psoriatic; Enthesopathy; Humans; Pain; Piperidines; Spondylarthritis

A significant proportion of triptan users exhibit an insufficient response or inadequate tolerability to a triptan, and some may develop a contraindication. Lasmiditan, a selective 5-HT. Patients were randomized to lasmiditan 200 mg for four attacks, lasmiditan 100 mg for four attacks, or placebo for three and lasmiditan 50 mg for one attack. Triptan insufficient responders were pre-defined as patients with insufficient efficacy or tolerability, or who developed a contraindication.. Lasmiditan was efficacious across multiple clinically relevant endpoints in the acute treatment of migraine independent of prior response to triptans.

Topics: Benzamides; Double-Blind Method; Humans; Migraine Disorders; Pain; Piperidines; Pyridines; Serotonin 5-HT1 Receptor Agonists; Serotonin Receptor Agonists; Treatment Outcome; Tryptamines

Ankylosing spondylitis (AS) impacts quality of life. We assessed patient-reported outcomes (PROs), pain, fatigue, health-related quality of life (HRQoL) and work productivity in a phase III trial of tofacitinib.. Adults with AS and with inadequate response/intolerance to ≥2 non-steroidal anti-inflammatory drugs received tofacitinib 5 mg twice daily or placebo for 16 weeks. Afterwards, all received open-label tofacitinib until week 48. Change from baseline to week 48 was determined for PROs: total back pain; nocturnal spinal pain; Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) overall spinal pain (Q2); Functional Assessment of Chronic Illness Therapy-Fatigue; BASDAI fatigue (Q1); AS Quality of Life (ASQoL); Short Form-36 Health Survey Version 2 (SF-36v2); EuroQoL-Five Dimension-Three Level health profile and Visual Analogue Scale; and the Work Productivity and Activity Impairment (WPAI) questionnaire. Improvements from baseline ≥minimum clinically important difference, and scores ≥normative values at week 16 were evaluated.. In 269 randomised and treated patients, at week 16, there were greater least squares mean improvements from baseline with tofacitinib 5 mg twice daily versus placebo in BASDAI overall spinal pain (-2.85 vs -1.34), BASDAI fatigue (-2.36 vs -1.08), ASQoL (-4.03 vs -2.01) and WPAI overall work impairment (-21.49 vs -7.64) (all p<0.001); improvements continued/increased to week 48. Improved spinal pain with tofacitinib was seen by week 2. Patients receiving tofacitinib reported clinically meaningful PRO improvements at week 16. Percentages with PRO scores ≥normative values at week 16 were greater with tofacitinib in SF-36v2 Physical Component Summary, physical functioning and bodily pain domains (p≤0.05).. In patients with AS, treatment with tofacitinib 5 mg twice daily resulted in clinically meaningful improvements in pain, fatigue, HRQoL and work productivity versus placebo to week 16, which were sustained to week 48.. NCT03502616.

Topics: Adult; Antirheumatic Agents; Fatigue; Humans; Pain; Piperidines; Pyrimidines; Pyrroles; Quality of Life; Spondylitis, Ankylosing; Treatment Outcome

In controlled clinical trials, compared with placebo, a significantly greater proportion of participants using lasmiditan to treat a migraine attack achieved 2-h pain freedom (PF) and experienced ≥ 1 treatment-emergent adverse event (TEAE).. To better inform clinicians about treatment expectations by evaluating the association between TEAEs and efficacy outcomes after lasmiditan treatment.. Pooled data from SAMURAI, SPARTAN, MONONOFU, and CENTURION were analyzed. A common TEAE (CTEAE) was defined as occurring in ≥ 2% in the overall population. Central nervous system (CNS)-CTEAEs were based on Medical Dictionary for Regulatory Activities.. At 2 h, a significantly higher percentage of lasmiditan 200 mg-treated participants who achieved PF experienced ≥ 1 CTEAE than non-responders who continued to experience moderate/severe pain (48.2% vs. 28.7%, respectively). Correspondingly, a significantly higher percentage of lasmiditan 200 mg-treated participants who experienced ≥ 1 CTEAE achieved PF at 2 h than those who did not (39.0% vs. 30.2%, respectively). Similar results were generally observed with individual CNS-CTEAEs, but for non-CNS-CTEAEs, this pattern was less evident or in the opposite direction. No consistent differences were observed for migraine-related functional disability freedom. The percentage of participants with improved patient global impression of change (PGIC) was greater with a CNS-CTEAE versus no CNS-CTEAE.. Those who had PF at 2 h were more likely to experience a CNS-CTEAE, and those with CNS-CTEAEs were more likely to experience PF. The occurrence of CTEAEs did not seem to negatively affect disability freedom or PGIC.. SAMURAI (NCT02439320), SPARTAN (NCT02605174), MONONOFU (NCT03962738), CENTURION (NCT03670810), ClinicalTrials.gov: NCT02439320, NCT02605174, NCT03962738, NCT03670810.

Topics: Benzamides; Double-Blind Method; Humans; Migraine Disorders; Pain; Piperidines; Pyridines; Randomized Controlled Trials as Topic; Serotonin Receptor Agonists; Treatment Outcome

Until now, target-controlled infusion of remifentanil with midazolam for transrectal ultrasound-guided prostate biopsy has not been described. Here, we investigate 2 effect-site concentrations of remifentanil with intermittent bolus midazolam for transrectal ultrasound-guided prostate biopsy under procedural analgesia and sedation.. A prospective, randomized controlled trial including patients who received a transrectal ultrasound-guided prostate biopsy between February 2019 and January 2021 was conducted. Group 1 and Group 2 were respectively administered an initial effect-site concentration of remifentanil of 1.0 ng/mL and 2.0 ng/mL by a target-controlled infusion pump with Minto model. In both groups, maintenance of the effect-site concentration of remifentanil was adjusted upward and downward by 0.5 ng/mL to keep patient comfort with acceptable pain (remaining moveless), and mean arterial pressure and heart rate within baseline levels ± 30%, and using intermittent bolus midazolam to keep the Observer's Assessment of Alertness/Sedation scale between 2 and 4. The primary outcome was to determine which effect-site concentration of remifentanil provide adequate patient comfort with acceptable pain (remaining moveless) during the procedure.. A total of 40 patients in Group 1 and 40 patients in Group 2 were eligible for analysis. Most parameters were insignificantly different between Group 1 and Group 2, except Group 1 having higher peripheral oxygen saturation while probe insertion compared with Group 2. Group 2 patients had less intraoperative movements affecting the procedure (2 vs 18; P < .001), and less total times of target-controlled infusion pump adjustment (0 [0-1] vs 1 [0-3], P < .001) compared with group 1. However, group 1 patients had less apnea with desaturation (peripheral oxygen saturation < 90%; 0 vs 9, P = .002) and less remifentanil consumption (94.9 ± 25.5 μg vs 106.2 ± 21.2 μg, P = .034) compared to Group 2.. In transrectal ultrasound-guided prostate biopsy, target-controlled infusion with remifentanil Minto model target 2.0 ng/mL with 3 to 4 mg midazolam use provided sufficient analgesia and sedation, and appropriate hemodynamic and respiratory conditions.

Topics: Analgesia, Patient-Controlled; Biopsy; Double-Blind Method; Humans; Male; Midazolam; Pain; Piperidines; Prospective Studies; Prostate; Remifentanil; Ultrasonography, Interventional

To investigate the efficacy of pre-emptive remifentanil in alleviating pain during tracheal suctioning in patients under mechanical ventilation.. Goal-directed sedation is recommended for patients under mechanical ventilation by the current guidelines. Whether goal-directed sedation can prevent pain during tracheal suctioning in these patients is unknown.. This was a two-centre, randomized, crossover, single-blind trial conducted between August and October 2019.. Patients under mechanical ventilation received low-dose remifentanil, high-dose remifentanil or placebo prior to each tracheal suctioning in a random order. The primary outcomes were evaluated using the critical-care pain observation tool and Richmond agitation-sedation scale after tracheal suctioning. Adverse events were also documented.. A total of 39 patients who underwent 117 tracheal suctions were enrolled. After the tracheal suction, changes in the critical-care pain observation tool and Richmond agitation-sedation scale scores were significantly lower in the low-dose and high-dose groups than in the placebo group (P < 0.001). A non-significant increase in the absence of spontaneous breathing was observed in the high-dose group compared to that in the placebo group.. A pre-emptive remifentanil bolus of 0.5 μg/kg can mitigate the pain associated with tracheal suctioning.

Topics: Feasibility Studies; Goals; Humans; Pain; Piperidines; Remifentanil; Respiration, Artificial; Single-Blind Method; Suction

We present findings from the multicenter, double-blind Phase 3 study, CENTURION. This study was designed to assess the efficacy of and consistency of response to lasmiditan in the acute treatment of migraine across four attacks.. Patients were randomized 1:1:1 to one of three treatment groups - lasmiditan 200 mg; lasmiditan 100 mg; or a control group that received placebo for three attacks and lasmiditan 50 mg for either the third or fourth attack. The primary endpoints were pain freedom at 2 h (first attack) and pain freedom at 2 h in ≥2/3 attacks. Secondary endpoints included pain relief, sustained pain freedom and disability freedom. Statistical testing used a logistic regression model and graphical methodology to control for multiplicity.. Overall, 1471 patients treated ≥1 migraine attack with the study drug. Both primary endpoints were met for lasmiditan 100 mg and 200 mg (. These results confirm the early and sustained efficacy of lasmiditan 100 mg and 200 mg and demonstrate consistency of response across multiple attacks.

Topics: Benzamides; Double-Blind Method; Humans; Migraine Disorders; Pain; Piperidines; Pyridines; Serotonin Receptor Agonists; Treatment Outcome

To describe the efficacy of tofacitinib in reducing pain in patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) or ankylosing spondylitis (AS) in a post-hoc analysis of randomised controlled trials.. Data were collected from patients in seven tofacitinib studies: six phase III (four RA, two PsA) and one phase II study (AS), and grouped into five analysis populations based on rheumatic disease diagnosis and category of prior inadequate response (IR) to treatment: conventional synthetic disease-modifying antirheumatic drugs-IR (RA and PsA), tumour necrosis factor inhibitors-IR (RA and PsA), or non-steroidal anti-inflammatory drugs-IR (AS). Only patients who received tofacitinib 5 or 10 mg twice daily or placebo were included. Pain assessments included: Patient's Assessment of Arthritis Pain, Short-Form Health Survey 36v2 Question (Q)7 and Bodily Pain domain, Ankylosing Spondylitis Quality of Life Q9 and Q14, EuroQol Five Dimensions Pain/Discomfort dimension and Bath Ankylosing Spondylitis Disease Activity Index Q2 and Q3. Data were reported to month 6 (placebo to month 3) in the RA and PsA populations, and week 12 (tofacitinib and placebo) in the AS population.. Overall, 3330 patients were included in this analysis. In the RA and PsA populations, pain improvements in tofacitinib-treated patients compared with placebo were observed at the earliest time point assessed and at month 3 (maintained to month 6). In the AS population, pain improvements compared with placebo were observed at week 12.. Tofacitinib was associated with rapid and sustained improvements across multiple pain measures in patients with inflammatory rheumatic musculoskeletal diseases.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Antirheumatic Agents; Arthritis, Psoriatic; Arthritis, Rheumatoid; Case-Control Studies; Female; Humans; Male; Middle Aged; Pain; Pain Management; Pain Measurement; Patient Reported Outcome Measures; Piperidines; Placebos; Protein Kinase Inhibitors; Pyrimidines; Quality of Life; Spondylitis, Ankylosing; Treatment Outcome; Tumor Necrosis Factor Inhibitors

Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). We examined the degree to which Patient Global Assessment of Disease Activity (PtGA) was driven by patient-reported assessments of pain (Pain), physical function, and fatigue in patients receiving tofacitinib 5 mg twice daily or placebo, each with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs).. This post hoc analysis used data pooled from three randomized controlled trials in csDMARD-inadequate responder (csDMARD-IR) patients (ORAL Scan: NCT00847613; ORAL Standard: NCT00853385; ORAL Sync: NCT00856544). Using subgroup analysis from 2 × 2 tables, associations between PtGA and Pain, Health Assessment Questionnaire-Disability Index (HAQ-DI), and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) at month 3 were evaluated using Pearson's Phi correlation coefficients. To support the main analysis, associations between select patient-reported outcomes (PROs) were also evaluated in csDMARD-naïve (ORAL Start; NCT01039688) and biologic (b)DMARD-IR (ORAL Step; NCT00960440) patients.. Across csDMARD-IR treatment groups, low disease activity (defined as PtGA ≤ 20 mm), and moderate (≥ 30%) and substantial (≥ 50%) improvements from baseline in PtGA were associated with mild Pain (Visual Analog Scale score ≤ 20 mm), and moderate (≥ 30%) and substantial (≥ 50%) improvements from baseline in Pain; lack of Pain improvement was associated with little/no improvement in PtGA. In contrast, large proportions of csDMARD-IR patients who reported PtGA improvements did not report HAQ-DI or FACIT-F scores ≥ normative values (≤ 0.25 and ≥ 43.5, respectively) or changes in HAQ-DI or FACIT-F scores ≥ minimum clinically important difference (≥ 0.22 and ≥ 4.0, respectively). Generally, PtGA and Pain outcomes were moderately-to-strongly correlated at month 3 in csDMARD-IR patients, with weaker correlations evident between PtGA and HAQ-DI/FACIT-F outcomes. Similar findings were generally evident in csDMARD-naïve and bDMARD-IR patients.. This analysis supports the role of Pain as a key driver of PtGA in RA; physical function and fatigue play lesser roles in patients' perceptions of disease activity. These findings corroborate the importance of improved PROs and attainment of low symptom states for optimizing patient care.. Clinicaltrials.gov: NCT00847613 (registered: February 19, 2009); NCT00853385 (registered: March 2, 2009); NCT00856544 (registered: March 5, 2009); NCT01039688 (registered: December 25, 2009); NCT00960440 (registered: August 17, 2009).

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Fatigue; Humans; Pain; Piperidines; Pyrimidines; Pyrroles; Treatment Outcome

Pain management following major spine surgery requires high doses of opioids and is associated with a risk of opioid-induced constipation. Peripheral mu-receptor antagonists decrease the gastrointestinal complications of perioperative systemic opioid administration without antagonizing the analgesic benefits of these drugs.. To investigate the impact of alvimopan in opioid-naive patients undergoing major spine surgery.. Patients undergoing >3 levels of thoracic and/or lumbar spine surgery were enrolled in this prospective, randomized, double-blind study to receive either alvimopan or placebo prior to and following surgery. Opioid consumption; pain scores; and time of first oral intake, flatus, and bowel movement were recorded.. A total of 24 patients were assigned to the active group and 25 were assigned to the placebo group. There was no significant difference in demographics between the groups. Postoperatively, the alvimopan group reported earlier time to first solid intake [median (range): alvimopan: 15 h (3-25) vs placebo: 17 h (3-46), P < .001], passing of flatus [median (range): alvimopan: 22 h (7-63) vs placebo: 28 h (10-58), P < .001], and first bowel movement [median (range): alvimopan: 50 h (22-80) vs placebo: 64 h (40-114), P < .001]. The alvimopan group had higher pain scores (maximum, minimum, and median); however, there was no significant difference between the groups with postoperative opioid use.. This study shows that the perioperative use of alvimopan significantly reduced the time to return of bowel function with no increase in postoperative opioid use despite a slight increase in pain scores.

Topics: Adult; Analgesics, Opioid; Constipation; Double-Blind Method; Female; Gastrointestinal Agents; Gastrointestinal Motility; Humans; Middle Aged; Pain; Piperidines; Prospective Studies; Receptors, Opioid, mu; Recovery of Function; Spinal Diseases; Young Adult

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

Decrease of the nociceptive stimulation induced by laryngoscopy could be an advantage for patients without risk of difficult intubation. The present study aimed to compare the difference in nociceptive stimulation between the use of a conventional laryngoscope or of a videolaryngoscope. Amount of nociception was assessed indirectly using the peak remifentanil concentration determined by a closed-loop administration of propofol and remifentanil with bispectral index (BIS) as the input signal (target 50).. A prospective single-center randomized study was performed including surgical patients without predictable risk of difficult mask ventilation or of difficult tracheal intubation. Forty consecutive surgery patients were randomly assigned to CL group (conventional laryngoscope) or VL group (McGrath Mac videolaryngoscope). Induction of anesthesia was performed automatically using the closed-loop system and myorelaxation with atracurium. The allocation was revealed just before tracheal intubation. The primary outcome was the peak plasma remifentanil concentration observed during the 5-minute period which followed intubation.. Sixteen patients in the CL group and 11 in the VL group were analyzed. Plasmatic remifentanil and propofol concentrations were similar in both groups either before tracheal intubation or during the 5 minutes following intubation. There was a nonsignificant between-group difference (P = .09) for the peak concentration of remifentanil. A comparable result was observed for other outcomes except for the heart rate which increased in the CL group.. Use of the videolaryngoscope McGrath Mac did not reduce the nociceptive stimulation induced during intubation as evaluated by the automatically administered remifentanil concentration.. ClinicalTrials.gov, NCT02245789.

Topics: Adult; Aged; Anesthetics, Intravenous; Female; Humans; Intubation, Intratracheal; Laryngoscopy; Male; Middle Aged; Pain; Piperidines; Propofol; Prospective Studies; Remifentanil; Video Recording

Propofol is associated with pain during injection, which is stressful to patients. The present study was designed to investigate the analgesic effect of pretreatment with remifentanil and esmolol in minimizing propofol injection pain, compared with placebo.. In a randomized, double-blind, prospective trial, 120 patients, scheduled for elective dental surgery under general anesthesia, were randomized to 1 of the 4 treatment arms (n = 30 each) receiving normal saline, remifentanil 0.35 μg/kg, esmolol 0.5 mg/kg, and 1 mg/kg before administration of propofol. During injection of 1% propofol 0.5 mg/kg, pain was evaluated by a 4-point score (0 = none, 1 = mild, 2 = moderate, 3 = severe). Any adverse effects such as hypotension and bradycardia were recorded during the perioperative periods.. In all, 120 patients completed this study. There were no significant differences in terms of demographic data. The incidence of pain on injection of propofol was 11 (36.7%) with remifentanil 0.35 μg/kg, 12 (40%) with esmolol 0.5 mg/kg, and 11 (36.7%) with esmolol 1 mg/kg, compared with 25 (83.3%) with normal saline (respectively, P < 0.05). There were no significant differences in the incidence of pain between groups with remifentanil 0.35 μg/kg, and esmolol 0.5 mg/kg and 1 mg/kg. There were no emergence reactions such as hypotension and bradycardia in all groups.. Pretreatment with esmolol 0.5 mg/kg and 1 mg/kg and remifentanil 0.35 μg/kg equally decreased pain during propofol injection.

Topics: Adrenergic beta-1 Receptor Antagonists; Adult; Analgesics, Opioid; Anesthetics, Intravenous; Double-Blind Method; Female; Humans; Injections; Male; Middle Aged; Pain; Piperidines; Propanolamines; Propofol; Remifentanil

The aim of the study was to assess the efficacy and safety of remifentanil for pain relief during external cephalic version (ECV) for breech presentation in nulliparous women at term.. A total of 144 nulliparous women with singleton breech presentation were randomly divided into the intervention group and the placebo group, with 72 subjects in each group. The subjects in the intervention group received remifentanil (infused at 0.1 μg kg min with demand boluses of 0.1 μg/kg), whereas those in the placebo group were given saline placebo. This study was conducted from May 2013 to April 2016. The outcomes measures include pain (measured with the visual analog scale, VAS), success rate of ECV, maternal satisfaction for ECV, and adverse events.. A total of 137 participants completed the study. The intervention with remifentanil showed greater efficacy than did placebo in decreasing the VAS score immediately after ECV (intervention group 4.3 ± 2.2 vs placebo group 6.4 ± 2.5, P < 0.01). A significant difference in the ECV success rate was also found between the 2 groups (intervention group 56.9% vs placebo group 38.9%, P = 0.03). In addition, a significant difference in the satisfaction score was also detected (intervention group 9.3 ± 0.9 vs placebo group 6.7 ± 1.2, P < 0.01). The observed adverse events were similar between the 2 groups.. This study shows that remifentanil could decrease pain, improve the ECV success rate, and improve satisfaction in nulliparous women at term during the period of ECV. Furthermore, it is also well tolerated with few adverse events.

Topics: Adult; Analgesics, Opioid; Double-Blind Method; Female; Humans; Pain; Parity; Piperidines; Pregnancy; Remifentanil; Version, Fetal

After surgical procedures, anesthesia itself may affect pain perception. Particularly, there is increasing evidence that opioids not only have analgesic effects but also provoke pronociceptive changes, that is, opioid-induced hyperalgesia. We investigated the effect of different anesthetic regimens on pain processing in volunteers using a transdermal electrical pain model. In this model, stimulation of epidermal nerve fibers representing mainly peptidergic C-nociceptors leads to secondary hyperalgesia and habituation to the stimulus.. Forty-eight healthy volunteers underwent conditioning noxious stimulation (CS) over 5 days. On day 2, the volunteers were randomized into 4 groups: control group (no anesthesia) and 3 groups receiving anesthesia before CS in anesthetic doses: propofol (P), propofol/remifentanil (PR), and propofol/remifentanil/S-ketamine (PRK). Quantitative sensory testing was performed on days 1 through 5 and on day 22.. In every group, CS was associated with short- and long-term habituation to the electrical stimulus. Repetitive CS resulted in unmodified short-term sensitization with stable areas of hyperalgesia. Although the PR group showed a trend toward increased areas of hyperalgesia on day 2, no significant differences were detectable between the groups. In contrast, anesthesia resulted in decreased intensity of the electrically evoked pain on day 2. Finally, the mechanical pain threshold before CS on day 5 was increased in all groups and remained elevated 3 weeks after the first CS, consistent with a long-term antinociceptive effect after CS.. The results suggest a short-term analgesic effect of general anesthesia. Furthermore, the conditioning stimulation over several days induced differential modulation of pro- and antinociceptive systems.

Topics: Adult; Analgesics, Opioid; Anesthetics; Female; Humans; Hyperalgesia; Ketamine; Male; Pain; Pain Measurement; Pain Threshold; Piperidines; Propofol; Remifentanil; Young Adult

Pregabalin is widely used perioperatively. The authors explored the effects of pregabalin, remifentanil, and their combination on experimental pain, ventilatory, and cognitive function.. In a randomized, double-blinded crossover study, 12 volunteers received (1) pregabalin + placebo, (2) placebo + remifentanil, (3) pregabalin + remifentanil, and (4) placebo + placebo. Pregabalin 150 mg/placebo was administered twice orally. After baseline, remifentanil/placebo was given as effect-site target-controlled infusion (TCI): 0.6, 1.2, and 2.4 ng/ml. Pain during cold pressor test was scored on visual analog scale (0 to 100 mm). Ventilation was measured by spirometry and cognition tested with Color-Word Interference and Rapid Information Processing tests.. Pain intensity after placebo was (mean) 72 mm (95% CI, 62 to 83). Pregabalin reduced pain score by -10 mm (-14 to -7, P < 0.001). Remifentanil had dose-dependent analgesic effect, reducing pain score by -47 mm (-54 to -39, P < 0.001) on highest TCI level, whereas pregabalin + remifentanil exerted additive effect, reducing pain score by -57 mm (-64 to -50, P < 0.001). Respiratory depression was potentiated by adding pregabalin to remifentanil; end-tidal carbon dioxide was 39.3 mmHg (37.2 to 41.3) with placebo, increased 1.8 mmHg (-0.9 to 4.6, P = 0.4) with pregabalin, 10.1 mmHg (4.9 to 15.4, P < 0.001) with remifentanil, and 16.4 mmHg (11.3 to 21.5, P < 0.001) with pregabalin + remifentanil on highest TCI level. The combination pregabalin + remifentanil, but not either drug alone, adversely affected all cognitive tests.. The combination of pregabalin and remifentanil had additive analgesic effects, pregabalin potentiated remifentanil ventilatory depression, and the combination adversely affected cognition. These results question the clinical benefit of the combination compared with higher doses of opioids.

Topics: Adult; Analgesics; Cognition; Cross-Over Studies; Double-Blind Method; Drug Synergism; Drug Therapy, Combination; Female; Humans; Hypnotics and Sedatives; Male; Pain; Piperidines; Pregabalin; Remifentanil; Respiration; Respiratory Function Tests; Young Adult

To determine the most effective time interval between remifentanil and propofol (TimeRP) for the prevention of propofol injection pain in association with remifentanil dosage.. Prospective randomized study.. Operating room of a university hospital.. Sixty American Society of Anesthesiologists physical status 1 and 2 patients scheduled for elective surgery under general anesthesia.. Patients were randomly assigned to 1 of 3 groups to receive remifentanil at dosages of 0.25, 0.5, or 0.75 μg/kg over 30 seconds before the injection of 1% propofol 2 mg/kg. TimeRP was defined as the time interval from the initiation of the remifentanil injection to the initiation of the propofol injection. TimeRP for each subsequent patient was determined by the response of the previous patient using an up-and-down sequential allocation method. Injection pain caused by propofol was evaluated using a 4-point scale during the propofol injection.. TimeRP50 was defined as the TimeRP at which propofol injection pain was absent in 50% of patients, and it was estimated using isotonic regression for each dose group.. TimeRP50 was significantly lower in the remifentanil 0.75 μg/kg group (38.6 seconds, 83% confidence interval [CI], 35.6-45.0) than in the 0.5 μg/kg group (65.0 seconds; 83% CI, 52.5-75.0) or the 0.25 μg/kg group (66.6 seconds; 83% CI, 57.1-76.5).. The efficacy of remifentanil pretreatment for preventing propofol injection pain can be influenced by the time interval between remifentanil and propofol as well as the remifentanil dose.

Topics: Adult; Analgesics, Opioid; Anesthesia, General; Anesthetics, Intravenous; Female; Humans; Injections, Intravenous; Male; Middle Aged; Pain; Pain Measurement; Piperidines; Propofol; Prospective Studies; Remifentanil; Time Factors

Tofacitinib is an oral Janus kinase inhibitor that improves clinical measures of psoriasis.. We sought to assess patient-reported outcomes in tofacitinib-treated patients with moderate to severe plaque psoriasis over 52 weeks.. In 2 identical, phase III studies (Oral treatment for Psoriasis Trial Pivotal 1 [NCT01276639], n = 901, and Pivotal 2 [NCT01309737], n = 960), patients were randomized 2:2:1 to receive 5 or 10 mg of tofacitinib or placebo, twice daily. At week 16, placebo-treated patients were re-randomized to tofacitinib. Dermatology Life Quality Index score, Itch Severity Item score, Patient Global Assessment score, and patient satisfaction were assessed.. Baseline Dermatology Life Quality Index score indicated substantial health-related quality of life impairment. At week 16, a greater proportion of patients achieved Dermatology Life Quality Index score of 1 or less (no effect of psoriasis on health-related quality of life) with tofacitinib 5 and 10 mg twice daily versus placebo (Oral treatment for Psoriasis Trial Pivotal 1/2: 26.7%/28.6% and 40.2%/48.2% vs 4.6%/6.0%, respectively; P < .0001); improvements were maintained through week 52. Similar patterns were observed with Patient Global Assessment. Improvements in itch were particularly rapid, observed 1 day after treatment initiation for both tofacitinib doses versus placebo (P < .05). At week 16, more patients were satisfied with tofacitinib versus placebo (P < .0001).. Clinical nonresponders discontinued at week 28.. Tofacitinib demonstrated improvement in health-related quality of life and patient-reported symptoms that persisted over 52 weeks.

Topics: Adult; Female; Humans; Male; Middle Aged; Pain; Patient Satisfaction; Piperidines; Protein Kinase Inhibitors; Pruritus; Psoriasis; Pyrimidines; Pyrroles; Quality of Life; Severity of Illness Index

Pethidine with midazolam-induced conscious sedation for pain relief during transvaginal oocyte retrieval for in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) procedures is associated with residual pain and oversedation. Patient-controlled analgesia (PCA) with remifentanil may serve as an alternative for pethidine. We investigated whether PCA remifentanil with diclofenac was associated with improved periprocedural pain relief than pethidine analgesia during IVF/ICSI procedures, with sedation scores, safety profiles, and patient satisfaction as secondary endpoints.. Seventy-six women were randomized to receive pethidine (2 mg/kg i.m.) and midazolam (7.5 mg)-induced conscious sedation (n = 40) or PCA with remifentanil and diclofenac (50 mg; n = 36). The Numeric Rating Scale, McGill Pain Questionnaire (MPQ), Ramsey Sedation Scale, and a 5-day pain-and-discomfort diary were used to evaluate pain and sedation levels.. There were no differences in baseline characteristics and reproductive outcomes between both groups. Periprocedural pain scores were comparable for remifentanil and pethidine groups (4 [3 to 7] vs. 6 [4 to 8]; P = 0.13). Pain scores in the pethidine group were significantly lower at 30 minutes after the procedure (1 [0 to 3] vs. 2 [1 to 5]; P = 0.016), but at cost of higher sedation levels when compared to remifentanil (4 [2 to 4] vs. 2 [2 to 2]; P < 0.001). Patient satisfaction was higher, and MPQ scores were lower in the remifentanil group. There were no differences in safety profiles between both analgesics.. Patient-controlled analgesia with remifentanil showed a similar reduction in pain scores than pethidine with midazolam during oocyte retrieval, while pethidine induced the highest pain relief after the procedure. However, PCA remifentanil was associated with less sedation and a better patient satisfaction profile than pethidine.

Topics: Adult; Analgesia, Patient-Controlled; Analgesics, Opioid; Anesthetics, Intravenous; Drug Therapy, Combination; Female; Fertilization in Vitro; Humans; Meperidine; Midazolam; Oocyte Retrieval; Pain; Pain Measurement; Patient Satisfaction; Piperidines; Prospective Studies; Remifentanil; Sperm Injections, Intracytoplasmic

To assess whether patient comfort could be increased by adding procedural sedation and analgesia (PSAA) to periprostatic nerve block (PNB) in patients undergoing transrectal ultrasound-guided prostatic biopsy (TRUS-PB).. This was a prospective, randomized (1:2) trial comparing PNB with the combination of PSAA+PNB in patients undergoing TRUS-PB. PNB was achieved by using lidocaine gel and lidocaine and bipuvacaine infiltration. PSAA-treated patients received midazolam and remifentanil. All biopsies were standardized and performed in a fully equipped endourology suite. PSAA was delivered by an anesthesiology nurse in the presence and availability of an anesthesiologist. An orally administered numeric scale of 0-10 was used to assess the patient's pain, and a visual scale of 0-4 was used to quantify their satisfaction. Pain and satisfaction scores were compared between the groups.. Data on 331 patients were analyzed: 235 received PNB, and 96 received PSAA+PNB. Distribution within the groups by age, prostate-specific antigen serum levels, prostate volume, and number of cores obtained was similar. Airway insertion was required in 4 of 96 patients in PSAA+PNB arm (4%), with no other complications related to sedation. The average pain level was significantly lower in the PSAA+PNB group than it was in the PNB group (0.88 versus 1.31; p = 0.008). The satisfaction level was high (3.5) and alike in the two groups; however, significantly more patients reported a perfect score of 4 in the PSAA+PNB arm (p = 0.03).. PSAA with midazolam and remifentanil used as an adjunct to the standard PNB is safe and effective during TRUS-PB. Patients undergoing PSAA in addition to PNB experienced significantly less pain and higher satisfaction scores than did those given PNB alone.

Topics: Aged; Anesthetics, Local; Biopsy; Gels; Humans; Hypnotics and Sedatives; Lidocaine; Male; Midazolam; Middle Aged; Nerve Block; Pain; Patient Satisfaction; Piperidines; Prospective Studies; Prostate; Remifentanil; Ultrasonography, Interventional

Opioids alter resting state brain oscillations by multiple and complex factors, which are still to be elucidated. To increase our knowledge, multi-channel electroencephalography (EEG) was subjected to multivariate pattern analysis (MVPA), to identify the most descriptive frequency bands and scalp locations altered by remifentanil in healthy volunteers. Sixty-two channels of resting EEG followed by independent measures of pain scores to heat and bone pain were recorded in 21 healthy males before and during remifentanil infusion in a placebo-controlled, double-blind crossover study. EEG frequency distributions were extracted by a continuous wavelet transform and normalized into delta, theta, alpha, beta and gamma bands. Alterations relative to pre-treatment responses were calculated for all channels and used as input to the MVPA. Compared to placebo, remifentanil increased the delta band and decreased the theta and alpha band oscillations as a mean over all channels (all p ≤ 0.007). The most discriminative channels in these frequency bands were F1 in delta (83.33%, p = 0.0023) and theta bands (95.24%, p < 0.0001), and C6 in the alpha band (80.95%, p = 0.0054). These alterations were correlated to individual changes in heat pain in the delta (p = 0.045), theta (p = 0.038) and alpha (p = 0.039) bands and to bone pain in the alpha band (p = 0.0092). Hence, MVPA of multi-channel EEG was able to identify frequency bands and corresponding channels most sensitive to altered brain activity during remifentanil treatment. As the EEG alterations were correlated to the analgesic effect, the approach may prove to be a novel methodology for monitoring individual efficacy to opioids.

Topics: Adult; Analgesics, Opioid; Brain; Brain Waves; Cross-Over Studies; Denmark; Double-Blind Method; Electroencephalography; Healthy Volunteers; Hot Temperature; Humans; Infusions, Parenteral; Male; Multivariate Analysis; Pain; Pain Measurement; Pain Perception; Pain Threshold; Piperidines; Predictive Value of Tests; Pressure; Remifentanil; Signal Processing, Computer-Assisted; Time Factors; Young Adult

Although the combination of midazolam-meperidine has been widely used as a sedation regimen for colonoscopy, its residual effect which is longer than the duration of a colonoscopy procedure can delay patient recovery and discharge. Remifentanil, an ultra-short-acting opioid, has a very brief duration of action. We hypothesized that using remifentanil alone for colonoscopy would provide shorter recovery time compared with the midazolam-meperidine combination.. Time to achieve Aldrete score = 10 was determined and compared in patients who were randomly allocated to receive remifentanil alone (group-R, n = 27) or a midazolam-meperidine combination (group-MM, n = 27) for colonoscopy. Intergroup differences in sedation, recall analgesia, cardio-respiratory profiles, and satisfaction of patient and endoscopist were also determined during and after colonoscopy.. Group-R showed a significantly shorter recovery time than group-MM (median [25-75%], 0 [0-10] vs 30 [15-30] min, P < 0.001). Group-R showed significantly higher bispectral-index values during colonoscopy (92 [85-96] vs 84 [80-87], P = 0.001); a higher incidence of recall of explanations given during and after colonoscopy (100 vs 48% and 96 vs 52%, both P < 0.001); and a lower distress score (visual analog scale 30/100 vs 37/100 mm, P = 0.002), than did group-MM. Neither extent of pain, incidence of hemodynamic instability nor incidence of respiratory depression differed between the groups.. Remifentanil for colonoscopy afforded faster recovery compared to midazolam-meperidine combination. It also provided greater patient-endoscopist communication and satisfaction with comparable patient analgesia and cardiorespiratory profile during colonoscopy.

Topics: Analgesics, Opioid; Anesthesia; Anesthesia Recovery Period; Anesthetics, Intravenous; Colonoscopy; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Humans; Injections, Intravenous; Male; Meperidine; Midazolam; Middle Aged; Pain; Pain Management; Piperidines; Remifentanil; Time Factors

Studies have demonstrated that both pain and opioids have actions on the central nervous system that may interfere with cognitive function, but their effects have mainly been analysed separately and not as an integrated process.. The objective of this study is to test two hypotheses: (1) the analgesic effect of opioids improves cognitive function by decreasing pain, and (2) pain antagonizes cognitive effects of opioids.. Randomized, placebo-controlled, crossover study. Three experiments were conducted with 22 healthy males. Sustained attention, memory and motor function/attention/mental flexibility were evaluated by continuous reaction time (CRT), verbal fluency test (VFT) and trail making test-B (TMT-B), respectively. In the 1st experiment, the cognitive effects of experimental tonic pain of mild and moderate intensities produced by a computer-controlled pneumatic tourniquet cuff were assessed; in the 2nd, the effects of saline solution and remifentanil were assessed in the absence of pain; and in the 3rd experiment, the cognitive effects of moderate pain intensity relieved by remifentanil infusion were assessed followed by increasing pain to moderate intensity during a constant remifentanil infusion.. The first two experiments demonstrated that pain and remifentanil impaired CRT. In the 3rd experiment, remifentanil infusion relieving pain significantly impaired CRT and further deterioration was noted following increasing pain intensity.. Pain and remifentanil seemed to have additive deleterious cognitive effects. This study represents an initial step to enhance our basic understanding of some of the cognitive effects following a painful stimulus and an opioid infusion separately and combined in a sequence comparable to clinical settings.

Topics: Adult; Analgesics, Opioid; Cognition; Cross-Over Studies; Double-Blind Method; Humans; Male; Memory; Mental Processes; Pain; Pain Measurement; Piperidines; Reaction Time; Remifentanil; Young Adult

The authors investigated the effect of remifentanil administration on resting electroencephalography functional connectivity and its relationship to cognitive function and analgesia in healthy volunteers.. Twenty-one healthy male adult subjects were enrolled in this placebo-controlled double-blind cross-over study. For each subject, 2.5 min of multichannel electroencephalography recording, a cognitive test of sustained attention (continuous reaction time), and experimental pain scores to bone-pressure and heat stimuli were collected before and after infusion of remifentanil or placebo. A coherence matrix was calculated from the electroencephalogram, and three graph-theoretical measures (characteristic path-length, mean clustering coefficient, and relative small-worldness) were extracted to characterize the overall cortical network properties.. Compared to placebo, most graph-theoretical measures were significantly altered by remifentanil at the alpha and low beta range (8 to 18 Hz; all P < 0.001). Taken together, these alterations were characterized by an increase in the characteristic path-length (alpha 17% and low beta range 24%) and corresponding decrements in mean clustering coefficient (low beta range -25%) and relative small-worldness (alpha -17% and low beta range -42%). Changes in characteristic path-lengths after remifentanil infusion were correlated to the continuous reaction time index (r = -0.57; P = 0.009), while no significant correlations between graph-theoretical measures and experimental pain tests were seen.. Remifentanil disrupts the functional connectivity network properties of the electroencephalogram. The findings give new insight into how opioids interfere with the normal brain functions and have the potential to be biomarkers for the sedative effects of opioids in different clinical settings.

Topics: Adult; Analgesia; Analgesics, Opioid; Attention; Brain; Cluster Analysis; Cognition; Cognition Disorders; Cross-Over Studies; Double-Blind Method; Electroencephalography; Humans; Male; Nerve Net; Neural Pathways; Pain; Pain Management; Piperidines; Reaction Time; Reference Values; Remifentanil; Young Adult

In this study, we compared the propofol-ketamine and propofol-remifentanil combinations for deep sedation and analgesia during pediatric burn wound dressing changes.. Fifty pediatric patients aged 12-36 months, undergoing burn wound dressing changes, were randomly assigned to receive propofol-remifentanil (group PR) or propofol-ketamine (group PK) for deep sedation and analgesia. Patients in the group PR received 2 mg·kg(-1) propofol and 0.1 μg·kg(-1) remifentanil, and 0.05 μg·kg(-1) ·min(-1) remifentanil was infused continuously until the end of the procedure. Patients in the group PK received 2 mg·kg(-1) propofol and 1 mg·kg(-1) ketamine, and the same volume of isotonic saline was infused continuously until the end of the procedure. Additional propofol with remifentanil or ketamine was administered when required. Hemodynamic variables, drug requirements, occurrence of patient movement, surgeon's satisfaction score, recovery time, and the incidence of adverse events were recorded throughout the procedure and recovery.. Recovery time was significantly shorter in the group PR compared to that in the group PK (10.3 [9.1-11.5] min vs 22.5 [20.3-25.6] min, median [interquartile range], respectively; P < 0.001). No significant hypotension or bradycardia occurred throughout the procedure. No significant differences were observed in terms of drug requirements, occurrence of patient movement, surgeon's satisfaction, incidence of respiratory depression, hypoxia, or nausea and vomiting. The combinations of propofol-ketamine and propofol-remifentanil were effective for sedation and analgesia in pediatric patients undergoing burn dressing changes, but the propofol-remifentanil combination provided faster recovery compared to the propofol-ketamine combination.

Topics: Analgesia; Anesthesia Recovery Period; Anesthetics, Dissociative; Anesthetics, Intravenous; Bandages; Burns; Child, Preschool; Deep Sedation; Drug Therapy, Combination; Female; Humans; Hypnotics and Sedatives; Infant; Ketamine; Male; Pain; Pain Management; Piperidines; Propofol; Remifentanil; Treatment Outcome

Postoperative nausea and vomiting (PONV) is the most common postoperative complication. The postoperative use of opioids is known to increase the incidence. We compared fosaprepitant, a neurokinin-1 (NK1) receptor antagonist, and ondansetron for their preventive effects on PONV in patients who underwent gynecologic abdominal surgery with patient-controlled epidural analgesia.. This prospective, double-blind, randomized study comprised 44 patients who underwent gynecologic abdominal surgery. They were randomly allocated to receive 150 mg intravenous fosaprepitant (n = 24; NKI group) or 4 mg ondansetron (n = 20; ONS group) before anesthesia, which was maintained with volatile anesthetics, remifentanil, fentanyl, and rocuronium. All patients received postoperative fentanyl by patient-controlled epidural anesthesia. The incidence of nausea and vomiting, complete response rate (i.e., no vomiting and no rescue antiemetic use), rescue antiemetic use, nausea score (0-3), and visual analog scale score (VAS 0-10) for pain were recorded at 2, 24, 48, and 72 h after surgery.. No (0 %) patient in the NKI group experienced vomiting after surgery; however, 4-6 (20-30 %) of 20 patients in the ONS group experienced vomiting. This difference was significant at 0-24, 0-48, and 0-72 h. During the study period, no significant differences existed between the NK1 and ONS groups in the incidence of PONV, complete response rate, rescue antiemetic use, nausea score, and VAS score for pain.. Compared to ondansetron, fosaprepitant more effectively decreased the incidence of vomiting in patients who underwent gynecologic abdominal surgery with patient-controlled epidural analgesia.

Topics: Adult; Analgesia, Epidural; Analgesia, Patient-Controlled; Analgesics, Opioid; Androstanols; Antiemetics; Double-Blind Method; Female; Fentanyl; Gynecologic Surgical Procedures; Humans; Middle Aged; Morpholines; Ondansetron; Pain; Piperidines; Postoperative Nausea and Vomiting; Postoperative Period; Prospective Studies; Remifentanil; Rocuronium

To explore the impacts on EC50 in the remifentanil inhibition of tracheal intubation response by the transcutaneous electrical acupoint stimulation (TEAS) at Hegu (LI 4) and Neiguan (PC 6).. Forty patients with selective surgery undergoing endotracheal intubation with intravenous general anesthesia were divided into I to II degree by the American Society of Anesthesiologists (ASA) and were randomized into an observation group and a control group, 20 cases in each one. Before general anesthesia induction, in the observation group, the transcutaneous electric stimulation was applied to bilateral Hegu (LI 4) and Neiguan (PC 6) for 30 min, with dense-disperse wave, 2 Hz/100 Hz in frequency; in the control group, the sham-stimulation was applied to the acupoints, with the lamp on, but without electric current output. Afterwards, the general anesthesia induction started. When the target concentration of propofol and remifentanil was stabilized at the preset value, the endotracheal intubation was conducted. Dixon sequential method was applied for the determination of ECs in remifentanil inhibition of tracheal intubation response.. The level of EC50 in remifentanil inhibition of tracheal intubation response was 3. 46 ng/mL, 95% confidence interval was 2. 80 ng/ml to 4. 27ng/mL in the observation group; those were 4. 18 ng/mL and 3. 30 ng/mL to 5. 29 ng/mL in the control group separately. The differences were significant in comparison of the two groups (P<0. 01).. TEAS apparently reduces EChe in the remifentanil inhibition of tracheal intubation response by around 17%as.

Topics: Acupuncture Points; Adult; Aged; Anesthetics, Intravenous; Female; Humans; Intubation, Intratracheal; Male; Middle Aged; Pain; Pain Management; Piperidines; Remifentanil; Transcutaneous Electric Nerve Stimulation

Using single anesthetic agent in endoscopic retrograde cholangiopancreatography (ERCP) may lead to inadequate analgesia and sedation. To achieve the adequate analgesia and sedation the single anesthetic agent doses must be increased which causes undesirable side effects. For avoiding high doses of single anesthetic agent nowadays combination with sedative agents is mostly a choice for analgesia and sedation for ERCP.. The aim of this study is to investigate the effects of propofol alone, propofol + remifentanil, and propofol + fentanyl combinations on the total dose of propofol to be administered during ERCP and on the pain scores after the process.. This randomized study was performed with 90 patients (ASA I-II-III) ranging between 18 and 70 years of age who underwent sedation/analgesia for elective ERCP. The patients were administered only propofol (1.5 mg/kg) in Group Ι, remifentanil (0.05 μg/kg) + propofol (1.5 mg/kg) combination in Group II, and fentanyl (1 μg/kg) + propofol (1.5 mg/kg) combination in Group III. All the patients' sedation levels were assessed with the Ramsey Sedation Scale (RSS). Their recovery was assessed with the Aldrete and Numerical Rating Scale Score (NRS) at 10 min intervals.. The total doses of propofol administered to the patients in the three groups in this study were as follows: 375 mg in Group I, 150 mg in Group II, and 245 mg in Group III.. It was observed that, in the patients undergoing ERCP, administration of propofol in combination with an opioid provided effective and reliable sedation, reduced the total dose of propofol, increased the practitioner satisfaction, decreased the pain level, and provided hemodynamic stability compared to the administration of propofol alone.

Topics: Anesthetics, Intravenous; Cholangiopancreatography, Endoscopic Retrograde; Conscious Sedation; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Fentanyl; Humans; Male; Middle Aged; Pain; Pain Measurement; Piperidines; Propofol; Remifentanil

To investigate the influence of the midazolam sedation based on remifentanil analgesia on the occurrence of delirium in critically ill patients in intensive care unit (ICU).. A single-center prospective randomized controlled trial was conducted. 140 consecutive critically ill patients admitted to ICU of Peking University People's Hospital, undergoing mechanical ventilation longer than 24 hours, with the need of sedation, from February 2014 to January 2015 were enrolled. They were randomly divided into two groups by computer generated random numbers table, each n = 70. The patients in observation group received midazolam 1 μg x kg(-1) x min(-1) for sedation, and 1 mg/mL remifentanil for analgesia with 0.05 mg/kg intravenous bolus, then continuous infusion of 0.02-0.10 mg x kg(-1) x h(-1). The patients in control group received midazolam for sedation only. The data were recorded as follows: the main indices for observation included the occurrence of delirium and its duration; the second item for observation was consumption of drug for sedation, followed by the mean arterial pressure (MAP) before and after sedation, the time of wake-up, duration of mechanical ventilation, the length of ICU stay, and 28-day fatality rate. The 28-day survival was analyzed by Kaplan-Meier survival curve.. The dosage of remifentanil used in observation group was (98.6 ± 24.9) mg/d, the dosage of midazolam was significantly lower than that of the control group (mg/d: 160.6 ± 33.3 vs. 178.9 ± 43.4, t = 2.829, P = 0.005), the incidence of delirium was obviously lower than that of the control group [22.9% (16/70) vs. 57.1% (40/70), χ2 = 15.700, P < 0.001], and the time of delirium was slightly shorter than that of the control group (hours: 162.9 ± 78.0 vs. 194.8 ± 117.3, t = 0.947, P = 0.348). Among the patients with delirium, the dosage of dexmedetomidine used in observation group was significantly less than that of the control group (mg/d: 0.54 ± 0.11 vs. 0.64 ± 0.14, t = 2.112, P = 0.041). The MAP before sedation was similar as the MAP after sedation in both groups, and there was no significant difference between observation group and control group [mmHg (1 mmHg = 0.133 kPa), before treatment: 84.7 ± 16.2 vs. 89.5 ± 37.7, after treatment: 82.3 ± 10.7 vs. 80.8 ± 13.9, both P > 0.05]. There was no significant difference in the time of waking-up between observation group and control group (hours: 2.3 ± 0.9 vs. 2.4 ± 0.8, t = 0.487, P = 0.627). The duration of mechanical ventilation (hours: 143.4? 138.3 vs. 163.9? 158.9, t = 0.812, P = 0.418), the length of ICU stay (days: 8.8 ± 7.7 vs. 10.0 ± 7.8, t = 0.917, P = 0.361) and 28-day fatality rate [11.4% (8/70) vs. 20.0% (14/70), χ2 = 1.941, P = 0.245] in observation group were slightly lower than those of the control group without significant difference. Kaplan-Meier survival curve showed that the cumulative 28-day survival rate in observation group was slightly higher than that of control group (χ2 = 1.647, P = 0.199) CONCLUSION: Analgesia based on sedation may reduce the occurrence of delirium and its severity, furthermore, even if delirium occurs, it may be less severe.

Topics: Analgesia; Arterial Pressure; Critical Illness; Delirium; Dexmedetomidine; Humans; Hypnotics and Sedatives; Intensive Care Units; Kaplan-Meier Estimate; Midazolam; Pain; Piperidines; Prospective Studies; Remifentanil; Respiration, Artificial

Breech presentation occurs in up to 3% of pregnancies at term and may be an indication for caesarean delivery. External cephalic version can be effective in repositioning the fetus in a cephalic presentation, but may be painful for the mother. Our aim was to assess the efficacy of remifentanil versus placebo for pain relief during external cephalic version.. A randomized, double-blind, controlled trial that included women at 36-41 weeks of gestation with non-cephalic presentations was performed. Women were randomized to receive either a remifentanil infusion at 0.1 μg/kg/min and demand boluses of 0.1 μg/kg, or saline placebo. The primary outcome was the numerical rating pain score (0-10) after external cephalic version.. Sixty women were recruited, 29 in the control group and 31 in the remifentanil group. There were significant differences in pain scores at the end of the procedure (control 6.5 ± 2.4 vs. remifentanil 4.7 ± 2.5, P = 0.005) but not 10 min later (P = 0.054). The overall success rate for external cephalic version was 49% with no significant differences between groups (remifentanil group 54.8% vs. control group 41.3%, P = 0.358). In the remifentanil group, there was one case of nausea and vomiting, one of drowsiness and three cases of fetal bradycardia. In the control group, there were three cases of nausea and vomiting, one of dizziness and nine cases of fetal bradycardia.. Intravenous remifentanil with bolus doses on demand during external cephalic version achieved a reduction in pain and increased maternal satisfaction. There were no additional adverse effects, and no difference in the success rate of external cephalic version or the incidence of fetal bradycardia.

Topics: Adult; Analgesia; Analgesics, Opioid; Bradycardia; Breech Presentation; Dizziness; Double-Blind Method; Female; Fetal Diseases; Humans; Nausea; Pain; Pain Management; Patient Satisfaction; Piperidines; Placebos; Pregnancy; Remifentanil; Treatment Outcome; Version, Fetal; Vomiting

To compare remifentanil and morphine-midazolam for use in nonurgent endotracheal intubation in neonates.. In this prospective noninferiority randomized trial, newborns of gestational age ≥28 weeks admitted in the neonatal intensive care unit requiring an elective or semielective endotracheal intubation were divided into 2 groups. One group (n = 36) received remifentanil (1 μg/kg), and the other group (n = 35) received morphine (100 μg/kg) and midazolam (50 μg/kg) at a predefined time before intubation (different in each group), to optimize the peak effect of each drug. Both groups also received atropine (20 μg/kg). The primary outcome was to compare the conditions of intubation, and the secondary outcome was to compare the duration of successful intubation, physiological variables, and pain scores between groups for first and second intubation attempts. Adverse events and neurologic test data were reported.. Intubation with remifentanil was not inferior to that with morphine-midazolam. At the first attempted intubation, intubation conditions were poor in 25% of the remifentanil group and in 28.6% of the morphine-midazolam group (P = .471). For the second attempt, conditions were poor in 28.6% of the remifentanil group, compared with 10% of the morphine-midazolam group (P = .360). The median time to successful intubation was 33 seconds (IQR, 24-45 seconds) for the remifentanil group versus 36 seconds (IQR, 25-59 seconds) for the morphine-medazolam group (P = .359) at the first attempt and 45 seconds (IQR, 35-64 seconds) versus 56 seconds (IQR, 44-68 seconds), respectively, for the second attempt (P = .302). No significant between-group difference was reported for hypotension, bradycardia, or adverse events.. In our cohort, remifentanil was at least as effective as the morphine-midazolam regimen for endotracheal intubation. Thus, premedication using this very-short-acting opioid can be considered in urgent intubations and is advantageous in rapid extubation.

Topics: Analgesics, Opioid; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Hypnotics and Sedatives; Infant, Newborn; Infant, Premature; Intensive Care, Neonatal; Intention to Treat Analysis; Intubation, Intratracheal; Male; Midazolam; Pain; Pain Measurement; Piperidines; Premedication; Prospective Studies; Remifentanil; Time Factors; Treatment Outcome

Remifentanil is an ultrashort-acting synthetic opioid, and the metabolism of which is not influenced by hepatic or renal function. This study aims to compare the efficacy of two remifentanil doses during procedures in ventilated preterm infants.. Prospective, randomized, double-blind, noninferiority trial.. Neonatal ICU.. Preterm infants who were supported by a mechanical ventilator with tracheal tube and requiring central venous access.. Two remifentanil dosages were administered in mechanically ventilated preterm infants during peripherally inserted central catheter insertion. Fourteen preterm infants were randomly assigned to low-dose (0.1 μg/kg/min) or high-dose (0.25 μg/kg/min) remifentanil infusion. The Premature Infant Pain Profile was used to score pain during the procedure, and changes in the Premature Infant Pain Profile score between needle puncture and baseline were analyzed to investigate the noninferiority of low-dose to high-dose remifentanil. Occurrence of cardiorespiratory complications was also recorded.. The median gestational age (minimum, maximum) was 26 weeks (24, 31), and the median birth weight was 825 g (610, 1,280). Changes in Premature Infant Pain Profile in the high-dose and low-dose groups were 1.43 ± 3.10 and -0.60 ± 5.32, respectively. The difference in changes in the Premature Infant Pain Profile score between the high-dose and low-dose groups was -2.03 ± 4.13. The corresponding lower limit of one-tailed 97.5% CI was -7.24, below the noninferiority margin. Apneic events and bradycardia did not occur in the low-dose group; however, there were three episodes of apnea (42.9%) and one of bradycardia (14.3%) in the high-dose group (p = 0.683 and 0.366, respectively).. For mechanically ventilated preterm infants, the use of remifentanil at 0.25 μg/kg/min as an analgesic for short procedures represents a therapeutic option. Our pilot study suggests the need for larger randomized trials.

Topics: Analgesics, Opioid; Apnea; Birth Weight; Bradycardia; Catheterization, Central Venous; Double-Blind Method; Female; Gestational Age; Humans; Infant, Newborn; Infant, Premature; Male; Pain; Pain Measurement; Piperidines; Prospective Studies; Remifentanil; Respiration, Artificial

Pain caused by intravenous injection of the muscle relaxant rocuronium bromide is common in children and adolescents. The cause of this unwanted effect is still unclear, and different pretreatment drugs have been administered in attempts to alleviate this side effect, with varying degrees of success.. This study used a 60-s venous occlusion technique to evaluate the effectiveness of pretreatment with lidocaine, fentanyl, or remifentanil in preventing pain-induced withdrawal caused by intravenous injection of rocuronium bromide during the induction of general anesthesia.. One hundred and one child and adolescent patients, ASA Ι-II, requiring various surgical procedures under general anesthesia with muscle relaxation and mechanical ventilation, were enrolled. Patients were allocated randomly using computer-generated randomization into one of four pretreatment groups: a remifentanil group (1 µg/kg, n = 25), fentanyl group (1 µg/kg, n = 26), lidocaine 1% group (0.5 mg/kg, n = 25), and normal saline group (n = 25). Drug doses were prepared in normal saline to a total volume of 5 ml. Venous occlusion was applied 10 cm above the venous access site. Pretreatment drugs were injected and retained for 60 s at the site of injection by an anesthetist blinded to group allocation. After release of the tourniquet, rocuronium (0.5 mg/kg) was then injected over 5 s, and withdrawal was recorded by another anesthetist blinded to group allocation. Descriptive statistics, analysis of variance, and a chi-squared test were used to statistically analyze the results as appropriate.. Compared to normal saline, all other pretreatment groups scored a significantly lower mean of withdrawal response (P < 0.001). Lidocaine was superior to both remifentanil (P < 0.05) and fentanyl (P < 0.05) in suppressing the withdrawal response to rocuronium injection. Remifentanil was superior to fentanyl in suppressing the withdrawal response caused by rocuronium injection (P < 0.001).. Using a venous occlusion technique for 60 s, lidocaine was found to be most effective in preventing the withdrawal effect caused by rocuronium injection in children and adolescents. Lidocaine was superior to remifentanil which, in turn, was more effective than fentanyl.

Topics: Adolescent; Androstanols; Anesthesia, General; Child; Child, Preschool; Double-Blind Method; Female; Fentanyl; Humans; Injections, Intravenous; Lidocaine; Male; Neuromuscular Nondepolarizing Agents; Pain; Piperidines; Prospective Studies; Remifentanil; Rocuronium

The study was designed to investigate postoperative nausea and vomiting (PONV) in low- and high-dose remifentanil regimens for total intravenous anaesthesia (TIVA) in adult female patients with American Society of Anaesthesiologists physical status classification I undergoing local breast excision. Propofol and remifentanil 5 ng · mL(-1) (L group) or 10 ng · mL(-1) (H group) were administered for anaesthesia induction and maintenance. Propofol was titrated within range of 0.1 μg · mL(-1) to maintain bispectral index (BIS) values between 40 and 60. Haemodynamic parameters during the intra- and postoperative periods and 24 h postoperative visual analogue scale (VAS) and PONV were evaluated. Each group with 63 patients was analyzed. The H group showed higher use of remifentanil and lower use of propofol, with similar recovery time. Mean systemic arterial blood pressure (MBP), heart rate, and BIS did not differ significantly before and after endotracheal intubation in the H group. However, significant increases in MBP and BIS were apparent in the L group. Postoperative VAS, PONV incidence and scale, and Rhodes index did not differ significantly between the two groups. In conclusion, TIVA with high-dose remifentanil did not aggravate PONV with similar postoperative pain, compared with low-dose remifentanil. Furthermore, high-dose remifentanil showed more haemodynamic stability after endotracheal intubation. This trial is registered with KCT0000185.

Topics: Adult; Anesthesia, Intravenous; Anesthetics, Intravenous; Breast Neoplasms; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Pain; Piperidines; Postoperative Nausea and Vomiting; Propofol; Remifentanil

This double-blind, placebo-controlled, 3-period cross-over, 4-treatment option, incomplete block study (ClinicalTrials.gov number NCT01485185), with an adaptive design for sample size re-estimation, was designed to evaluate gabapentin plus donepezil in an established experimental model of electrical hyperalgesia. Thirty healthy male subjects aged 18-55 years were randomized to receive gabapentin 900 mg or gabapentin 900 mg+donepezil 5mg for 2 of the 3 treatment periods, with 50% of subjects randomized to receive placebo (negative control) and 50% to gabapentin 1800 mg (positive control) for the remaining period. Each treatment period was 14 days. Gabapentin or corresponding placebo was administered on Day 13 and the morning of Day 14. Donepezil or corresponding placebo was administered nocturnally from Day 1-13 and the morning of Day 14. Co-primary endpoints were the area of pinprick hyperalgesia (260 mN von Frey filament) and allodynia (stroking by cotton bud) evoked by electrical hyperalgesia on Day 14. Gabapentin 1800 mg (n=14) significantly reduced the area of allodynia vs placebo (n=14; -12.83 cm(2); 95% confidence interval [CI] -23.14 to -2.53; P=0.015) with supportive results for hyperalgesia (-14.04 cm(2); 95% CI -28.49-0.41; P=0.057), validating the electrical hyperalgesia model. Gabapentin+donepezil (n=30) significantly reduced the area of hyperalgesia vs gabapentin 900 mg (n=30; -11.73 cm(2); 95% CI -21.04 to -2.42; P=0.014), with supportive results for allodynia (-6.62 cm(2); 95% CI -13.29-0.04; P=0.052). The adverse event profile for gabapentin+donepezil was similar to the same dose of gabapentin. Data are supportive of further clinical investigation of a gabapentin-and-donepezil combination in patients with an inadequate response to gabapentin.

Topics: Adolescent; Adult; Amines; Analgesics, Non-Narcotic; Cross-Over Studies; Cyclohexanecarboxylic Acids; Donepezil; Double-Blind Method; Drug Therapy, Combination; Electric Stimulation; Female; Follow-Up Studies; Gabapentin; gamma-Aminobutyric Acid; Healthy Volunteers; Humans; Indans; Male; Middle Aged; Nootropic Agents; Pain; Pain Measurement; Piperidines; Skin; Sural Nerve; Young Adult

To evaluate the pain on injection of propofol via different combinations of fentanyl, sufentanil or remifentanil in gastrointestinal endoscopy.. Total 439 patients were randomly allocated into 6 groups. Propofol & fentanil (PF) group received 1 μg/kg fentanyl, propofol & sufentanil (PS) group received 0.1 μg/kg sufentanil and propofol & remifentanyl (PR) group received 1 μg/kg remifentanyl prior to administration of 1-2 mg/kg of propofol. The propofol & half-fentanil (Pf) group, propofol & half-sufentanil (Ps) group and propofol & half-remifentanyl (Pr) group were given 0.5 μg/kg fentanyl, 0.05 μg/kg sufentanil and 0.5 μg/kg remifentanyl, respectively and later administrated 1-2 mg/kg propofol. All patients were monitored for the blood pressure (MAP), heart rate (HR), and oxygen saturation (SpO2). Additionally, the pain intensity was assessed using a 4-point verbal rating scale (VRS) by professional doctors.. The incidence of pain due to propofol injection in Ps group (33.8%) was significantly lower than other 5 groups. The heart rate (HR) and mean arterial pressure (MAP) were maintained within the normal limits in all six groups and there was no hypotension or bradycardia encountered during the study period.. Propofol and sufentanil group was the most suitable program for painless gastroscopy.

Topics: Adult; Aged; Analgesics, Opioid; Drug Combinations; Endoscopy, Gastrointestinal; Female; Fentanyl; Heart Rate; Humans; Hypnotics and Sedatives; Injections, Intravenous; Male; Middle Aged; Pain; Pain Measurement; Piperidines; Propofol; Remifentanil; Reproducibility of Results; Severity of Illness Index; Sufentanil; Time Factors; Treatment Outcome

Recent studies have suggested that some single nucleotide polymorphisms (SNPs) in the human µ-opioid receptor gene (OPRM1) affect the postoperative analgesic efficacy of opioids and their side effects. In this study, we assessed the association between SNPs in the OPRM1 gene and intraoperative remifentanil consumption as well as perioperative side effects during gynecological hysteroscopic surgery in women from Northern China.. We analyzed 178 women undergoing gynecological hysteroscopic surgery. SNP genotyping was performed using the SNaPshot method. The state anxiety index (SAI) and pressure pain threshold (PPT) of all patients were assessed preoperatively. Monitored anesthesia care was maintained by the intravenous infusion of remifentanil. Intraoperative remifentanil usage and perioperative side effects were recorded. Statistical analyses were performed using SPSS software.. Patients carrying one or two copies of the minor allele (G allele) of rs558025 required significantly more intraoperative remifentanil than patients without the minor allele (p = 0.001, corrected p = 0.006). There were no significant associations between the six SNPs and various clinical characteristics. No significant associations between the six SNPs and PPT or SAI were found in our study.. SNP rs558025 in the OPRM1 gene was associated with intraoperative remifentanil consumption during gynecological hysteroscopic surgery in our subjects.

Topics: Adult; Analgesics, Opioid; Anesthetics, Intravenous; Asian People; Female; Genotype; Humans; Hysteroscopy; Pain; Perioperative Period; Piperidines; Polymorphism, Single Nucleotide; Postoperative Period; Receptors, Opioid, mu; Remifentanil

Epidural analgesia (EA) has significant contraindications including coagulation disorders and parturient refusal. One alternative is intravenous self-administered analgesia using the ultra short-acting opioid remifentanil (rPCA). We compared the efficiency and safety of standard epidural analgesia with parturient-controlled intravenous analgesia using remifentanil as well as personal satisfaction.. We enrolled twelve ASA I classified women with singleton pregnancy who delivered vaginally in the period 3/2010-5/2010 and who received rPCA (n=12) in standard analgesic protocol: 20 µg boluses using PCA pump with a lockout interval of 3 min. The control group consisted of 12 pregnant women who received EA (n=12): 0.125% bupivacaine with sufentanil 0.5 µg/mL in top-up boluses every hour until delivery. Data were acquired from standard Acute Pain Service (APS) form and patient medical records (demographic, labour course parameters), Visual Analogue Scale (VAS), Bromage Scale (BS) and adverse effects of analgesia.. There were no demographic or labour course parameter differences between groups (P>0.05). The differences in VAS decrease (P=0.056) and parturient satisfaction (P=0.24) during the whole analgesia administration were statistically insignificant. The main limitation of the study was small sample and enrolment of healthy singleton pregnant women only.. Remifentanil use in obstetric analgesia is a viable alternative to EA, especially in cases of EA contraindications and parturient disapproval.

Topics: Adult; Analgesia, Epidural; Analgesia, Patient-Controlled; Analgesics, Opioid; Anesthetics, Local; Bupivacaine; Female; Humans; Obstetric Labor Complications; Pain; Pain Measurement; Parturition; Piperidines; Pregnancy; Prospective Studies; Remifentanil; Sufentanil; Young Adult

The presence of the A118G single nucleotide polymorphism in the OPRM1 gene as well as noxious stimulation might affect the requirements of remifentanil for patients undergoing ultrasonographic endoscopy under sedation-analgesia with propofol and remifentanil. Bispectral index (BIS) was used as a surrogate measure of effect.. A total of 207 patients were screened for A118G and randomly received different combinations of propofol and remifentanil, changed depending on the nausea response to endoscopy tube introduction. Nonlinear mixed effects modelling was used to establish the relation between propofol and remifentanil with respect to BIS and to investigate the influence of A118G or noxious stimulation. The value of k e0 for propofol and remifentanil was estimated to avoid the hysteresis between predicted effect site concentration (Ce) and BIS.. Data from 176 patients were analysed. Eleven were recessive homozygous for A118G (OPRM = 1). A total of 165 patients were either dominant homozygous or heterozygous and considered normal (OPRM = 0). The estimated values of k e0 for propofol and remifentanil were 0.122 and 0.148 min(-1). Propofol and remifentanil were synergistic with respect to the BIS (α = 1.85). EC50 estimate for propofol was 3.86 µg/ml and for remifentanil 19.6 ng/ml in normal patients and 326 ng/ml in OPRM = 1 patients. BIS increases around 4% for the same effect site concentrations with noxious stimulation.. Predicted effect site concentration of remifentanil ranging 1-5 ng/ml synergistically potentiates the effects of propofol on the BIS but has no effect in A118G patients. Noxious stimulation increases BIS values by 4% at the same concentrations of propofol and remifentanil.

Topics: Acoustic Stimulation; Adult; Aged; Aged, 80 and over; Analgesia; Anesthetics, Combined; Anesthetics, Intravenous; Drug Synergism; Endoscopy; Female; Humans; Male; Middle Aged; Monitoring, Intraoperative; Nonlinear Dynamics; Pain; Piperidines; Polymorphism, Single Nucleotide; Propofol; Receptors, Opioid, mu; Remifentanil; Young Adult

To evaluate the influence of 3 anesthetic protocols and multiples of minimum alveolar concentration (MAC) on heart rate variability (HRV) with and without nociceptive stimulation in dogs.. 6 healthy adult Beagles.. Each dog was anesthetized 3 times: with isoflurane alone, with isoflurane and a constant rate infusion of dexmedetomidine (IsoD; 3 μg/kg/h, IV), and with isoflurane and a constant rate infusion of remifentanil (IsoR; 18 μg/kg/h, IV). Individual MAC was determined via supramaximal electrical stimulation. Sinus rhythm-derived intervals between 2 adjacent R-R intervals were exported from ECG recordings. Selected HRV time and frequency domain variables were obtained (at 2-minute intervals) and analyzed offline with signed rank tests before and after stimulation at 0.75, 1.0, and 1. 5 MAC for each anesthetic session.. The isoflurane session had the overall lowest prestimulation SDNN (SD of all R-R intervals) values. Prestimulation SDNN values decreased significantly with increasing MAC in all sessions. For the IsoD session, SDNN (milliseconds) or high-frequency power (milliseconds(2)) was inversely correlated with MAC (Spearman rank correlation coefficient for both variables, -0.77). In the isoflurane and IsoR sessions, heart rate increased significantly after stimulation. In the IsoD session, poststimulation SDNN was increased significantly, compared with prestimulation values, at 0.75 and 1.0 MAC.. On the basis of SDNN and high-frequency power values, anesthetic levels between 0.75 and 1.5 MAC within the same anesthetic protocol could be differentiated, but with a large overlap among protocols. Usefulness of standard HRV variables for assessment of anesthetic depth and nociception in dogs is questionable.

Topics: Adrenergic alpha-2 Receptor Agonists; Anesthesia, Inhalation; Anesthetics, Inhalation; Anesthetics, Intravenous; Animals; Cross-Over Studies; Dexmedetomidine; Dogs; Drug Therapy, Combination; Female; Heart Rate; Isoflurane; Male; Pain; Piperidines; Pulmonary Alveoli; Remifentanil

To prospectively determine the safety and effectiveness of continuous infusion of low-dose remifentanil for the reduction of pain in patients for epidural catheterization.. This study was approved by the institutional review board. Written informed consent was obtained. Fifty two patients (27 men, 25 women, age range 16-96 years, mean age 68 years) were given continuous infusion of various rates of application (none, 0.02, 0.05, and 0.07 microg x kg -1 x hr-1) of remifentanil. Blood pressure, heart rate, pulse oximetry oxygen saturation and respiratory rate were recorded during the procedure of epidural catheterization. Pain score was measured with the visual analogue scale (VAS), and complications including muscle stiffness, nausea and vomiting, and depressed level of consciousness were monitored.. Every rate of application, pulse oximetry oxygen saturation and systemic blood pressure were decreased but the reduction was not marked. The muscle stiffness, nausea and vomiting, and depressed level of consciousness were not observed in all the cases. No other serious complications were observed.. Continuous infusion of low-dose remifentanil is a safe and effective method for palliation of pain in epidural catheterization.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Analgesics, Opioid; Anesthesia, Epidural; Catheterization; Epidural Space; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Pain; Perioperative Care; Piperidines; Prospective Studies; Remifentanil; Young Adult

Surrogates may provide easy and quick access to information about pharmacological parameters of interest that can be directly measured only with difficulty. Surrogates have been proposed for opioid blood concentrations to replace invasive sampling, serving as a basis for target-controlled infusion systems to optimize analgesia. We aimed at identifying surrogates of remifentanil steady-state blood concentrations with relevance for its clinical, in particular, analgesic, effects. A "single ascending dose" study design assessed concentration-dependent effects of remifentanil in a double-blind randomized fashion in 16 healthy volunteers. Remifentanil was administered by means of computerized infusion aimed at steady-state effect-site concentrations of 0, 1.2, 1.8, 2.4, 3, 3.6, 4.8, and 6 ng/ml (one concentration per subject, two subjects per concentration). Arterial remifentanil blood concentrations were measured during apparent steady state. Pharmacodynamic parameters were measured at baseline and during steady-state conditions. Potential surrogate parameters included the pupil diameter, the amplitude of pupil light reflex, and the performance in a visual tracking task. Clinical parameters were analgesia to experimental pain, nausea, tiredness, and visual acuity. Remifentanil blood concentrations were well predicted by its effects on the pupil light reflex amplitude, better than by its miotic effects. However, the best prediction for both remifentanil blood concentrations and analgesic effects was obtained using a combination of three surrogate parameters (pupil diameter, light reflex amplitude, and tracking performance). This combination of pharmacodynamic parameters provided even better predictions of analgesia than could be obtained using the measured opioid blood concentrations. Developing surrogates only for opioid blood concentrations is insufficient when opioid effects are the final goal. Combining pharmacodynamic surrogate parameters seems to provide a promising approach to obtain acceptable predictions of relevant clinical effects, with better results than obtained with measuring or estimating blood concentrations.

Topics: Adult; Analgesia; Analgesics, Opioid; Dose-Response Relationship, Drug; Double-Blind Method; Fatigue; Female; Humans; Male; Nausea; Pain; Photic Stimulation; Piperidines; Pupil; Reflex; Remifentanil; Sleep Stages; Visual Acuity; Young Adult

To prospectively assess the effect of remifentanil for analgesia and sedation, the impact on sustenance duration of mechanical ventilation and hemodynamics, and also its adverse reaction in the mechanically ventilated patients in the intensive care unit (ICU).. Sixty patients with invasive mechanical ventilation forever 24 hours after tumor operation were randomly allocated to fentanyl group (n = 30) or remifentanil group n = 30) to receive a persistent infusion of either fentanyl or remifentanil for sedation and analgesia. The level of analgesia was assessed according to facial pain scale (FPS), while the level of sedation was assessed according to the Ramsay score (RS). A propofol infusion was started if additional sedation was necessary. During the therapy, the daily awakening procedure was performed, and the scores of FPS and RS and the vital signs were recorded respectively before and after medication. The number of patients receiving additional propofol infusion, and number of daily interruption of medication and that of daily arousal, the duration of mechanical ventilation, ICU length of stay, and ICU cost were recorded. Furthermore, the incidence of adverse reactions was documented.. The ideal targets of analgesia and sedation were reached in both groups. There were nearly no significant differences between the groups with respect to the effect of sedation and analgesia. However, the FPS scores in fentanyl group at the 30 minutes of the medication were. obviously higher than those of remifentanil group (3. 70 ± 1.20 vs. 2.70 ± 1.17, P<0.05). The mean arterial pressure (MAP,mm Hg, I mm Hg = 0.133 kPa) of remifentanil group at 30 minutes was significantly lower than that of fentanyl group (72.9 ± 6.9 vs. 77.6 ± 9.1, P<0.05). There was no difference between two groups with respect to the other vital signs. More patients in fentanyl group needed the additional propofol infusion (9 vs. 8) and interruption of medication (12 vs. 4, both P<0.05). The spontaneous breathing frequency (RRs, bpm) in patients of remifentanil group was lower obviously at 30 minutes and 1, 6, 24 hours than that of fentanyl group (7.0 ± 2.8 vs. 10.4 ± 3.5, 5.4 ± 3.4 vs. 10.6 ± 3.6, 5.4 ± 3.0 vs. 7.2 ± 3.1 , 6.1 ± 3.0 vs. 9.2 ± 3.4, all P< 0.05) . The duration of mechanical ventilation (hours) and ICU length of stay (hours) were shortened in remifentanil group comparted with fentanyl group (73.6 ± 26.7 vs. 94.9 ± 37.3, 125.9 ± 37.1 vs. 150.8 ± 50.9, both P<0.05). With respect to the cost of hospitalization (10 thousand), no significant difference was found between two groups (6.06 ± 2.29 vs. 5.83 ± 2.38, P>0.05). The number of patients showing hypotension was much more in remifentanil group than that of fentanyl group (8 vs. 2, P<0.05).. The effect of remifentanil was similar to that of the conventional therapy. Remifentanil gives rapid effect, shortens the duration of mechanical ventilation, reduces the dosage of propofol, and has no severe adverse effect.

Topics: Adult; Aged; Aged, 80 and over; Analgesics; Critical Care; Female; Humans; Hypnotics and Sedatives; Male; Middle Aged; Pain; Piperidines; Postoperative Period; Remifentanil; Respiration, Artificial

Intravenous administration of rocuronium bromide causes pain at the site of injection in most patients. The mechanism that leads to this side effect is still unknown and multiple drugs' pretreatments were used to prevent its occurrence with varying success rates.. The study aimed to evaluate the effects of the pretreatment with lidocaine, fentanyl, and remifentanil using a venous occlusion technique in preventing pain caused by intravenous injection of rocuronium during induction of general anesthesia.. Two hundred patients, ASA I-II, requiring various types of surgical procedures under general anesthesia with muscle relaxation and mechanical ventilation, were enrolled. Patients were pre-educated to report pain severity on rocuronium injection on a 4-point severity scale. Patients were allocated randomly using sealed envelopes method into one of four pretreatment groups: (Xylocaine group, 50), Remifentanyl group 50), (Fentanyl group, 50), and (Normal saline group, 50). After venous occlusion, study drugs were injected and the venous occlusion was maintained for one minute. Rocuronium was then administered and patients were asked to report their pain. Compared to control group, all pretreatment drugs were effective in reducing pain on rocuronium injection. Xylocaine was the most effective (Mean difference-1.42, P <0.001), followed by Remifentanil (Mean difference-1.32, P <0.001) and Fentanyl (Mean difference-0.50, P <0.001) in reducing pain on rocuronium injection. Remifentanil was statistically comparable to Xylocaine (P = 0.820) and both drugs were superior to Fentanyl in reducing pain on rocuronium injection.. Remifentanyl is a better choice of opioid in preventing pain on rocuronium injection using venous occlusion technique than fentanyl, with efficacy comparable to Xylocaine.

Topics: Adult; Aged; Androstanols; Double-Blind Method; Female; Fentanyl; Humans; Injections, Intravenous; Lidocaine; Male; Middle Aged; Neuromuscular Nondepolarizing Agents; Pain; Piperidines; Prospective Studies; Remifentanil; Rocuronium; Sex Characteristics

Pain is a negative emotional experience that is modulated by a variety of psychological factors through different inhibitory systems. For example, endogenous opioids and cannabinoids have been found to be involved in stress and placebo analgesia. Here we show that when the meaning of the pain experience is changed from negative to positive through verbal suggestions, the opioid and cannabinoid systems are co-activated and these, in turn, increase pain tolerance. We induced ischemic arm pain in healthy volunteers, who had to tolerate the pain as long as possible. One group was informed about the aversive nature of the task, as done in any pain study. Conversely, a second group was told that the ischemia would be beneficial to the muscles, thus emphasizing the usefulness of the pain endurance task. We found that in the second group pain tolerance was significantly higher compared to the first one, and that this effect was partially blocked by the opioid antagonist naltrexone alone and by the cannabinoid antagonist rimonabant alone. However, the combined administration of naltrexone and rimonabant antagonized the increased tolerance completely. Our results indicate that a positive approach to pain reduces the global pain experience through the co-activation of the opioid and cannabinoid systems. These findings may have a profound impact on clinical practice. For example, postoperative pain, which means healing, can be perceived as less unpleasant than cancer pain, which means death. Therefore, the behavioral and/or pharmacological manipulation of the meaning of pain can represent an effective approach to pain management.

Topics: Adult; Arm; Attitude to Health; Cannabinoid Receptor Antagonists; Culture; Double-Blind Method; Female; Humans; Ischemia; Male; Naltrexone; Narcotic Antagonists; Opioid Peptides; Pain; Persuasive Communication; Physical Endurance; Piperidines; Pyrazoles; Receptors, Cannabinoid; Reward; Rimonabant; Suggestion; Time Factors; Young Adult

The use of epidural ropivacaine may result in significant haemodynamic fluctuations during combined epidural and general anaesthesia. We designed this study to investigate whether epidural anaesthesia with a goal-directed approach, when combined with general anaesthesia, improved haemodynamic stability in elderly patients undergoing major abdominal surgery. Seventy-five elderly patients undergoing major abdominal surgery were randomly and evenly assigned to one of three groups receiving intraoperative epidural anaesthesia with either ropivacaine 0.1% (Group 1), ropivacaine 0.375% (Group 2) or ropivacaine 0.375% for abdominal wall pain and ropivacaine 0.1% for visceral pain (Group 3). General anaesthesia was induced using a target-controlled infusion of combined propofol and remifentanil. The remifentanil target concentration was adjusted according to the mean arterial pressure and heart rate, and vasoactive agents were administered to maintain stable haemodynamics. The need for vasoactive drug administrations was 1.4 (standard deviation 0.9) in Group 3 (n=24), representing a significantly lower frequency of administration compared with Groups 1 (n=24) and 2 (n=24) (P <0.05 versus Group 1; P <0.01 versus Group 2). The total intraoperative dose of remifentanil was significantly greater in Group 1 (P <0.01 versus Group 2; P <0.05 versus Group 3) but did not differ significantly between Groups 2 and 3. Goal-directed epidural anaesthesia with different ropivacaine concentrations can improve haemodynamic stability when combined with general anaesthesia for elderly patients undergoing major abdominal surgery.

Topics: Abdomen; Age Factors; Aged; Amides; Anesthesia, Epidural; Anesthesia, General; Anesthetics, Local; Blood Pressure; Dose-Response Relationship, Drug; Double-Blind Method; Female; Follow-Up Studies; Heart Rate; Humans; Male; Pain; Piperidines; Propofol; Remifentanil; Ropivacaine; Visceral Pain

Obstructive sleep apnea (OSA) is characterized by recurrent nocturnal hypoxia and sleep disruption. Sleep fragmentation caused hyperalgesia in volunteers, while nocturnal hypoxemia enhanced morphine analgesic potency in children with OSA. This evidence directly relates to surgical OSA patients who are at risk for airway compromise due to postoperative use of opioids. Using accepted experimental pain models, we characterized pain processing and opioid analgesia in male volunteers recruited based on their risk for OSA.. After approval from the Intitutional Review Board and informed consent, we assessed heat and cold pain thresholds and tolerances in volunteers after overnight polysomnography (PSG). Three pro-inflammatory and 3 hypoxia markers were determined in the serum. Pain tests were performed at baseline, placebo, and two effect site concentrations of remifentanil (1 and 2 µg/ml), an μ-opioid agonist. Linear mixed effects regression models were employed to evaluate the association of 3 PSG descriptors [wake after sleep onset, number of sleep stage shifts, and lowest oxyhemoglobin saturation (SaO(2)) during sleep] and all serum markers with pain thresholds and tolerances at baseline, as well as their changes under remifentanil.. Forty-three volunteers (12 normal and 31 with a PSG-based diagnosis of OSA) were included in the analysis. The lower nadir SaO(2) and higher insulin growth factor binding protein-1 (IGFBP-1) were associated with higher analgesic sensitivity to remifentanil (SaO(2), P = 0.0440; IGFBP-1, P = 0.0013). Other pro-inflammatory mediators like interleukin-1β and tumor necrosis factor-α (TNF-α) were associated with an enhanced sensitivity to the opioid analgesic effect (IL-1β, P = 0.0218; TNF-α, P = 0.0276).. Nocturnal hypoxemia in subjects at high risk for OSA was associated with an increased potency of opioid analgesia. A serum hypoxia marker (IGFBP-1) was associated with hypoalgesia and increased potency to opioid analgesia; other pro-inflammatory mediators also predicted an enhanced opioid potency.. Clinicaltrials.gov NCT00672737.

Topics: Adult; Analgesics, Opioid; Biomarkers; Humans; Hypoxia; Inflammation Mediators; Male; Middle Aged; Pain; Pain Threshold; Piperidines; Remifentanil; Sleep; Sleep Apnea, Obstructive; Young Adult

Quantitative pain assessment in human beings is useful for developing new analgesics. This study assessed the analgesic effect of remifentanil in 20 healthy Korean men using three pain models to investigate whether these models can be used in Asians. The study was a double-blind, placebo-controlled, two-way cross-over study. The subjects received intravenous remifentanil with doses starting at 0.01 μg/kg/min. and increasing by 0.01 μg/kg/min. up to 0.10 μg/kg/min. in one session; they received placebo in another session. Heat pain thresholds were assessed at dose levels of 0.02, 0.05, 0.08 and 0.10 μg/kg/min. Pressure pain threshold and tolerance and mechanical pain threshold were assessed at 0.08 μg/kg/min. Remifentanil dose-dependently increased the heat pain threshold. The differences (95% confidence interval) between remifentanil and placebo were 1.54°C (0.78, 2.31), 1.82°C (1.11, 2.54) and 2.47°C (1.55, 3.38) at 0.05, 0.08 and 0.10 μg/kg/min. remifentanil, respectively. Remifentanil conferred a significantly higher pressure pain threshold and tolerance than placebo (p = 0.0001). There was a trend of increasing mechanical pain threshold with remifentanil, although it was not statistically significant. The results suggest that heat pain and pressure pain models are valid in East Asians for assessing analgesic effects.

Topics: Adult; Analgesics, Opioid; Analysis of Variance; Asian People; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Hot Temperature; Humans; Infusions, Intravenous; Least-Squares Analysis; Male; Pain; Pain Measurement; Pain Threshold; Piperidines; Pressure; Remifentanil; Republic of Korea; Treatment Outcome; Young Adult

Irritable bowel syndrome is characterised by chronic abdominal pain and frequent comorbid anxiety. The substance P ⁄ neurokinin-1 receptor system is implicated in the regulation of both pain and anxiety, suggesting a potential therapeutic target in IBS.. To determine whether inhibition of the neurokinin-1 receptor (NK1R) will change pain ratings and brain responses to experimental visceral pain and anxiety symptoms in women with IBS or not.. Rome II positive IBS women were recruited for a double-blind, placebo-controlled, cross-over study of NK1R antagonist AV608. Treatment periods were 3 weeks with a 2-week washout period. Functional MRI during a visceral distension paradigm was performed before first treatment and after treatment blocks. SPM8 was used to compare brain activity during painful and nonpainful visceral stimuli in regions associated with emotional arousal and interoception. Negative affect, anxiety symptoms and pain ratings were assessed.. Eleven subjects completed the study and eight subjects provided fMRI data. AV608, compared with placebo, was associated with reduced anxiety, negative affect, and pain ratings. During AV608 treatment, the amygdala, hippocampus and anterior cingulate gyrus showed decreased activity during visceral distension. AV608 was also associated with decreases in activity in brain regions associated with interoception (posterior insula, anterior mid-cingulate gyrus).. Chronic treatment with AV608 in IBS is associated with improved mood and pain ratings and activity of emotional arousal related brain regions. This suggests that further exploration of NK1R antagonists is warranted in visceral pain disorders, particularly in patients with comorbid anxiety symptoms.

Topics: Abdominal Pain; Adolescent; Adult; Aged; Anxiety; Arousal; Cross-Over Studies; Dilatation, Pathologic; Double-Blind Method; Emotions; Female; Humans; Irritable Bowel Syndrome; Middle Aged; Neurokinin-1 Receptor Antagonists; Pain; Pain Measurement; Pain Threshold; Pilot Projects; Piperidines; Receptors, Neurokinin-1; Stress, Psychological; Visceral Pain; Young Adult

To compare patient-controlled analgesia (PCA) with tramadol with PCA with remifentanil in second trimester abortion.. Prospective, randomized double-blinded study. University-affiliated medical center.. 30 ASA physical status 1 and 2 patients undergoing a second trimester abortion.. Patients received PCA with either tramadol or remifentanil. Analgesia was initiated in the tramadol group by an initial loading dose of tramadol 1.0 mg/kg with 10 mg of metoclopramide followed by a PCA bolus of 0.3 mg/kg/mL of tramadol every 5 minutes. For remifentanil, which does not require a loading dose, a placebo of 100 mL of 0.9% normal saline was given followed by PCA of 0.4 μg/kg/mL every two minutes.. Women were evaluated for pain via verbal analog score (VAS; 0-100), sedation, nausea, blood pressure, pulse, and respiratory rate. On the day of discharge, women were analyzed for overall satisfaction. Primary outcome was pain scores and general satisfaction.. Analysis by time yielded no statistically significant difference in VAS scores between the groups at any point except 16-20 hours after induction of labor, when pain was lower in the tramadol group (11.3 ± 18.1 vs. 36.7 ± 27.4; P = 0.04). The average VAS score was low in both groups, with no significant differences noted between groups (P = 0.74). Satisfaction scores were high in both groups, with no significant differences noted between them (P = 0.89).. Both drugs are acceptable choices for pain control in patients undergoing second trimester abortions.

Topics: Abortion, Induced; Academic Medical Centers; Adult; Analgesia, Patient-Controlled; Analgesics, Opioid; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Metoclopramide; Pain; Pain Measurement; Patient Satisfaction; Piperidines; Pregnancy; Pregnancy Trimester, Second; Prospective Studies; Remifentanil; Tramadol; Young Adult

Pain relief during labour is a topic of major interest in the Netherlands. Epidural analgesia is considered to be the most effective method of pain relief and recommended as first choice. However its uptake by pregnant women is limited compared to other western countries, partly as a result of non-availability due to logistic problems. Remifentanil, a synthetic opioid, is very suitable for patient controlled analgesia. Recent studies show that epidural analgesia is superior to remifentanil patient controlled analgesia in terms of pain intensity score; however there was no difference in satisfaction with pain relief between both treatments.. The proposed study is a multicentre randomized controlled study that assesses the cost-effectiveness of remifentanil patient controlled analgesia compared to epidural analgesia. We hypothesize that remifentanil patient controlled analgesia is as effective in improving pain appreciation scores as epidural analgesia, with lower costs and easier achievement of 24 hours availability of pain relief for women in labour and efficient pain relief for those with a contraindication for epidural analgesia.Eligible women will be informed about the study and randomized before active labour has started. Women will be randomly allocated to a strategy based on epidural analgesia or on remifentanil patient controlled analgesia when they request pain relief during labour. Primary outcome is the pain appreciation score, i.e. satisfaction with pain relief.Secondary outcome parameters are costs, patient satisfaction, pain scores (pain-intensity), mode of delivery and maternal and neonatal side effects.The economic analysis will be performed from a short-term healthcare perspective. For both strategies the cost of perinatal care for mother and child, starting at the onset of labour and ending ten days after delivery, will be registered and compared.. This study, considering cost effectiveness of remifentanil as first choice analgesia versus epidural analgesia, could strongly improve the care for 180.000 women, giving birth in the Netherlands yearly by giving them access to pain relief during labour, 24 hours a day.. Dutch Trial Register NTR2551, http://www.trialregister.nl.

Topics: Adolescent; Adult; Analgesia, Epidural; Analgesia, Obstetrical; Analgesia, Patient-Controlled; Analgesics, Opioid; Cost-Benefit Analysis; Female; Humans; Infant, Newborn; Labor, Obstetric; Pain; Pain Measurement; Patient Satisfaction; Piperidines; Pregnancy; Remifentanil; Research Design; Young Adult

To assess if there is a difference in duration of labor, the mode of delivery, average Visual Analog Scale (VAS) pain scores, maternal overall satisfaction with analgesia, side effects and neonatal outcomes in nulliparous women who received early labor analgesia with either epidural, patient-controlled IV analgesia (PCIA) with remifentanil or combined spinal-epidural (CSE) techniques.. This is a prospective randomized interventional study.. The study included 1,140 healthy nulliparous women (with term, singleton pregnancies) early in labor, requesting labor analgesia, during the period from September 2009 to August 2011 at TAIBA Hospital in Kuwait. The participants were randomized to receive either epidural analgesia (Group I), or PCIA with remifentanil (Group II) or CSE analgesia (Group III). The primary outcome was the rate of cesarean delivery.. CSE analgesia was associated with a statistically highly significant decrease in labor duration (from analgesia to vaginal delivery), duration of latent and active phases of the first stage, and duration of the second stage of labor, average VAS pain scores, and a highest maternal overall satisfaction score with analgesia (P<0.01) as compared to epidural analgesia or PCIA with remifentanil.. In terms of labor duration, average VAS pain scores, and maternal overall satisfaction score with analgesia, CSE analgesia is superior to that provided by epidural analgesia or PCIA with remifentanil for pain relief in early labor in nulliparous women. However, there were no differences in the mode of delivery, side effects or neonatal outcomes between the three techniques.

Topics: Adult; Analgesia, Epidural; Analgesia, Obstetrical; Analgesia, Patient-Controlled; Analgesics, Opioid; Anesthesia, Spinal; Cesarean Section; Extraction, Obstetrical; Female; Humans; Labor Stage, First; Labor Stage, Second; Labor, Obstetric; Pain; Pain Measurement; Parity; Patient Satisfaction; Piperidines; Pregnancy; Remifentanil; Time Factors; Young Adult

Propofol injection pain is a frequent and a well-known complaint distressing for the patients. Although the ethiology of this pain remains obscure, the ideal method for the prevention of propofol injection pain is still controversial. Local anesthetics, opioids, nonsteroidal anti-inflammatory drugs, ketamine, metoclopramide, droperidol have been tested. We aimed to conduct a study comparing various drugs with saline, lidocaine and together at the same time.. In this randomized, double-blind, prospective trial a total of 250 patients (ASA I-II) undergoing elective surgery with general anesthesia were randomly allocated into five groups. After premedication of 3 mg midazolam im, patients received either 2 mL (0.02 mg) of remifentanil (n = 50, Group R), 2mL (40 mg) of lidocaine (n = 50, Group L), 2 mL (10 mg) of metoclopramide (n = 50, Group M), or 2mL (100 microg/kg) of ketamine (n = 50, Group K) and 2 mL of saline. Pain intensity was evaluated through the use of a verbal rating scale, 0 = none, 1 = mild pain, 2 = moderate pain, and 3 = severe pain.. Pretreatment with remifentanil 0.02 mg, % 2 lidocaine 40 mg, metoclopramide 10 mg, and ketamine 100 microg/kg yields propofol induced pain 38%, 76%, 76%, and 58% respectively. Pretreatment with lidocaine or metoclopramide equally and significantly reduced the incidence and severity of propofol induced pain (76%).. Lidocaine and metoclopramide were equally and the most effective treatments in attenuating pain during intravenous injection of propofol compared to pretreatment with remifentanil and ketamine.

Topics: Adult; Aged; Analgesics; Double-Blind Method; Female; Humans; Injections, Intravenous; Ketamine; Lidocaine; Male; Metoclopramide; Middle Aged; Pain; Piperidines; Propofol; Prospective Studies; Remifentanil

The Surgical Pleth Index (SPI) is proposed as a means to assess the balance between noxious stimulation and the anti-nociceptive effects of anaesthesia. In this study, we compared SPI, mean arterial pressure (MAP), and heart rate (HR) as a means of assessing this balance.. We studied a standard stimulus [head-holder insertion (HHI)] and varying remifentanil concentrations (CeREMI) in a group of patients undergoing neurosurgery. Patients receiving target-controlled infusions were randomly assigned to one of the three CeREMI (2, 4, or 6 ng m⁻¹), whereas propofol target was fixed at 3 µg ml⁻¹. Steady state for both targets was achieved before HHI. Intravascular volume status (IVS) was evaluated using respiratory variations in arterial pressure. Prediction probability (Pk) and ordinal regression were used to assess SPI, MAP, and HR performance at indicating CeREMI, and the influence of IVS and chronic treatment for high arterial pressure, as possible confounding factors.. The maximum SPI, MAP, or HR observed after HHI correctly indicated CeREMI in one of the two patients [accurate prediction rate (APR)=0.5]. When IVS and chronic treatment for high arterial pressure were taken into account, the APR was 0.6 for each individual variable and 0.8 when all of them predicted the same CeREMI. That increase in APR paralleled an increase in Pk from 0.63 to 0.89.. SPI, HR, and MAP are of comparable value at gauging noxious stimulation-CeREMI balance. Their interpretation is improved by taking account of IVS, treatment for chronic high arterial pressure, and concordance between their predictions.

Topics: Adult; Aged; Aged, 80 and over; Anesthesia, General; Anesthetics, Intravenous; Blood Pressure; Female; Heart Rate; Hemodynamics; Humans; Male; Middle Aged; Monitoring, Intraoperative; Neurosurgical Procedures; Pain; Pain Measurement; Piperidines; Propofol; Remifentanil; Young Adult

To compare the quality of analgesia provided by a remifentanil-based analgesia regime with that provided by a fentanyl-based regime in critically ill patients.. This was a registered, prospective, two-center, randomized, triple-blind study involving adult medical and surgical patients requiring mechanical ventilation (MV) for more than 24 h. Patients were randomized to either remifentanil infusion or a fentanyl infusion for a maximum of 30 days. Sedation was provided using propofol (and/or midazolam if required).. Primary outcome was the proportion of patients in each group maintaining a target analgesia score at all time points. Secondary outcomes included duration of MV, discharge times, and morbidity. At planned interim analysis (n = 60), 50% of remifentanil patients (n = 28) and 63% of fentanyl patients (n = 32) had maintained target analgesia scores at all time points (p = 0.44). There were no significant differences between the groups with respect to mean duration of ventilation (135 vs. 165 h, p = 0.80), duration of hospital stay, morbidity, or weaning. Interim analysis strongly suggested futility and the trial was stopped.. The use of remifentanil-based analgesia in critically ill patients was not superior regarding the achievement and maintenance of sufficient analgesia compared with fentanyl-based analgesia.

Topics: Aged; Analgesics, Opioid; Consciousness; Critical Care; Double-Blind Method; Endpoint Determination; Female; Fentanyl; Germany; Humans; Male; Middle Aged; Pain; Pain Measurement; Piperidines; Prospective Studies; Remifentanil; Respiration, Artificial

To investigate the cardiorespiratory, nociceptive and endocrine effects of the combination of propofol and remifentanil, in dogs sedated with acepromazine.. Prospective randomized, blinded, cross-over experimental trial.. Twelve healthy adult female cross-breed dogs, mean weight 18.4 ± 2.3 kg.. Dogs were sedated with intravenous (IV) acepromazine (0.05 mg kg(-1) ) followed by induction of anesthesia with IV propofol (5 mg kg(-1) ). Anesthesia was maintained with IV propofol (0.2 mg kg(-1) minute(-1) ) and remifentanil, infused as follows: R1, 0.125 μg kg(-1) minute(-1) ; R2, 0.25 μg kg(-1) minute(-1) ; and R3, 0.5 μg kg(-1) minute(-1) . The same dogs were administered each dose of remifentanil at 1-week intervals. Heart rate (HR), mean arterial pressure (MAP), respiratory rate (f(R) ), end tidal CO(2) (Pe'CO(2) ), arterial hemoglobin O(2) saturation, blood gases, and rectal temperature were measured before induction, and 5, 15, 30, 45, 60, 75, 90, and 120 minutes after beginning the infusion. Nociceptive response was investigated by electrical stimulus (50 V, 5 Hz and 10 ms). Blood samples were collected for plasma cortisol measurements. Statistical analysis was performed by anova (p<0.05).. In all treatments, HR decreased during anesthesia with increasing doses of remifentanil, and increased significantly immediately after the end of infusion. MAP remained stable during anesthesia (72-98 mmHg). Antinociception was proportional to the remifentanil infusion dose, and was considered satisfactory only with R2 and R3. Plasma cortisol concentration decreased during anesthesia in all treatments. Recovery was smooth and fast in all dogs.. Infusion of 0.25-0.5 μg kg(-1) minute(-1) remifentanil combined with 0.2 mg kg(-1) minute(-1) propofol produced little effect on arterial blood pressure and led to a good recovery. The analgesia produced was sufficient to control the nociceptive response applied by electrical stimulation, suggesting that it may be appropriate for performing surgery.

Topics: Acepromazine; Anesthesia, General; Animals; Blood Pressure; Dogs; Dopamine Antagonists; Female; Heart Rate; Hydrocortisone; Hypnotics and Sedatives; Pain; Piperidines; Preanesthetic Medication; Propofol; Remifentanil; Time Factors

Performance of middle-ear surgery under local anaesthesia has several advantages, but many patients complain of pain, anxiety and adverse events (e.g. dizziness and nausea). To minimise such problems, we compared sedation with midazolam alone versus midazolam with remifentanil.. We initially observed 19 patients undergoing middle-ear surgery under local anaesthesia, as controls. We then sedated a further 40 patients undergoing such surgery, with either midazolam or midazolam plus remifentanil.. The sedated patients had significantly lower incidences of local anaesthesia injection pain (p < 0.001), intra-operative pain (p < 0.001), intra-operative anxiety (p < 0.001) and adverse events, compared with the control group. Patients sedated with midazolam plus remifentanil reported less intra-operative anxiety (p = 0.010) and greater post-operative satisfaction with sedation (p = 0.007), compared with those sedated with midazolam only.. Patients undergoing middle-ear surgery under local anaesthesia alone frequently report pain, anxiety and adverse events. However, the majority of our patients who were sedated with midazolam satisfactorily overcame pain, anxiety and adverse events. Results were better still when midazolam was accompanied by remifentanil.

Topics: Adult; Anesthetics, Local; Anxiety; Conscious Sedation; Dizziness; Drug Therapy, Combination; Ear, Middle; Female; Humans; Hypnotics and Sedatives; Infusions, Intravenous; Injections, Intradermal; Intraoperative Complications; Male; Midazolam; Middle Aged; Otologic Surgical Procedures; Pain; Patient Satisfaction; Piperidines; Postoperative Nausea and Vomiting; Remifentanil

Gastrointestinal (GI) side effects are common with opioid medication, and constipation affects ∼40% of patients. Such symptoms considerably impair patients' quality of life. Alvimopan is an orally administered, systemically available, peripherally acting mu-opioid receptor (PAM-OR) antagonist approved in the US for short-term, in-hospital management of postoperative ileus in patients undergoing bowel resection. This double-blind, placebo-controlled trial was conducted as part of a recently discontinued clinical program, in which alvimopan was being developed for opioid-induced constipation (OIC). Patients (N = 518) receiving opioids for non-cancer pain were randomized to receive alvimopan .5 mg once daily, alvimopan .5 mg twice daily, or placebo for 12 weeks. The primary efficacy endpoint was the proportion of patients experiencing ≥ 3 spontaneous bowel movements (SBMs; bowel movements with no laxative use in the previous 24 hours) per week over the treatment period and an average increase from baseline of ≥ 1 SBM per week. A significantly greater proportion of patients in the alvimopan .5 mg twice-daily group met the primary endpoint compared with placebo (72% versus 48%, P < .001). Treatment with alvimopan twice daily improved a number of other symptoms compared with placebo and reduced the requirement for rescue laxative use. The opioid-induced bowel dysfunction Symptoms Improvement Scale (SIS) responder rate was 40.4% in the alvimopan .5 mg twice daily group, versus 18.6% with placebo (P < .001). In general, alvimopan .5 mg once daily produced qualitatively similar but numerically smaller responses than twice-daily treatment. Active treatment did not increase the requirement for opioid medication or increase average pain intensity scores. Over the 12-week treatment period, alvimopan appeared to be well tolerated.. These results demonstrate the potential for a PAM-OR antagonist to improve the symptoms of OIC without antagonizing opioid analgesia.

Topics: Analgesics, Opioid; Constipation; Double-Blind Method; Humans; Intestines; Narcotic Antagonists; Pain; Piperidines; Placebos

The balance between the pain relief provided by opioid analgesics and the side effects caused by such agents is of particular significance to patients who take opioids for the long-term relief of non-cancer pain. The spectrum of signs and symptoms affecting the gastrointestinal (GI) tract associated with opioid use is known as opioid-induced bowel dysfunction. Alvimopan is an orally administered, systemically available, peripherally acting mu-opioid receptor (PAM-OR) antagonist, approved in the US for the management of postoperative ileus in patients undergoing bowel resection (short-term, in-hospital use only). Alvimopan was under clinical development for long-term treatment of opioid-induced constipation (OIC) but this program has been discontinued. This double-blind, placebo-controlled trial, part of the former OIC development program, enrolled patients (N = 485) receiving opioids for non-cancer pain. Patients were randomized to receive alvimopan .5 mg once daily, alvimopan .5 mg twice daily, or placebo, for 12 weeks. The primary efficacy endpoint was the proportion of patients who experienced ≥ 3 spontaneous bowel movements (SBMs; bowel movements with no laxative use in the previous 24 hours) per week over the treatment period, and an average increase from baseline of ≥ 1 SBM per week. There were greater proportions of SBM responders in both alvimopan treatment groups (63% in both groups) compared with placebo (56%), although these differences were not statistically significant. Secondary efficacy analyses indicated that alvimopan was numerically superior to placebo in improving opioid-induced bowel dysfunction symptoms and patients' global assessment of opioid-induced bowel dysfunction, and reduced the requirement for rescue laxatives. Active treatment was well tolerated and alvimopan did not antagonize opioid analgesia.. Although the primary endpoint was not met in this study, the magnitude of alvimopan-induced improvements versus baseline, together with previous study results, suggest that a PAM-OR antagonist has the potential to improve OIC.

Topics: Adult; Aged; Aged, 80 and over; Analgesics, Opioid; Constipation; Double-Blind Method; Female; Humans; Intestines; Male; Middle Aged; Narcotic Antagonists; Pain; Piperidines; Placebos; Young Adult

Evidence from behavioral and self-reported data suggests that the patients' beliefs and expectations can shape both therapeutic and adverse effects of any given drug. We investigated how divergent expectancies alter the analgesic efficacy of a potent opioid in healthy volunteers by using brain imaging. The effect of a fixed concentration of the μ-opioid agonist remifentanil on constant heat pain was assessed under three experimental conditions using a within-subject design: with no expectation of analgesia, with expectancy of a positive analgesic effect, and with negative expectancy of analgesia (that is, expectation of hyperalgesia or exacerbation of pain). We used functional magnetic resonance imaging to record brain activity to corroborate the effects of expectations on the analgesic efficacy of the opioid and to elucidate the underlying neural mechanisms. Positive treatment expectancy substantially enhanced (doubled) the analgesic benefit of remifentanil. In contrast, negative treatment expectancy abolished remifentanil analgesia. These subjective effects were substantiated by significant changes in the neural activity in brain regions involved with the coding of pain intensity. The positive expectancy effects were associated with activity in the endogenous pain modulatory system, and the negative expectancy effects with activity in the hippocampus. On the basis of subjective and objective evidence, we contend that an individual's expectation of a drug's effect critically influences its therapeutic efficacy and that regulatory brain mechanisms differ as a function of expectancy. We propose that it may be necessary to integrate patients' beliefs and expectations into drug treatment regimes alongside traditional considerations in order to optimize treatment outcomes.

Topics: Adult; Analgesics, Opioid; Brain; Female; Humans; Magnetic Resonance Imaging; Male; Pain; Piperidines; Remifentanil; Young Adult

Opioids may enhance pain sensitivity resulting in opioid-induced hyperalgesia (OIH). Activation of spinal cyclooxygenase may play a role in the development of OIH. The aim of this study was to demonstrate remifentanil-induced postinfusion hyperalgesia in an electrical pain and a cold pain model, and to investigate whether COX-2 (parecoxib) or COX-1 (ketorolac) inhibition could prevent hyperalgesia after remifentanil infusion. Sixteen healthy males were enrolled in this randomized, double-blind, placebo-controlled crossover study. Each subject went through 4 sessions: control, remifentanil, parecoxib+remifentanil, and ketorolac+remifentanil. Transcutaneous electrical stimulation induced acute pain and areas of pinprick hyperalgesia. The areas of pinprick hyperalgesia were assessed before, during, and after a 30-minute infusion of either remifentanil or saline. The cold-pressor test (CPT) was performed before, at the end of, and 1 hour after the infusions. The subjects received a bolus of either saline, 40 mg parecoxib, or 30 mg ketorolac intravenously after the first CPT. The areas of pinprick hyperalgesia and CPT pain after the end of remifentanil infusion increased significantly compared to control (P < 0.001 and P = 0.005, respectively). Pretreatment with parecoxib or ketorolac reduced the postinfusion area of pinprick hyperalgesia (P < 0.001 and P = 0.001, respectively), compared to the remifentanil group. Parecoxib reduced the area significantly more than ketorolac (P = 0.009). In the CPT, pretreatment with parecoxib or ketorolac did not prevent postinfusion hyperalgesia. These results demonstrated OIH in both models, and may suggest that COX-2 inhibition is more important than COX-1 inhibition in reducing hyperalgesia. Remifentanil-induced hyperalgesia was demonstrated for both electrically induced pain and cold-pressor pain. Both parecoxib and ketorolac prevented hyperalgesia in the electrical model, parecoxib to a larger extent.

Topics: Adult; Analgesics, Opioid; Blood Pressure; Cross-Over Studies; Cyclooxygenase Inhibitors; Double-Blind Method; Drug Interactions; Humans; Hyperalgesia; Isoxazoles; Ketorolac; Male; Middle Aged; Pain; Pain Measurement; Pain Threshold; Physical Stimulation; Piperidines; Remifentanil; Time Factors; Young Adult

Post-procedural pain control after uterine artery embolization (UAE) of urethral leiomyomata remains a major problem.. This double-blind, randomized study tested the possibility to obtain a quicker onset of analgesia by using effect-compartment controlled remifentanil patient-controlled analgesia (remifentanil TCI-PCA) than by using i.v. morphine PCA. Both systems were connected to an i.v. catheter. Active drug or matching placebo administration was activated by a single push-button. Pain was assessed using a numerical rating scale (NRS) from 0 to 10.. NRS values were lower in the remifentanil group (with a possible difference from two to seven points on the scale) during the initial 4 h post-embolization. After the fourth hour, the NRS values were identical between the groups. No major respiratory or haemodynamic side-effect was observed.. Remifentanil PCA-TCI with a slow and progressive adapted algorithm without any associated premedication or co-medication is feasible in young healthy women undergoing UAE.

Topics: Adult; Analgesia, Patient-Controlled; Analgesics, Opioid; Double-Blind Method; Drug Administration Schedule; Embolization, Therapeutic; Female; Humans; Infusions, Intravenous; Leiomyomatosis; Morphine; Pain; Pain Measurement; Piperidines; Remifentanil; Uterine Neoplasms; Uterus

To determine the analgesic efficacy of three different rates of remifentanil infusion in patients undergoing insertion or removal of long-term central venous access devices during monitored anesthesia care and local anesthetic field infiltration.. Double-blinded, randomized, controlled study.. Operating theatre of an University hospital.. 44 unpremedicated, ASA physical status 1 and 2 patients, aged 18-65 years, undergoing insertion or removal of a Port-a-Cath or Hickman catheter.. Patients sedated with a propofol target-controlled infusion were randomly allocated to three groups: Group R25 (n = 14), Group R50 (n = 15), and Group R75 (n = 15), to receive remifentanil 0.025, 0.05, and 0.075 μg/kg/min, respectively. Rescue remifentanil 0.5 μg/kg was administered for pain scores > 3. The remifentanil infusion rate was maintained constant unless respiratory and/or cardiovascular unwanted events occurred, whereupon the rate was adjusted in 0.01 μg/kg/min decrements as necessary.. Pain scores (primary outcome), sedation, and movement scores (secondary outcomes) were assessed during local anesthetic infiltration of the anterior chest wall and 5 other procedural steps.. All infusion rates had equal analgesic efficacy, as shown by comparable pain scores, number of rescue boluses, and number of patients requiring rescue analgesia. Excessive sedation was associated with the highest remifentanil rate such that Group R75 patients were significantly more sedated than Groups R25 or R50 at selective procedural steps (P < 0.05). More Group R75 patients (6/15) required remifentanil rate reduction than did patients from Group R50 (1/15) or Group R25 (0/14), P < 0.01, most commonly because of respiratory depression.. For the insertion or removal of long-term central venous access devices, all three remifentanil infusion rates proved to be equally analgesic-efficient. However, the excessive sedation and tendency to respiratory and cardiovascular events associated with the highest remifentanil infusion rate renders such a rate less desirable for this purpose.

Topics: Adult; Aged; Analgesics, Opioid; Anesthetics, Intravenous; Catheterization, Central Venous; Catheters, Indwelling; Device Removal; Double-Blind Method; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Pain; Piperidines; Propofol; Prospective Studies; Remifentanil; Young Adult

Endovascular abdominal aortic aneurysm (AAA) repair was performed with local anaesthesia and intravenous analgesia. The objective of the study was to evaluate how two analgesia protocols affected stress response, measured as cortisol, 17-OH progesterone (17OHP) and prolactin (PRL) concentration during the procedure.. 44 patients undergoing elective AAA endovascular repair were included to either receive regular boluses of fentanyl midazolam or remifentanil continuous infusion, analgesia was monitored by Visual Analogue Scale (VAS) measurement; cortisol, 17OHP and PRL were sampled preoperatively, at skin incision, endovascular prosthesis release and skin suture.. 42 patients were included. Mean VAS values were lower in the remifentanil group 0.50±0.68 vs 1.48±1.20, p=0.002 at incision, 0.24±0.58 vs 1.45±1.18, p<0.001 prosthesis release, 0.51±0.90 vs 1.73±1.45, p=0.002 suture. No statistically significant difference was found among cortisol and 17OHP levels; PRL was significantly lower in the fentanyl-midazolam group (23.83±16.92 ng/ml vs 40.81±22.45 p=0.009 at prosthesis release and 28.23±15.05 vs 41.37±14.54, p=0.007 at suture).. Although statistically significant VAS difference had a limited clinical impact due to its small entity. The group that experienced less pain showed a more intense PRL response, while cortisol and 17OHP did not reach statistical significance.

Topics: 17-alpha-Hydroxyprogesterone; Aged; Aged, 80 and over; Analgesics, Opioid; Aortic Aneurysm, Abdominal; Endovascular Procedures; Fentanyl; Humans; Hydrocortisone; Hypnotics and Sedatives; Intraoperative Period; Male; Midazolam; Middle Aged; Pain; Piperidines; Prolactin; Remifentanil; Stress, Physiological

The intravenous injection of microemulsion propofol to induce anaesthesia causes more intense and frequent pain than lipid emulsion propofol. This study investigated whether different target effect-site concentrations of remifentanil could prevent pain due to microemulsion propofol injection. In total, 96 patients were randomly assigned to one of three groups receiving target effect-site concentrations of remifentanil 0 (control group), 4 or 6 ng/ml, followed by injection with microemulsion propofol. Remifentanil pretreatment significantly reduced the incidence and severity of injection pain compared with the control group. Although no difference in pain reduction between the two remifentanil-treated groups was observed, those receiving a target effect-site concentration of 6 ng/ml exhibited an increased rate of complications, compared with those receiving 4 ng/ml. In conclusion, prior administration of remifentanil at a target effect-site concentration of 4 ng/ml is a useful strategy to decrease the injection pain of microemulsion propofol.

Topics: Adult; Anesthetics, Intravenous; Demography; Emulsions; Female; Humans; Infusions, Intravenous; Injections, Intravenous; Male; Middle Aged; Pain; Piperidines; Postoperative Complications; Propofol; Remifentanil

Mu-opioidergic agonists are believed to induce euphoria, whereas kappa-agonists are thought to lead to dysphoria. Our study investigated mood effects of remifentanil, a mu-receptor opioid agonist, in healthy male volunteers. Moreover, we examined interactions between mood and pain. Three conditions were investigated in 21 volunteers: saline, 0.05 and 0.15 microg kg(-1) min(- 1) remifentanil. Each condition was investigated during non-painful heat and during painful heat stimulation. Mood was measured with the von Zerssen's mood scale (Bf-S score) and pain intensity using a Visual Analogue Scale (VAS). High Bf-S scores are reflecting discontent and dysphoria. Changes were tested for significance using a linear mixed model approach. Remifentanil significantly increased Bf-S scores during painful heat (+91.4%), indicating a negative mood effect, although it reduced VAS scores of painful heat intensity (-49.0%). The type of sensory stimulation (non-painful versus painful) had no effect on mood. There was no interaction between remifentanil dose and type of stimulation. Our results provide evidence for negative mood effects of remifentanil. These effects occur with and without pain. Taken into account that remifentanil reduces pain, one could have expected analgesia-related amelioration of mood instead. In clinical practice, these remifentanil effects should be considered and a comedication might be advisable.

Topics: Adult; Affect; Analgesics, Opioid; Dose-Response Relationship, Drug; Humans; Male; Pain; Piperidines; Receptors, Opioid, mu; Remifentanil

To determine the efficacy of CP-690,550 in improving pain, function and health status in patients with moderate to severe active rheumatoid arthritis (RA) and an inadequate response to methotrexate or a tumour necrosis factor alpha inhibitor.. Patients were randomised equally to placebo, CP-690,550 5, 15 or 30 mg twice daily for 6 weeks, with 6 weeks' follow-up. The patient's assessment of arthritis pain (pain), patient's assessment of disease activity, Health Assessment Questionnaire-Disability Index (HAQ-DI) and Short Form-36 (SF-36) were recorded.. At week 6, significantly more patients in the CP-690,550 5, 15 and 30 mg twice-daily groups experienced a 50% improvement in pain compared with placebo (44%, 66%, 78% and 14%, respectively), clinically meaningful reductions in HAQ-DI (> or =0.3 units) (57%, 75%, 76% and 36%, respectively) and clinically meaningful improvements in SF-36 domains and physical and mental components.. CP-690,550 was efficacious in improving the pain, function and health status of patients with RA, from week 1 to week 6.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Dose-Response Relationship, Drug; Epidemiologic Methods; Female; Humans; Janus Kinase 3; Male; Middle Aged; Pain; Pain Measurement; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Recovery of Function; Treatment Outcome

Early recovery of patients following sedation/analgesia and anesthesia is important in ambulatory practice. The aim of this study was to assess whether modafinil, used for the treatment of narcolepsy, improves recovery following sedation/analgesia.. Patients scheduled for extracorporeal shock wave lithotripsy were randomly assigned to one of four groups. Two groups received a combination of fentanyl/midazolam with either modafinil or placebo. The remaining groups received remifentanil/propofol with either modafinil or placebo. Modafinil 200 mg was administered to the treatment group patients 1 h before sedation/analgesia. Groups were compared using the digital symbol substitution test (DSST), trail making test (TMT), observer scale of sedation and analgesia (OAA/S) and Aldrete score. Verbal rating scale (VRS) scores for secondary outcome variables e.g. energy, tiredness and dizziness were also recorded before and after treatment.. Sixty-seven patients successfully completed the study. Groups received similar doses of sedation and analgesic drugs. No statistically significant difference was found for DSST between groups. No significant adverse effects occurred in relation to modafinil. No statistically significant difference between groups was identified for TMT, OAA/S and Aldrete scores. The mean VRS score for tiredness was lesser in the modafinil/fentanyl/midazolam group [1.3 (2.0)] compared with the placebo group [3.8 (2.5)], P=0.02. Such a difference was not found between the remifentanil/propofol groups [placebo 2.6 (2.2) vs. modafinil 3.1(2.7)], p>0.05. Dizziness was greater in the modafinil/remifentanil/propofol group 1.7 (2.0) vs. placebo 0.0 (0.5), p<0.05.. Modafinil reduces patient-reported tiredness after sedation/analgesia but does not improve recovery in terms of objective measures of patient psychomotor skills.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Analgesia; Anesthesia Recovery Period; Anesthetics, Inhalation; Appetite; Benzhydryl Compounds; Central Nervous System Stimulants; Deep Sedation; Dizziness; Fatigue; Fentanyl; Humans; Lithotripsy; Midazolam; Middle Aged; Modafinil; Nausea; Neuropsychological Tests; Pain; Piperidines; Placebos; Propofol; Psychomotor Agitation; Psychomotor Performance; Relaxation; Remifentanil; Sleep Stages; Young Adult

Awake fiberoptic tracheal intubation is the best choice for situations in which neck movement is limited or hazardous, and remifentanil is one of the most popular drugs that are used in these circumstances. We administered remifentanil with target-controlled and manually controlled infusion techniques in two groups of patients who had cervical trauma and semielective maxillofacial surgery.. Twenty-two patients were enrolled and randomly assigned to two groups. Bronchoscopy data were gathered in four data points. In the target-controlled infusion (TCI) group, patients received 0.8 ng · mL remifentanil as effect-site target, and in the manually controlled group, patients received remifentanil with a loading dose of 0.75 μg · kg and 0.075 μg · kg · min as maintenance. Patients were evaluated separately for recall and pain during procedure 24 hours after operation by visual analog scale. Comparison of vital signs was performed using Mann-Whitney U test. Fischer's exact test was used to analyze quantitative data when appropriate.. Preparation time was shorter in the TCI group, and remifentanil effect-site targets were higher in the TCI group. Vital signs were more stable in the TCI group. Levels of sedation were comparable in both groups. Recall and pain during endoscopy were more common in the manually controlled infusion group.. Remifentanil infusion could be recommended to provide good conscious sedation in procedures such as awake nasotracheal intubation, but target-controlled remifentanil infusion seems to provide better conditions compared with manually controlled remifentanil infusion and is easier to use.

Topics: Adolescent; Adult; Anesthetics, Intravenous; Cervical Vertebrae; Follow-Up Studies; Humans; Infusions, Intravenous; Intubation, Intratracheal; Middle Aged; Nose; Optical Fibers; Pain; Pain Measurement; Piperidines; Remifentanil; Retrospective Studies; Spinal Injuries; Treatment Outcome; Young Adult

To determine the effect-site target concentration (C(et)) of remifentanil that provides optimal conditions for patients and operators during cataract surgery during monitored anesthesia care using a target controlled infusion (TCI) of propofol and remifentanil.. Prospective, randomized, double-blinded study.. Operating room and postoperative recovery area of a university-affiliated hospital.. 66 adult, ASA physical status I, II, and III patients undergoing cataract surgery.. Group I received C(et) of remifentanil 0.5 ng/mL; Group 2 received C(et) of remifentanil one ng/mL; and Group 3 received C(et) of remifentanil 1.5 ng/mL. After giving TCI propofol (C(et); one μg/mL)-remifentanil, an ophthalmologist administered topical anesthesia.. Intraoperative hemodynamics, pain scores, sedation scores, patient satisfaction scores, and operators' satisfaction scores regarding surgical conditions were recorded. No statistical differences in heart rate or mean blood pressure were detected among the three groups during surgery. Pain scores (Group 1: 31.9 ± 17.9 vs. Group 2: 11.8 ± 7.7 and Group 3: 11.8 ± 7.7; P < 0.05) were higher and patient satisfaction scores (Group 1: 4.7 ± 0.8 vs. Group 2: 5.4 ± 0.4 and Group 3: 5.5 ± 0.4; P < 0.05) were lower in Group 1 than Groups 2 and 3. On the other hand, surgeon satisfaction was lowest in Group 3 (Group 3: 2.9 ± 1.3 vs. Group 1: 4.7 ± 0.4 and Group 2: 4.6 ± 0.7; P < 0.05) due to ocular movement.. C(et) values of remifentanil and propofol of one ng/mL and one μg/mL, respectively, appear to provide optimal conditions for patients and operators during cataract surgery using monitored anesthesia care with TCI.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anesthetics, Intravenous; Cataract Extraction; Dose-Response Relationship, Drug; Double-Blind Method; Female; Hospitals, University; Humans; Lens Implantation, Intraocular; Male; Middle Aged; Monitoring, Intraoperative; Pain; Patient Satisfaction; Piperidines; Propofol; Prospective Studies; Remifentanil; Young Adult

Endovascular repair offers a less surgically invasive procedure for abdominal aortic aneurysms but nevertheless, still requires analgesic sedative cover to ensure an acceptable level of patient comfort and cardiorespiratory stability. The peculiarity of this kind of operation is that painful stimuli are concentrated in specific moments separated by intervals devoid of pain, so the insurgence of pain can be predicted and prevented with a bolus of analgesic, making a continuous infusion not essential, but potentially useful in achieving a better analgesic stability. The primary objective of the study was pain control measured by Visual Analogue Scale; secondary endpoints were cardiorespiratory stability and an acceptable level of sedation.. The sedative analgesic protocols of two groups of randomly allocated patients, undergoing abdominal aortic aneurysm endovascular repair, were compared. The experimental group received remifentanil infusion (0.03-0.1 microg kg min) and the control group received intravenous doses of fentanyl and midazolam (1-3 microg kg and 0.05-0.1 mg kg, respectively).. Fifty patients were investigated out of 60 enrolled. There were no relevant differences concerning cardiorespiratory stability and level of sedation, but pain levels were significantly lower in the experimental group: mean Visual Analogue Scale 0.35+/-0.40 vs. 1.49+/-0.62 (P<0.001) and area under the curve 17.48+/-5.09 vs. 33.05+/-8.19 (P<0.001).. Both techniques were shown to be safe and most importantly effective in offering cardiovascular stability and analgesia for American Society of Anaesthesiologists III-IV patients undergoing endovascular abdominal aortic aneurysm repair. However, remifentanil continuous infusion proved to offer significantly more stable pain control compared with the currently used combination fentanyl-midazolam.

Topics: Aged; Analgesia; Analgesics, Opioid; Aortic Aneurysm, Abdominal; Area Under Curve; Blood Pressure; Conscious Sedation; Female; Fentanyl; Heart Rate; Humans; Hypnotics and Sedatives; Intraoperative Care; Male; Midazolam; Oxygen; Pain; Pain Measurement; Piperidines; Remifentanil; Stents; Treatment Outcome

Propofol produces anaesthesia with rapid recovery but also causes pain or discomfort on injection. The effect of remifentanil in prevention of propofol-induced injection pain has been demonstrated in earlier studies. However, sufentanil, an opioid analgesic, has not been evaluated as an agent for managing pain on injection of propofol. In this study we aimed to compare the efficacy of remifentanil and sufentanil for the prevention of propofol-induced pain.. This double-blind, placebo-controlled clinical study was carried out from July 2006 to February 2007, and included patients who were candidates for elective surgery in a university hospital. From 92 American Society of Anesthesiologists (ASA) status I-II adult patients, 80 were randomly assigned to four groups of 20 each. Patients received 2 mL of sufentanil 0.01 mg, 2 mL of remifentanil 0.01 mg, 2 mL of remifentanil 0.02 mg, or 2 mL of saline 60 seconds prior to administration of 5 mL of propofol 1%. Patients were asked prior to losing consciousness whether they felt any pain due to propofol injection, and their pain scores were evaluated on the four-point scale of Ambesh et al.. The incidence of pain was significantly lower in the remifentanil 0.02-mg group, remifentanil 0.01-mg group and sufentanil group compared with the saline group (40%, 70%, 75% and 100%, respectively, p < 0.05). Median pain intensity scores were significantly lower in the group receiving remifentanil 0.02 mg than in the sufentanil group (0 and 1 respectively, p < 0.05). The median intensity of propofol-induced pain was statistically similar between the groups receiving sufentanil or remifentanil 0.01 mg and the placebo group (1, 1 and 1, respectively, p > 0.05).. Remifentanil 0.02 mg administered over 60 seconds before propofol administration is more effective than sufentanil 0.01 mg, remifentanil 0.01 mg or placebo administered 1 minute prior to propofol in reducing the incidence and intensity of injection pain.

Topics: Adult; Analgesics, Opioid; Anesthetics, Intravenous; Dose-Response Relationship, Drug; Double-Blind Method; Humans; Hypotension; Injections, Intravenous; Middle Aged; Pain; Pain Measurement; Piperidines; Placebos; Propofol; Remifentanil; Sufentanil; Time Factors; Treatment Outcome

Our objective was to investigate the efficacy and safety of alvimopan, a peripherally acting mu-opioid receptor (PAM-OR) antagonist, in subjects with non-cancer pain and opioid-induced bowel dysfunction (OBD), and to identify at least one treatment regimen that improves OBD. Following a 2-week baseline period, 522 subjects reporting <3 spontaneous bowel movements (SBMs)/week (with >or=25% accompanied by a sensation of incomplete evacuation, straining, or lumpy hard stools), requiring analgesia equivalent to >or=30 mg oral morphine/day were randomized to alvimopan 0.5mg twice daily (BID), 1mg once daily (QD), 1mg BID, or placebo for 6 weeks. Compared with placebo, there was a statistically and clinically significant increase in mean weekly SBM frequency over the initial 3 weeks of treatment (primary endpoint) with alvimopan 0.5mg BID (+1.71 mean SBMs/week), alvimopan 1mg QD (+1.64) and alvimopan 1mg BID (+2.52); P<0.001 for all comparisons. Increased SBM frequency and additional treatment effects, including improvements in symptoms such as straining, stool consistency, incomplete evacuation, abdominal bloating/discomfort, and decreased appetite, were sustained over 6 weeks. The most frequently reported adverse events were abdominal pain, nausea, and diarrhea, occurring more frequently in the higher dosage groups. The alvimopan 0.5mg BID regimen demonstrated the best benefit-to-risk profile for managing OBD with alvimopan in this study population, with a side effect profile similar to that of placebo. There was no evidence of opioid analgesia antagonism. Competitive peripheral antagonism of opioids with alvimopan can restore GI function and relieve OBD without compromising analgesia.

Topics: Adult; Analgesics, Opioid; Colic; Constipation; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Enteric Nervous System; Female; Gastrointestinal Motility; Humans; Intestines; Male; Middle Aged; Narcotic Antagonists; Pain; Piperidines; Placebos; Receptors, Opioid, mu; Risk Assessment; Treatment Outcome

This study was designed to compare the efficacy of remifentanil and alfentanil without the venous occlusion technique in preventing the withdrawal response associated with rocuronium injection in children.. One hundred and twenty children aged between 3 and 10 years were randomly allocated into one of four groups to receive either i.v. remifentanil 0.5 microg.kg(-1) (remi 0.5 group), remifentanil 1 microg.kg(-1) (remi 1.0 group), alfentanil 15 microg.kg(-1) (alfentanil group) or saline 5 ml (saline group). Anesthesia was induced with 2.5% thiopental sodium 5 mg.kg(-1) and the test drug was injected over 30 s. One minute later, 1% rocuronium 0.6 mg.kg(-1) was injected over 5 s and the response was recorded. Mean arterial pressure (MAP) and heart rate (HR) were recorded on arrival in the operating room, before and 1 min after tracheal intubation.. The incidence of withdrawal movement in the saline group (93%) was significantly higher than that in the remi 0.5, remi 1.0, and alfentanil groups (53%, 17%, and 20%, respectively) (P < 0.05). The incidence in the remi 1.0 and alfentanil groups was significantly less than that in the remi 0.5 group (P < 0.05). After intubation, MAP and HR were significantly higher in the saline group than that in remi 1.0 and alfentanil groups.. Both remifentanil 1 microg.kg(-1) and alfentanil 15 microg.kg(-1) can be used to prevent rocuronium-associated withdrawal movement in children because they are equally effective and attenuate the increase in MAP and HR after intubation.

Topics: Alfentanil; Analgesics, Opioid; Androstanols; Blood Pressure; Child; Child, Preschool; Double-Blind Method; Female; Heart Rate; Humans; Intubation, Intratracheal; Male; Movement; Neuromuscular Nondepolarizing Agents; Pain; Piperidines; Prospective Studies; Remifentanil; Rocuronium

The treatment of acute pain in patients maintained on methadone is difficult due to increased pain sensitivity (hyperalgesia) and cross-tolerance to other opioids. This study aimed to investigate whether remifentanil elicits antinociception in methadone-maintained subjects in a dose-dependent manner. Eight chronic methadone-maintained subjects attended the testing session approximately 20 h after their normal methadone dose (range 50-110 mgday(-1)). Following a 20 min saline infusion, subjects were administered intravenous remifentanil in seven increasing doses ranging from 0.5 to 3.5 microgkg(-1)min(-1), each for 2 0min. Testing was performed in the last 10 min of each infusion. The testing measures included nociception, as measured by the cold pressor test, withdrawal using the subjective opiate withdrawal scale (SOWS), and subjective opioid effects using the morphine-benzedrine group scale (MBG). Results showed dose-dependent increase in cold pressor tolerance time from baseline of 15.6+/-3.5 (mean+/-SEM)s up to 77.3+/-24.7s during this dosing protocol. During the infusion typical mu-opioid receptor agonist side effects were observed, but with no withdrawal. Methadone-maintained patients demonstrate significant tolerance to remifentanil and may require opioid doses 20-30 higher than required for the treatment of acute pain in opioid-naïve patients.

Topics: Adult; Analgesics, Opioid; Cold Temperature; Drug Interactions; Drug Tolerance; Humans; Infusions, Intravenous; Male; Methadone; Opioid-Related Disorders; Pain; Pain Measurement; Piperidines; Remifentanil

To compare the efficacy of fentanyl and remifentanil as prodrugs in the prevention of rocuronium injection pain by using a control group.. In a randomized, double-blinded, controlled study, 102 adult patients aged between 18-60 undergoing elective surgery under general anesthesia and classified into American Society of Anesthesiologists (ASA) I and ASA II risk groups were included in the study. The study was carried out from July 2005 to April 2006 at Dokuz Eylul University, Izmir, Turkey. Unpremedicated patients were randomly allocated to one of 3 groups. Patients received 2 mL (0.02 mg) of remifentanil (n =34), 2 mL of fentanyl 0.1 mg (n =34), and 2 mL of saline (n =34), by injection over 10 seconds. Thirty seconds after prodrug administration, 10 mg (10 mg/mL) intravenous rocuronium bromide was administered over 5 seconds and pain assessment was performed by using a 5-point scale.. When the 3 groups of 34 patients were compared in terms of pain assessment scoring, a statistically significant difference was determined (p=0.02). When the groups were paired, it was seen that this difference resulted from the remifentanil and saline groups (p=0.02).. This study shows that a bolus dose of 0.02 mg of remifentanil is a more effective prodrug administration compared to the application of saline, however, remifentanil and fentanyl have no superiority over one another and the administration of fentanyl is equally effective as saline prodrug administration.

Topics: Adult; Aged; Analgesics, Opioid; Androstanols; Double-Blind Method; Female; Fentanyl; Humans; Injections, Intravenous; Male; Middle Aged; Neuromuscular Nondepolarizing Agents; Pain; Piperidines; Remifentanil; Rocuronium

The incidence of pain induced withdrawal movement following intravenous injection of rocuronium is high. This randomized, double-blind, placebo-controlled study was designed to evaluate the effect of pretreatment of remifentanil on the withdrawal movements due to intravenous injection of rocuronium during anesthetic induction.. Ninety adult female patients undergoing thyroidectomy were randomly allocated to three groups. Each patient intravenously received one of three solutions of equal volume (4 mL): normal saline (Group I, n=30), 0.5 microg/kg remifentanil (Group II, n=30) or 1 microg/kg remifentanil (Group III, n=30). Thirty seconds after remifentanil administration, anesthesia was induced with 5 mg/kg IV thiopental. Twenty seconds after thiopental injection, 0.6 mg/kg IV rocuronium was administered (injection rate of 0.5 mL/sec) and patients' withdrawal movements were assessed. Mean arterial pressure (MAP) and heart rate were assessed on arrival in the operation room, before the tracheal intubation and immediately, 1 and 2 min after the tracheal intubation.. The incidence of withdrawal movements was significantly lower in both of the remifentanil groups (3 and 0% in Group II and III, respectively) than in the saline group (70%). Remifentanil attenuated the increase of heart rate and MAP immediately and 1 min after the tracheal intubation.. The pretreatment with 0.5 and 1.0 microg/kg remifentanil of bolus doses prevented the withdrawal movements caused by rocuronium injection, and effectively blunted cardiovascular activation following tracheal intubation.

Topics: Adult; Aged; Analgesics, Opioid; Androstanols; Female; Humans; Injections, Intravenous; Middle Aged; Pain; Piperidines; Remifentanil; Rocuronium

Our aim was to compare patients' satisfaction and cooperation, and clinical efficacy, of midazolam alone, and midazolam and remifentanil for patient-controlled sedation during removal of third molars. Forty patients, American Society of Anesthesiologists grades I and II, admitted for extraction of impacted mandibular third molars were included in this randomised, prospective study. They were given an intravenous bolus of midazolam 0.03 mg/kg and then allowed to use patient-controlled sedation. In the midazolam group, 2 ml of 0.5 mg/ml midazolam was given automatically. In the midazolam-remifentanil group, 2 ml of 0.5 mg/ml midazolam and 12.5 microg/ml remifentanil were given in the same manner. The lockout period was 5 min. Vital signs and oxygen saturation were recorded. Patients' and surgeons' satisfaction, and the patients' degree of amnesia about the local anaesthetic, drilling, removal of the tooth, and pain during extraction were also assessed. There were no significant differences between systolic and diastolic blood pressures during sedation, but heart rate after 30 min in the combined group was significantly lower than in the midazolam group (p<0.05). Surgeons described the midazolam group as excellent in 9 and good in 11. In the combined group, satisfaction was excellent in 11, good in 7, and satisfactory or unacceptable in 1 of each. Immediately postoperatively, 19 patients in each group ranked their satisfaction as excellent and 1 as good. Twenty-four hours later it was unchanged in the midazolam group, while 15 patients in the other group thought it was excellent, 3 good, and 2 poor. Patient-controlled analgesia with midazolam or midazolam and remifentanil is safe and reliable during extraction of third molars.

Topics: Adolescent; Adult; Anesthesia, Local; Blood Pressure; Conscious Sedation; Cooperative Behavior; Female; Heart Rate; Humans; Hypnotics and Sedatives; Male; Mandible; Mental Recall; Midazolam; Molar, Third; Pain; Patient Satisfaction; Piperidines; Prospective Studies; Remifentanil; Self Administration; Time Factors; Tooth Extraction; Tooth, Impacted; Treatment Outcome

Pain from rocuronium injection is a common side-effect reported to occur in 50-80% of the patients. This randomized, double-blind, placebo-controlled study was designed to evaluate the efficacy of pretreatment with i.v. remifentanil on prevention of withdrawal response during rocuronium injection in paediatric patients.. After obtaining parental consents, 70 paediatric patients were randomly allocated into two groups to receive either i.v. remifentanil 1 mug kg(-1) (remifentanil group, n=35) or i.v. saline 5 ml (saline group, n=35). Anaesthesia was induced with thiopental sodium 2.5% (5 mg kg(-1)) and the test drug was injected over 30 s. One minute after the test drug injection, rocuronium 1% (0.6 mg kg(-1)) was injected over 5 s and the response was recorded. Mean arterial pressure (MAP) and heart rate were recorded on arrival in the operating theatre, before and 1 min after the tracheal intubation.. The overall incidence of withdrawal movements was significantly higher in the saline group (33 patients; 94%) than that in the remifentanil group (8 patients; 23%) (P<0.001). No patient in the remifentanil group showed generalized movement, whereas 51% of patients in the saline group did. Remifentanil prevented significant increase in MAP after intubation.. This study demonstrated that pretreatment with remifentanil 1 microg kg(-1) provided a safe and simple method for reducing the incidence of rocuronium-associated withdrawal movement with haemodynamic stability in children.

Topics: Analgesics, Opioid; Androstanols; Blood Pressure; Child; Child, Preschool; Double-Blind Method; Female; Heart Rate; Humans; Injections, Intravenous; Male; Movement; Neuromuscular Nondepolarizing Agents; Pain; Piperidines; Prospective Studies; Remifentanil; Rocuronium

Propofol has a high incidence of pain on injection, particularly when a vein on the back of hand is used. Administration of lidocaine, either before or mixed with propofol remains the most widely used method to attenuate this pain. The use of opioids such as alfentanil and fentanyl has been found to decrease pain induced by propofol injection. The purpose of this study was to evaluate the effects of different doses of remifentanil and alfentanil in minimizing the pain caused by propofol.. In this randomized, double-blind, placebo-controlled study, healthy premedicated children between the age group of 5-12 years admitted for adenotonsillectomy were randomly allocated to one of 6 treatment groups. Group I: remifentanil 0.25 microg kg(-1); Group II: remifentanil 0.50 microg kg(-1); Group III: alfentanil 15 microg kg(-1); Group IV: alfentanil 20 microg kg(-1) 60 s prior to propofol mixed with 1 mL of 0.9% normal saline; Group V: lidocaine 1 mL of 1% (10 mg) added to 100 mg of propofol and Group VI: normal saline. During the injection of propofol (3 mg kg(-1)) pain perception was assessed with a four-point behavioural scale: none, mild, moderate, or severe.. There were 52 subjects in Group I, 51 in Group II, 49 in Group III, 52 in Group IV, 52 in Group V and 52 in Group VI; 63.46% of patients in Group I, 39.21% in Group II, 38.77% in Group III, 36.53% in Group IV, 38.46% in Group V and 84.61% in Group VI experienced pain. Statistically, Groups II, III, IV and V were significantly better than placebo in the reduction of propofol pain (P<0.0001). Groups II, III and IV significantly reduced the pain in comparison with Group I (P<0.001).. Pretreatment with intravenous remifentanil 0.5 microg kg(-1), alfentanil 15 microg kg(-1) and 20 microg kg(-1) were equally effective in reducing pain associated with propofol injection in children between the age group of 5-12 years.

Topics: Alfentanil; Analgesics, Opioid; Anesthesia, Intravenous; Anesthetics, Intravenous; Child; Child, Preschool; Double-Blind Method; Female; Humans; Male; Pain; Piperidines; Propofol; Remifentanil

There is a high incidence of pain following intravenous injection of propofol, and many studies have been conducted to find a way of reducing this. The administration of lidocaine and, recently, remifentanil has also been used for this purpose, but it is only partially effective. Thus, the purpose of this study was to investigate the analgesic effect of a combination of pretreatment with remifentanil and premixture of lidocaine with propofol and to compare either treatment alone during propofol injection in dorsal hand-veins.. In a prospective, randomized, double-blinded trial, we studied 141 adult patients scheduled for elective surgery. The combination of pretreatment of remifentanil (0.35 microg kg(-1) min(-1)) and a premixture of lidocaine with propofol (mixture of propofol 1% and lidocaine 1% in a 10:1 ratio) was compared with either treatment alone in the prevention of pain on propofol injection. Pain was assessed on a four-point scale (0=none, 1=mild, 2=moderate, 3=severe) during propofol injection. Patients in Group B received remifentanil (0.35 microg kg(-1) min(-1)) 30 s before the injection of propofol.. The reduction of pain on propofol injection was similar in both the remifentanil pretreatment and lidocaine premixture groups (62.2% vs. 62.2%). Combination therapy was associated with a higher incidence of patients without pain (91.3%) than either treatment alone (P<0.001). On analysing the injection pain scores, we found a significant reduction of the score in the remifentanil and lidocaine Group C compared with the lidocaine Group A (P<0.001) and the remifentanil Group B (P<0.001).. The combination of pretreatment of remifentanil and premixture of lidocaine with propofol was more effective in reducing the incidence of pain on injection of propofol than either treatment alone.

Topics: Adult; Analysis of Variance; Anesthetics, Intravenous; Anesthetics, Local; Double-Blind Method; Drug Combinations; Female; Humans; Injections, Intravenous; Lidocaine; Male; Middle Aged; Pain; Pain Measurement; Piperidines; Propofol; Prospective Studies; Remifentanil; Treatment Outcome

Previous imaging studies have demonstrated a number of cortical and subcortical brain structures to be activated during noxious stimulation and infusion of narcotic analgesics. This study used O-water and positron emission tomography to investigate dose-dependent effects of the short-acting mu-selective opioid agonist remifentanil on regional cerebral blood flow during experimentally induced painful heat stimulation in healthy male volunteers.. Positron emission tomography measurements were performed with injection of 7 mCi O-water during nonpainful heat and painful heat stimulation of the volar forearm. Three experimental conditions were used during both sensory stimuli: saline, 0.05 microg x kg x min remifentanil, and 0.15 microg x kg x min remifentanil. Cardiovascular and respiratory parameters were monitored noninvasively. Across the three conditions, dose-dependent effects of remifentanil on regional cerebral blood flow were analyzed on a pixel-wise basis using a statistical parametric mapping approach.. During saline infusion, regional cerebral blood flow increased in response to noxious thermal stimulation in a number of brain regions as previously reported. There was a reduction in pain-related activations with increasing doses of remifentanil in the thalamus, insula, and anterior and posterior cingulate cortex. Increasing activation occurred in the cingulofrontal cortex (including the perigenual anterior cingulate cortex) and the periaqueductal gray.. Remifentanil induced regional cerebral blood flow increases in the cingulofrontal cortex and periaqueductal gray during pain stimulation, indicating that mu-opioidergic activation modulates activity in pain inhibitory circuitries. This provides direct evidence that opioidergic analgesia is mediated by activation of established descending antinociceptive pathways.

Topics: Adult; Analgesics, Opioid; Blood Gas Analysis; Blood Pressure; Brain; Brain Mapping; Cerebrovascular Circulation; Dose-Response Relationship, Drug; Heart Rate; Hot Temperature; Humans; Male; Pain; Pain Measurement; Physical Stimulation; Piperidines; Positron-Emission Tomography; Reference Values; Remifentanil; Sodium Chloride

To date, the anesthesia-induced blockade of nociceptive inputs is insufficiently reflected by commercially available electroencephalographic depth-of-anesthesia monitors. The aim of the current study was to evaluate the potential of somatosensory (SSEP) and intracutaneous pain evoked (iSEP) potentials during remifentanil and propofol anesthesia as electroencephalographic indicators of the nociceptive blockade.. Ten healthy men were investigated in a double-blind crossover design during three sessions with remifentanil, propofol, and placebo administration. All dosages were increased in a step-by-step mode. SSEP and iSEP recordings were performed followed by subjective pain ratings and measurement of level of sedation (modified Observer's Assessment of Alertness and Sedation Scale). Changes from baseline in evoked potential components, pain ratings, and sedation scale were assessed by Bonferroni-Holms-corrected Wilcoxon tests.. Pain ratings were significantly reduced by remifentanil. Sedation scale was significantly reduced by propofol. Early SSEP components were not affected by medication. The amplitudes of the long latency SSEP components increased significantly with remifentanil, decreased with propofol, and did not change with placebo. The amplitudes of long latency components of the iSEP decreased significantly with both remifentanil and propofol and did not change with placebo.. Long latency components of the SSEP are differently affected by remifentanil and propofol administration. Further studies are needed to clarify whether they can serve as a specific indicator of the nociceptive blockade during anesthesia.

Topics: Adult; Analgesics, Opioid; Double-Blind Method; Electroencephalography; Evoked Potentials; Evoked Potentials, Somatosensory; Humans; Hypnotics and Sedatives; Male; Pain; Piperidines; Propofol; Remifentanil

Propofol is well-known for its pain on injection. Premixture with lidocaine or pretreatment with remifentanil reduces injection pain. A multimodal approach might offer additional mitigation of propofol injection pain.. In a randomized, prospective, double-blind study of 156 patients, we compared the incidence and severity of propofol pain among three groups. Patients in the lidocaine group (n = 54) received 2% lidocaine premixed with propofol (40 mg lidocaine in 180 mg propofol). Patients in the remifentanil group (n = 50), received pretreatment with remifentanil 2 microg x kg(-1) IV over 30 s. Patients in the combination group (n = 52) received both lidocaine and remifentanil.. A significant decrease in the overall incidence of propofol pain at induction was achieved in the combination group (9.6%) compared with that in the remifentanil group (36%) and the lidocaine group (35%) (P = 0.003). The incidence of severe and moderate pain was also significantly different in the combination group (0%), compared with that in the remifentanil (18%) and lidocaine groups (12.9%) (P < 0.02). Similar, statistically significant differences among the three groups were achieved concerning recalled pain in the postanesthesia care unit.. The combination of two different analgesic modalities, remifentanil and lidocaine completely abolishes moderate and severe pain associated with propofol injection, and significantly reduces the incidence of mild pain when compared with each drug used alone.

Topics: Adult; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Injections, Intravenous; Lidocaine; Male; Middle Aged; Pain; Pain Measurement; Piperidines; Propofol; Prospective Studies; Remifentanil

Pain on injection is a well known adverse effect of propofol. The purpose of this study was to compare the analgesic effect of a lidocaine (lignocaine)/remifentanil combination compared with either lidocaine alone or remifentanil alone during propofol injection for induction of anaesthesia.. In a randomised, double-blind, prospective trial, 129 patients were allocated to one of three groups (each n = 43) receiving lidocaine 20mg, remifentanil 0.3 microg/kg or lidocaine 20 mg plus remifentanil 0.3 microg/kg as pretreatment, followed by injection of 5 mL of 1% propofol. Pain severity was evaluated on a four-point scale.. Two patients (4.7%) complained of pain in the lidocaine plus remifentanil group compared with 15 (35.7%) in the lidocaine alone group and 18 (42.9%) in the remifentanil alone group (p < 0.001). There was no significant difference in the incidence of injection pain between the lidocaine alone and remifentanil alone groups (p = 0.21).. Pretreatment with a combination of lidocaine and remifentanil is more effective than either pretreatment alone in reducing pain on injection of propofol.

Topics: Adolescent; Adult; Aged; Analgesics, Opioid; Anesthetics, Intravenous; Anesthetics, Local; Double-Blind Method; Female; Humans; Lidocaine; Male; Middle Aged; Pain; Piperidines; Propofol; Prospective Studies; Reflex; Remifentanil

Pain on injection of propofol is unpleasant. We hypothesized that propofol infusion pain might be prevented by infusing remifentanil before starting the propofol infusion in a clinical setting where target-controlled infusions (TCI) of both drugs were used. A prospective, randomized, double-blind, placebo-controlled trial was performed to determine the effect-site concentration (Ce) of remifentanil to prevent the pain without producing complications.. A total of 128 patients undergoing general surgery were randomly allocated to receive normal saline (control) or remifentanil to a target Ce of 2 ng ml(-1) (R2), 4 ng ml(-1) (R4), or 6 ng ml(-1) (R6) administered via TCI. After the target Ce was achieved, the infusion of propofol was started. Remifentanil-related complications were assessed during the remifentanil infusion, and pain caused by propofol was evaluated using a four-point scale during the propofol infusion.. The incidence of pain was significantly lower in Groups R4 and R6 than in the control and R2 groups (12/32 and 6/31 vs 26/31 and 25/32, respectively, P<0.001). Pain was less severe in Groups R4 and R6 than in the control and R2 groups (P<0.001). However, both incidence and severity of pain were not different between Groups R4 and R6. No significant complications were observed during the study.. During induction of anaesthesia with TCI of propofol and remifentanil, a significant reduction in propofol infusion pain was achieved without significant complications by prior administration of remifentanil at a target Ce of 4 ng ml(-1).

Topics: Adolescent; Adult; Aged; Analgesics, Opioid; Anesthetics, Intravenous; Double-Blind Method; Drug Delivery Systems; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Pain; Pain Measurement; Piperidines; Propofol; Prospective Studies; Remifentanil

The injection of retrobulbar block is associated with significant pain and discomfort. Therefore a short-acting IV analgesic before retrobulbar injection has been advocated.. To compare remifentanil, alfentanil and fentanyl in providing analgesia for retrobulbar block injection.. 69 patients were enrolled randomly into three groups of 23 each to receive either Remifentanil 1 microg/kg, Alfentanil 20 microg/kg or Fentanyl 2 microg/kg as an IV bolus dose prior to retrobulbar injection. Mean arterial pressure (MAP) and heart rate (HR) were recorded and Numerical Pain Score (NPS) were assessed by a blinded observer.. Remifentanil prevented increase in MAP and HR while alfentanil and fentanyl were ineffective in this purpose (p < 0.05). NPS was significantly lower in remifentanil group (p < 0.05).. Remifentanil 1 microg/kg prior to retrobulbar injection provide excellent hemodynamic stability and ensure analgesia.

Topics: Aged; Alfentanil; Analgesics, Opioid; Anesthesia, Spinal; Blood Pressure; Double-Blind Method; Female; Fentanyl; Heart Rate; Humans; Male; Ophthalmologic Surgical Procedures; Pain; Pain Measurement; Piperidines; Remifentanil

Radio frequency treatment in cardiology generates short acute pain during the heating process. The present study evaluates two techniques used for sedation/analgesia for this procedure.. Two groups of 20 patients each were studied prospectively. Patients were randomized to receive sedation for the procedure using either a patient-controlled analgesia device with remifentanil (Group R), or a target controlled infusion of propofol (Group P). Patients in Group R had a basal infusion of remifentanil 0.02-0.04 microg x kg(-1) x min(-1) with self administered bolus doses of 0.3 microg x kg(-1) i.v. every minute as required, with a delivery time greater than 30 sec. Patients in Group P had an initial plasma target concentration set at 3-4 microg x mL(-1).. Sedation scores were significantly higher in Group P, and two patients required supplementation with remifentanil and insertion of an laryngeal mask airway. Pain scores were higher in Group R, and two patients experienced muscular rigidity, one with transient apnea. Systolic blood pressure decreased significantly in Group P, and at the end of the procedure, PaCO(2) values were higher in that group (P < 0.01). Recovery time was significantly longer in Group P. Patient and physician satisfaction scores were similar in the two groups.. A basal infusion of remifentanil plus remifentanil patient controlled analgesia and target controlled infusion of propofol were adequate but not optimal techniques for sedation/analgesia for radio frequency treatment of atrial flutter.

Topics: Aged; Analgesia, Patient-Controlled; Analysis of Variance; Anesthetics, Intravenous; Atrial Flutter; Blood Pressure; Catheter Ablation; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Length of Stay; Male; Pain; Pain Measurement; Patient Satisfaction; Piperidines; Propofol; Remifentanil; Time Factors

A hysterosalpingogram is an integral part of the evaluation of infertility, however, it is often painful.. We conducted a randomized double-blinded, placebo-controlled trial of intravenous infusion of remifentanil in women undergoing hysterosalpingography (HSG). We randomly allocated 62 patients scheduled for HSG to receive either a continuous infusion of 0.25 microg.kg(-1) of remifentanil or placebo. The degree of pain was documented via 10-cm visual analog scales (VAS). Patients' discomfort, side effects and recovery times were also recorded.. The VAS scores during HSG were 1.25 +/- 1.31 in the remifentanil group and 4.78 +/- 1.7 in the placebo group (p < 0.001). There were more patients in the remifentanil group that rated their condition as excellent (p < 0.001). The groups did not differ with regard to the incidence of side effects. The recovery times were found statistically longer in the remifentanil group (14 +/- 5 vs. 10 +/- 3 min). All the patients were discharged 30 min after the procedures without any side effects.. Remifentanil infusion during HSG is superior to placebo for relief of pain with minimal opioid side effects.

Topics: Adult; Analgesics, Opioid; Double-Blind Method; Female; Humans; Hysterosalpingography; Pain; Pain Measurement; Piperidines; Prospective Studies; Remifentanil

Little is known of the effect on oocytes of anesthesia administered during retrieval. The main objective of this study was to compare the prolactin and stress hormone responses to surgical stimulus under 4 anesthetic techniques and to determine whether there is an effect of technique on the number and quality of oocytes retrieved.. We designed a clinical trial to determine the plasma and follicular levels of prolactin and cortisol in patients in an assisted reproduction program. The patients were randomized to 3 anesthetic groups: general anesthesia, spinal anesthesia, or sedation with alfentanil and midazolam plus paracervical block. Patients were consecutively assigned to the fourth group to receive sedation with remifentanil plus paracervical block.. We studied 90 patients. The patients receiving general anesthesia had the greatest increase in prolactin by the end of the procedure. Follicular cortisol increased in the paracervical block group in which remifentanil was used for sedation. The only significant difference between groups was seen for the rate of gestation of 0% in the group receiving sedation with alfentanil and midazolam before a paracervical block. Adverse effects were few with all the techniques. All patients reported a high degree of satisfaction.. Plasma increases in prolactin and hormonal responses to follicular puncture were fully attenuated by spinal anesthesia and partially attenuated by the techniques requiring sedation. None of the anesthetic techniques proved harmful to oocytes or embryos. Nor was the effectiveness of the in vitro fertilization technique affected by any of the anesthetic techniques studied.

Topics: Adult; Alfentanil; Anesthesia, General; Anesthesia, Spinal; Anesthetics; Anesthetics, General; Anesthetics, Local; Autonomic Nerve Block; Body Fluids; Conscious Sedation; Female; Fertilization in Vitro; Humans; Hydrocortisone; Hypnotics and Sedatives; Midazolam; Oocytes; Ovarian Follicle; Pain; Piperidines; Prolactin; Prospective Studies; Remifentanil; Stress, Physiological; Tissue and Organ Harvesting; Treatment Outcome

Alvimopan has been shown to reverse the inhibitory effect of opioids on gastrointestinal transit without affecting analgesia. We evaluated oral alvimopan, 0.5 or 1 mg, versus placebo, once daily for 21 days, in 168 patients with opioid-induced bowel dysfunction (OBD) who were receiving chronic opioid therapy (minimum, 1 month) for nonmalignant pain (n = 148) or opioid dependence (n = 20). The primary outcome was the proportion of patients having at least one bowel movement (BM) within 8 hours of study drug on each day during the 21-day treatment period. Averaged over the 21-day treatment period, 54%, 43%, and 29% of patients had a BM within 8 hours after alvimopan 1 mg, 0.5 mg, or placebo, respectively (P < .001). Secondary outcomes of median times to first BM were 3, 7, and 21 hours after initial doses of 1 mg, 0.5 mg, and placebo, respectively (P < .001; 1 mg vs placebo). Weekly BMs and overall patient satisfaction were increased after the 1-mg dose (P < .001 at weeks 1 and 2 vs placebo, and P = .046, respectively). Treatment-emergent adverse events were primarily bowel-related, occurred during the first week of treatment, and were of mild to moderate severity. Alvimopan was generally well tolerated and did not antagonize opioid analgesia. Patients treated with chronic opioid therapy often experience opioid-induced bowel dysfunction as a result of undesirable effects on peripheral opioid receptors located in the gastrointestinal tract. Alvimopan, a novel peripheral opioid mu-receptor antagonist, has demonstrated significant efficacy for the management of opioid-induced bowel dysfunction without compromise of centrally mediated opioid-induced analgesia.

Topics: Administration, Oral; Analgesics, Opioid; Cathartics; Chronic Disease; Constipation; Female; Follow-Up Studies; Gastrointestinal Motility; Humans; Male; Middle Aged; Pain; Piperidines; Receptors, Opioid, mu; Treatment Outcome

Flavopiridol is a cyclin-dependent kinase inhibitor that prevents cell cycle progression and tumor growth. In initial phase I studies, encouraging responses were seen in advanced renal cell cancer (RCC). In a phase II study of flavopiridol given as a 72-h continuous infusion every 2 weeks in RCC, a response rate of 6% was seen but with considerable grade 3 or 4 asthenia, diarrhea, and thrombosis. Subsequently, an alternative 1-h bolus schedule was reported to have enhanced tolerability in a phase I trial. We therefore conducted a phase II study of this bolus regimen.. A total of 38 patients with advanced RCC were entered into this multi-institutional phase II study. Flavopiridol (50 mg/m(2) per day) was administered by bolus intravenous injection daily for three consecutive days, repeated every 3 weeks.. Out of 34 eligible patients, one complete response and three partial responses were observed, for an overall response rate of 12% (95% CI 3-27%). Of the 34 patients, 14 (41%) had stable disease (SD). The probability of not failing treatment by 6 months was 21% (95% CI 9-35%). Median overall survival time was 9 months (95% CI 8-18 months). The most common grade 3 or 4 toxicities were diarrhea (35%) and tumor pain (12%) along with anemia, dyspnea, and fatigue (9% each).. Flavopiridol at this dose and schedule is feasible with an acceptable toxicity profile. Flavopiridol has some modest biologic activity against advanced RCC, as evidenced by its single-agent objective response and SD rates.

Topics: Adult; Aged; Antineoplastic Agents; Carcinoma, Renal Cell; Diarrhea; Drug Administration Schedule; Female; Flavonoids; Humans; Injections, Intravenous; Kidney Neoplasms; Male; Middle Aged; Pain; Piperidines; Survival Analysis; Treatment Outcome

Patients undergoing eye surgery under regional anaesthesia often require concomitant medication for analgesia and comfort. Remifentanil, with its ultra-short acting-profile, may be useful to reduce pain during retrobulbar nerve block for cataract surgery.. We performed a prospective, randomized, double-blind study to compare the efficacy of remifentanil for analgesia during retrobulbar nerve block placement. Ninety patients undergoing cataract surgery were randomly divided to receive either remifentanil 0.3 microg kg(-1) (n = 45) or an equivalent volume of saline (n = 45). The injection was administered within 30 s in both groups. Patients rated their amount of pain on a 10 cm visual analogue scale. Respiratory frequency, oxygen saturation, cardiac rhythm and postoperative nausea and vomiting (PONV) were recorded.. The mean visual analogue score in the Remifentanil group was 2.56; it was 5.51 in the Saline group (P = 0.001, U-test). Three patients developed bradycardia and three had PONV in the Remifentanil group. Two patients developed tachycardia and one had PONV in the Saline group. No patient developed respiratory depression.. In patients undergoing retrobulbar block placement for eye surgery, 0.3 microg kg(-1) remifentanil over 30 s significantly reduced their reported pain. In addition, remifentanil did not increase the risk of untoward side-effects.

Topics: Aged; Analgesics, Opioid; Cataract Extraction; Double-Blind Method; Female; Hemodynamics; Humans; Male; Monitoring, Intraoperative; Nerve Block; Pain; Pain Measurement; Piperidines; Postoperative Nausea and Vomiting; Prospective Studies; Remifentanil

Target-controlled infusions (TCIs) of remifentanil and fentanyl in conscious sedation regimes for extra-corporeal shock-wave lithotripsy have not been reported. We estimated the effect site concentrations of remifentanil and fentanyl needed to obtain adequate analgesia in 50% of patients (EC50) and compared both drugs in terms of intra- and post-procedure complications.. Forty-four adult patients were randomly distributed into two groups: Group R received remifentanil and Group F received fentanyl TCI with initial effect site concentrations of 1.5 and 2 ng mL(-1), respectively. Pain was assessed using a 10-point verbal analogue scale and <3 was considered adequate analgesia. Increments or decrements of 0.5 ng mL(-1) were then introduced for subsequent patients according to Dixon's up and down method. During the rest of the procedure, TCI was adjusted to maintain verbal analogue scale <3.. Remifentanil and fentanyl EC50 were 2.8 ng mL(-1) (95% confidence interval (CI): 1.8-3.7 ng mL(-1)) and 2.9 ng mL(-1) (95% CI: 1.7-4.1 ng mL(-1)), respectively (n.s.). At EC50, the probability of having a respiratory rate <10 was 4% (95% CI: 0-57%) for remifentanil and 56% (95% CI: 13-92%) for fentanyl. Hypoxaemia, vomiting and sedation were more frequent in Group F during and after the procedure (P < 0.05).. A similar EC50 but more respiratory depression, sedation and PONV were found with fentanyl TCI than with remifentanil TCI.

Topics: Adolescent; Adult; Analgesics, Opioid; Conscious Sedation; Drug Delivery Systems; Female; Fentanyl; Humans; Hypoxia; Infusions, Intravenous; Lithotripsy; Male; Middle Aged; Pain; Pain Measurement; Piperidines; Remifentanil; Respiratory Function Tests; Vomiting

Percutaneous transhepatic biliary drainage (PTBD) and stenting are very painful procedures in interventional radiology and require potent analgesia; employing remifentanil in spontaneously breathing patients may be one possible strategy.. The study group was composed of 18 men and 2 women with a mean age of 63+/-10 (mean+/-SD) years. Pain intensity was measured with a VAS score before the procedure, after local anesthesia on the rib cage, after stenting and after the radiology procedure.. Remifentanil infusion (dosage: 0.12-0.30 microg/kg body weight/min) was infused throughout the entire radiology procedure according to physical status, past medical history, individual pain, and clinical assessment. During insufflation of 10l O(2)/min via a venturi mask, oxygen saturation did not fall below 96% at any time-point during the procedure. In the VAS score, we noted a decrease after starting the remifentanil infusion towards the end of procedure. All patients were able to move into bed without help. Postoperatively, no analgesics and no antiemetics were needed.. Employing a remifentanil infusion for brief interventional radiology procedures in palliative treatment of patients resulted in high patient and radiologist comfort.

Topics: Adult; Aged; Aged, 80 and over; Analgesia; Analgesics, Opioid; Biliary Tract; Drainage; Female; Humans; Male; Middle Aged; Pain; Pain Measurement; Patient Satisfaction; Piperidines; Remifentanil; Stents

Topics: Adult; Aged; Analgesics, Opioid; Anesthetics, Intravenous; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Humans; Injections, Intravenous; Male; Meperidine; Middle Aged; Pain; Pain Measurement; Piperidines; Propofol; Remifentanil

Unlike propofol, the self-administration of remifentanil for sedation in gastrointestinal endoscopies has never been evaluated formally. We wanted to compare the efficacy and tolerance of patient self-administration of remifentanil vs propofol during gastrointestinal endoscopy.. This prospective randomized, single-blinded study, included 77 patients undergoing gastrointestinal endoscopy. Patients were divided into two groups: group R received remifentanil (5 microg.kg(-1).hr(-1) infusion, 25 microg boli, refractory period of five minutes) and group P received propofol (2 mg.kg(-1).hr(-1) infusion, 0.5 mg.kg(-1) boli, refractory period of ten minutes). A 1 mg.kg(-1) bolus of propofol was administered before the procedure began in cases of marked anxiety. Additional boli of 25 microg of remifentanil or 0.5 mg.kg(-1) of propofol were administered when patients complained during the refractory period. The evaluation targeted analgesic efficacy during the procedure and patient satisfaction. The degree of sedation during the procedure and the occurrence of adverse reactions were analyzed.. Patient satisfaction was high and comparable in both groups, with the number of awake and oriented patients being significantly higher in group R. Hemodynamic and respiratory tolerance was comparable in both groups, despite two episodes of desaturation in group R. The incidence of nausea was significantly higher in group R.. The self-administration of remifentanil for sedation during gastrointestinal endoscopies is as effective as the self-administration of propofol and can be offered to patients, especially when it is desirable that they remain conscious during the procedure.

Topics: Adult; Aged; Aged, 80 and over; Analgesia, Patient-Controlled; Anesthetics, Intravenous; Endoscopy, Gastrointestinal; Female; Humans; Male; Middle Aged; Pain; Pain Measurement; Piperidines; Propofol; Prospective Studies; Remifentanil; Respiration; Single-Blind Method; Time Factors; Treatment Outcome

Remifentanil, an ultra-short-acting opioid, is used as an on-top analgesic in head trauma patients during transient painful procedures, e.g. endotracheal suctioning, physiotherapy, on the intensive care unit. However, previous studies have shown that opioids may increase intracranial pressure and decrease cerebral blood flow.. The present study investigates the effect of remifentanil on mean arterial blood pressure, intracranial pressure measured with intraparenchymal or epidural probes, and on cerebral blood flow velocity assessed by transcranial Doppler flowmetry in 20 head trauma patients sedated with propofol and sufentanil. Ventilation was adjusted for a target PaCO2 of 4.7-5.1 kPa. After baseline measurements a bolus of remifentanil (0.5 microg x kg(-1) i.v.) was administrated followed by a continuous infusion of remifentanil (0.25 microg x kg(-1) x min(-1) i.v.) for 20 min.. There was no change in mean arterial blood pressure, intracranial pressure, and cerebral blood flow velocity in response to remifentanil infusion over time. Statistical analysis was performed using the Wilcoxon Signed Rank test.. These data suggest that remifentanil can be used for on-top analgesia in head trauma patients without adverse effects on cerebrovascular haemodynamics, cerebral perfusion pressure or intracranial pressure.

Topics: Analgesics, Opioid; Blood Flow Velocity; Blood Pressure; Body Temperature; Cerebrovascular Circulation; Craniocerebral Trauma; Female; Humans; Intracranial Pressure; Male; Middle Aged; Pain; Piperidines; Remifentanil; Statistics, Nonparametric; Time Factors

Topics: Analgesics, Opioid; Anesthesia, Intravenous; Anesthetics, Intravenous; Child; Child, Preschool; Humans; Pain; Piperidines; Propofol; Remifentanil

There are conflicting results concerning the pre-emptive effect of ketamine on central sensitization following surgery. The aim of this prospective, randomized, double-blind, placebo-controlled study was to assess the effect of the N-methyl-D-aspartate receptor antagonist ketamine on postoperative morphine consumption and pain score after remifentanil-based anaesthesia in adult patients scheduled for tonsillectomy.. We studied 40 adult patients undergoing elective tonsillectomy. Total intravenous anaesthesia was induced and maintained with remifentanil (0.125-1.0 microg kg(-1) min(-1)) and propofol target-controlled infusion. Patients in group K received a bolus dose of ketamine 0.5 mg kg(-1) immediately after anaesthetic induction, followed by a continuous infusion of 2 microg kg(-1) min(-1). Saline was administered in the same sequence in group S. Propofol, remifentanil, and the study drug infusions were discontinued at the end of surgery.. Intraoperative remifentanil consumption (0.57 +/- 0.18 in group K vs. 0.55 +/- 0.14 microg kg(-1) min(-1) in group S), morphine requirement in the PACU (11 +/- 3 in group K vs. 9 +/- 4 mg in group S) and in the ward (22 +/- 11 in group K vs. 25 +/- 14 mg in group S), median time to first analgesia in the ward (338 +/- 126 in group K vs. 328 +/- 144 min in group S), and VAS pain scores were comparable in both groups.. Small-dose of ketamine does not seem to be a useful adjunct to remifentanil-based anaesthesia during short, painful surgical procedures.

Topics: Adult; Analgesics; Analgesics, Opioid; Analysis of Variance; Anesthesia, Intravenous; Anesthetics, Intravenous; Double-Blind Method; Female; Humans; Ketamine; Male; Middle Aged; Morphine; Pain; Pain Measurement; Patient Satisfaction; Piperidines; Postoperative Complications; Prospective Studies; Remifentanil; Sodium Chloride; Time Factors; Tonsillectomy

Remifentanil is a short acting, potent synthetic opioid that does not accumulate after infusion or repeated bolus doses. It may be rapidly titrated to the requirements of individual patients. Titrated infusion of remifentanil may be able to provide potent analgesia required for pediatric cardiac surgery and obtund the stress response in theater whilst not having the persistent respiratory depression and sedation seen with longer acting opioids.. Twenty patients were randomized to receive a titrated infusion of remifentanil (0-1 microg x kg(-1) x min(-1)) or a standard dose of fentanyl (30 microg x kg(-1)) prebypass plus morphine (1 mg x kg(-1)) on rewarming. Blood samples for glucose and cortisol were taken at regular intervals from induction through bypass and into the first 24 h of postoperative intensive care. In addition to biochemical indicators of the stress response we recorded baseline hemodynamic parameters and any acute physiological events.. Ten patients received morphine, seven received remifentanil. There were no statistically significant differences between the two treatment groups in cortisol measurements, mean arterial pressure or heart rate recordings. In the last time period the remifentanil group had a larger rise in blood glucose concentration (baseline 3.9, rise 3 mmol x l(-1)) than the fentanyl/morphine group (baseline 4.2 rise 1.9 mmol x l(-1)), CI -4.3 to -0.2.. The only significant difference was in glucose in the postbypass time periods. Although statistically significant, this difference is insufficient evidence of increased stress in the remifentanil group. The results show that in the patients studied there was no clinically important difference between the two techniques.

Topics: Analgesics, Opioid; Blood Glucose; Blood Pressure; Cardiac Surgical Procedures; Child; Child, Preschool; Drug Combinations; Female; Fentanyl; Heart Rate; Humans; Infant; Male; Morphine; Pain; Pain, Postoperative; Piperidines; Remifentanil; Stress, Physiological

To compare the efficacy of alfentanil, remifentanil, and saline in minimizing the propofol injection pain.. Randomized, double-blind study.. University hospital.. 175 ASA physical status I and II, adult female patients undergoing minor gynecological procedures with general anesthesia.. Unpremedicated patients were randomly allocated to one of four groups. Patients received 2 mL (1 mg) of alfentanil (n=43), 2 mL of remifentanil 0.01 mg (n = 43), 2 mL of remifentanil 0.02 mg (n=45), or 2 mL of saline (n=44) 30 seconds prior to administration 5 mL of propofol 1%.. Patients were asked whether they had pain due to propofol injection. Their pain scores were evaluated with a Visual Analogue Scale. In the Postanesthesia Care Unit, frequency of postoperative nausea, vomiting, hypotension, and flushing were all determined.. The remifentanil and alfentanil groups showed significantly less frequency and severity of pain than the saline group (p <0.05). When the alfentanil group was compared with the remifentanil groups, significant differences in pain relief associated with injection of propofol (p <0.001) were noted. Remifentanil 0.02 mg relieved pain associated with injection of propofol more effectively than remifentanil 0.01 mg (p <0.001).. The remifentanil and alfentanil groups showed significantly less frequency and severity of pain than did the saline group. Remifentanil was effective in preventing propofol injection pain, and should be used at a dose of at least 0.02 mg for this purpose. Remifentanil may be an alternative drug for prevention of propofol injection pain.

Topics: Adult; Alfentanil; Anesthetics, Intravenous; Double-Blind Method; Drug Therapy, Combination; Female; Gynecologic Surgical Procedures; Humans; Injections, Intravenous; Middle Aged; Pain; Pain Measurement; Piperidines; Propofol; Remifentanil

Stapedotomy for otosclerosis presents particular anaesthesiology demands as the surgeon has to assess functional results during the operation, work with some bleeding, be ensured the collaboration of the patient, and limit the occurrence of intra- and post-operative symptoms (dizziness, nausea, vomiting and pain). Remifentanyl, a micro-opioid selective agonist characterised by short latency and duration, has been used for about 2 years at the Otolaryngological Unit of the "Federico II" University of Naples for patients with otosclerosis undergoing stapedotomy. Aim of the study was, therefore, to assess: efficacy and tolerability of Remifentanyl in combination with a local anaesthetic in surgical procedures for otosclerosis; intra- and post-operative reduction in patient symptoms of dizziness, nausea, vomiting and pain; reduction of intra-operative bleeding; degree of patient collaboration and optimisation of anaesthesiological and vital parameters monitored during surgery. The study was carried out on 92 patients with otosclerosis, (17 M, 75 F), median age 41 years (range 25-56), undergoing stapedotomy. Patients were randomly assigned to one of two groups, which were homogeneous as far as concerns age, sex and pre-operative hearing: i. Group A (50 patients), received Remifentanyl infusion in combination with canal injection for local anaesthesia with Mepivacaine 2% and Adrenalin 1/100,000; ii. Group B (42 patients), received only local anaesthetic by infiltration of the external canal ear. Remifentanyl led to an improvement over the local anaesthetic technique previously used, with a clear decrease in intra- and post-operative neurovegetative symptoms such as dizziness, nausea, vomiting and pain, as well as reduced bleeding.

Topics: Adult; Analgesics, Opioid; Dizziness; Female; Humans; Hypnotics and Sedatives; Intraoperative Complications; Male; Middle Aged; Nausea; Otosclerosis; Pain; Piperidines; Postoperative Complications; Remifentanil; Stapes Surgery; Vomiting

Cerebral blood flow is affected by painful stimuli, and analgesic agents may alter the response of cerebral blood flow to pain. We set out to quantify the effects of remifentanil and nitrous oxide on blood flow changes caused by experimental pain.. We simulated surgical pain in 10 conscious volunteers using increasing mechanical pressure to the tibia. We measured changes in cerebral blood flow velocity in the middle cerebral artery (CBFV(MCA)) caused by the pain, using transcranial Doppler sonography. We gave increasing doses of remifentanil (0.025, 0.05 and 0.1 micro g kg(-1) min(-1)) or nitrous oxide [20%, 35% and 50% end-tidal concentration (FE'(N(2)O))] and compared these effects on blood flow changes.. Nitrous oxide increased CBFV(MCA) only when given at 50% FE'(N(2)O). Remifentanil did not affect CBFV(MCA). Pain increased CBFV(MCA). Both agents attenuated this pain-induced change in CBFV(MCA) with the exception of nitrous oxide at 20% FE'(N(2)O).. Inhalation of nitrous oxide or adminstration of remifentanil attenuated pain-induced changes in CBFV(MCA).

Topics: Adolescent; Adult; Analgesics, Non-Narcotic; Analgesics, Opioid; Anesthetics, Inhalation; Blood Flow Velocity; Cerebrovascular Circulation; Humans; Infusions, Parenteral; Intraoperative Period; Male; Middle Cerebral Artery; Nitrous Oxide; Pain; Piperidines; Remifentanil; Ultrasonography, Doppler, Transcranial

Experimental pain models inducing hyperalgesia, i.e. an increased sensitivity to noxious stimuli often present in clinical pain, are important tools for studying antinociceptive drug profiles. The correct interpretation of results obtained in these models necessitates their mechanistic understanding. This study evaluated the freeze lesion, an experimental model of hyperalgesia, in humans. Twelve healthy subjects were tested with mechanical (brush, punctuated and blunt) and electrical (5, 250, and 2000 Hz sine wave current) stimuli before and after freezing the skin, and during a computer-controlled infusion of the mu-opioid agonist remifentanil targeting five different plasma concentrations between 0 and 6 ng/ml in a two-staged, single occasion, randomized, and double blind study design. Pharmacodynamic modeling techniques were used to describe the effect of freezing and drug administration on the mechanical and electrical pain thresholds. Freezing the skin resulted in hyperalgesia to blunt and punctuated stimuli and lowered the respective pain threshold by 29 and 73%. Hyperalgesia to brushing or electrical stimuli was not detected. Remifentanil attenuated hyperalgesia to blunt stimuli about twice as potently as hyperalgesia to punctuated stimuli, as indicated by a significantly steeper linear relationship between the remifentanil plasma concentration and the increase of the pain threshold to blunt stimuli. Remifentanil attenuated electrical pain with greater potency for low frequency stimulation. The potency difference of remifentanil suggests that different neuronal mechanisms mediate hyperalgesia to blunt and punctuated stimulation. Absence of brush-evoked and electrical hyperalgesia is compatible with the view that mechanical hyperalgesia to blunt and punctuated stimulation of the freeze lesion is predominantly caused by a peripheral mechanism.

Topics: Adolescent; Adult; Analgesics, Opioid; Dose-Response Relationship, Drug; Double-Blind Method; Electric Stimulation; Female; Freezing; Humans; Hyperalgesia; Male; Pain; Pain Measurement; Physical Stimulation; Piperidines; Receptors, Opioid, mu; Remifentanil; Sensory Thresholds; Skin Temperature; Time Factors; Wounds and Injuries

In a randomised, double-blind study we compared the efficacy of continuous remifentanil infusion (0.25 microg x kg(-1) x min(-1) with 40 mg lidocaine and placebo in the prevention of injection pain due to intravenous propofol administration (1.5-2 mg x kg(-1)) in 155 patients scheduled for elective surgery. Pain severity was evaluated using a four-point scale. The incidence of injection pain was 62% in the placebo group and could be reduced significantly by using remifentanil (30%; p < 0.0015) or lidocaine (33%; p < 0.005). Analysis of the pain scores showed a significant difference between remifentanil and placebo (p < 0.00005) as well as between lidocaine and placebo (p < 0.0002). There was no significant difference between remifentanil and lidocaine. Remifentanil provided effective pain relief, comparable with lidocaine, and is an alternative as part of an intravenous anaesthesia regimen to using another concomitant drug.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Analgesics, Opioid; Anesthetics, Intravenous; Anesthetics, Local; Double-Blind Method; Female; Humans; Infusions, Intravenous; Injections, Intravenous; Lidocaine; Male; Middle Aged; Pain; Pain Measurement; Piperidines; Propofol; Remifentanil

A randomised, double-blind, placebo-controlled three-way cross-over study was performed to investigate the effect of two muscle relaxants (tolperisone hydrochloride and pridinol mesilate) on experimental jaw-muscle pain and jaw-stretch reflexes. Fifteen healthy men participated in three randomised sessions separated by at least 1 week. In each session 300 mg tolperisone, 8 mg pridinol mesilate or placebo was administered orally as a single dose. One hour after drug administration 0.3 ml hypertonic saline (5.8%) was injected into the right masseter to produce muscle pain. Subjects continuously rated their perceived pain intensity on an electronic 10-cm visual analogue scale (VAS). The pressure pain threshold (PPT) was measured and short-latency reflex responses were evoked in the pre-contracted (15% maximal voluntary contraction) masseter and temporalis muscles by a standardised stretch device (1 mm displacement, 10 ms ramp time) before (baseline), 1 h after medication (post-drug), during ongoing experimental muscle pain (pain-post-drug), and 15 min after pain had vanished (post-pain). Analysis of variance demonstrated significantly lower VAS peak pain scores (5.9 +/- 0.4 cm) after administration of tolperisone hydrochloride compared with pridinol mesilate (6.8 +/- 0.4 cm) and placebo (6.6 +/- 0.4 cm) (P=0.020). Administration of pridinol mesilate was associated with a significant decrease in PPTs compared with tolperisone hydrochloride and placebo (P=0.002) after medication, but not after experimental jaw-muscle pain. The normalised peak-to-peak amplitude of the stretch reflexes were not significantly influenced by the test medication (P=0.762), but were in all sessions significantly facilitated during ongoing experimental jaw-muscle pain (P=0.034). In conclusion, tolperisone hydrochloride provides a small, albeit significant reduction in the perceived intensity of experimental jaw-muscle pain whereas the present dose had no effect on the short-latency jaw-stretch reflex.

Topics: Adult; Cross-Over Studies; Double-Blind Method; Humans; Male; Masticatory Muscles; Muscle Relaxants, Central; Pain; Pain Measurement; Pain Threshold; Piperidines; Reaction Time; Reflex, Stretch; Temporomandibular Joint Dysfunction Syndrome; Tolperisone; Trismus

We compared recovery from high-dose propofol/low-dose remifentanil ('propofol-pronounced') compared with high-dose remifentanil/low-dose propofol ('remifentanil-pronounced') anaesthesia.. Adult patients having panendoscopy, microlaryngoscopy, or tonsillectomy were randomly assigned to receive either propofol-pronounced (propofol 100 microg x kg(-1) min(-1); remifentanil 0.15 microg x kg(-1) min(-1)) or remifentanil-pronounced (propofol 50 microg x kg(-1) min(-1); remifentanil 0.45 microg x kg(-1) min(-1)) anaesthesia. In both groups, the procedure was started with remifentanil 0.4 microg x kg(-1), propofol 2 mg x kg(-1), and mivacurium 0.2 mg x kg(-1). Cardiovascular measurements and EEG bispectral index (BIS) were recorded. To maintain comparable anaesthetic depth, additional propofol (0.5 mg x kg(-1)) was given if BIS values were greater than 55 and remifentanil (0.4 microg x kg(-1)) if heart rate or arterial pressure was greater than 110% of pre-anaesthetic values.. Patient and surgical characteristics, cardiovascular measurements, and BIS values were similar in both groups. There were no differences in recovery times between the groups (time to extubation: 12.7 (4.5) vs 12.0 (3.6) min, readiness for transfer to the recovery ward: 14.4 (4.4) vs. 13.7 (3.6) min, mean (SD)).. In patients having short painful surgery, less propofol does not give faster recovery as long as the same anaesthetic level (as indicated by BIS and clinical signs) is maintained by more remifentanil. However, recovery times were less variable following remifentanil-pronounced anaesthesia suggesting a more predictable recovery.

Topics: Adolescent; Adult; Aged; Anesthesia Recovery Period; Anesthesia, Intravenous; Anesthetics, Intravenous; Blood Pressure; Female; Heart Rate; Humans; Intraoperative Care; Male; Middle Aged; Pain; Piperidines; Propofol; Prospective Studies; Remifentanil

Numerous animal studies suggest that acute and chronic exposure to opioids can be associated with the development of hyperalgesia, i.e. an increased sensitivity to noxious stimuli. Hyperalgesia has been documented during withdrawal and on occasion while animals were still exposed to opioids. A pivotal role in the genesis of opioid-associated hyperalgesia has been attributed to a pain facilitating system involving the N-methyl-D-aspartate (NMDA)-receptor. In humans little direct evidence documents opioid-associated hyperalgesia, albeit observational data suggest that such hyperalgesia may be relevant in a clinical context. This study used a double blind, randomized, crossover and placebo-controlled design to test in opioid-naïve, healthy human volunteers whether hyperalgesia would develop within 30 min of stopping a 90-min infusion with the mu-opioid agonist remifentanil, and whether co-administration of the NMDA-receptor antagonist S-ketamine would prevent such hyperalgesia. We found that a skin area with pre-existing mechanical hyperalgesia was significantly enlarged after stopping the remifentanil infusion. However, the pain response to heat assessed in regular skin was not different before and after the infusion of remifentanil. Co-administration of the NMDA-receptor antagonist S-ketamine abolished observed enlargement of the hyperalgesic skin area. This study provides direct evidence in humans that short-term administration of an opioid can enhance hyperalgesia as observed during withdrawal and points to a potential role of the NMDA-receptor system in mediating such a hyperalgesic response. This study also points to a differential susceptibility of different pain modalities for the expression of hyperalgesia associated with opioid administration.

Topics: Adult; Analgesics, Opioid; Cross-Over Studies; Excitatory Amino Acid Antagonists; Hot Temperature; Humans; Hyperalgesia; Ketamine; Pain; Physical Stimulation; Piperidines; Receptors, N-Methyl-D-Aspartate; Receptors, Opioid, mu; Remifentanil; Substance Withdrawal Syndrome

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

Opioid-induced sedation is a major complication in patients with cancer pain. This study assessed the effectiveness of donepezil in opioid-induced sedation and related symptoms in patients with cancer pain. Twenty-seven patients who were receiving strong opioids for pain and reported sedation were enrolled. Donepezil 5 mg was given every morning for 7 days. Changes between baseline and Day 7 in sedation, pain, fatigue and other symptoms were evaluated using the Edmonton Symptom Assessment Scale. Fatigue was also measured using the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue). Overall usefulness of donepezil was measured by the patient at the end of the study. In 20 evaluable patients, sedation, fatigue, anxiety, well-being, depression, anorexia and problems with sleep were significantly improved. Side effects included nausea, vomiting, diarrhea, muscle and abdominal cramps, and anorexia. Overall, however, the treatment was well tolerated. Donepezil appears to improve sedation and fatigue in patients receiving opioids for cancer pain. Randomized controlled trials of this agent are justified.

Topics: Adult; Aged; Analgesics, Opioid; Donepezil; Female; Humans; Indans; Male; Middle Aged; Neoplasms; Nootropic Agents; Pain; Pilot Projects; Piperidines; Prospective Studies; Sleep Stages

In this randomized double-blind placebo-controlled study, the analgesic effect of oral lamotrigine (400 mg) on cutaneous sensitization induced with the heat/capsaicin sensitization model was compared with the effect of oral hydromorphone (8 mg) in healthy volunteers. In a separate session, intravenous remifentanil (0.10 microg.kg(-1).min(-1)) and placebo were administered. This session was used as an additional reference comparator. Outcome measures were the areas of secondary hyperalgesia to brush and von Frey hair stimulation and the painfulness of noxious thermal stimulation in nonsensitized skin. Compared with placebo, both intravenous remifentanil and oral hydromorphone significantly suppressed secondary hyperalgesia and acute thermal nociception. Oral lamotrigine did not reduce secondary hyperalgesia or acute thermal nociception but produced side effects of severity comparable with that of oral hydromorphone. Although lamotrigine is efficacious in the management of some types of chronic neuropathic pain, the lack of effect of this agent on human experimental pain suggests that its analgesic effects depend on nerve injury-associated abnormalities, which cannot be simulated in healthy human volunteers.

Topics: Adult; Analgesics, Opioid; Anticonvulsants; Capsaicin; Double-Blind Method; Drug Therapy, Combination; Excitatory Amino Acid Antagonists; Hot Temperature; Humans; Hydromorphone; Hyperalgesia; Lamotrigine; Pain; Pain Measurement; Piperidines; Remifentanil; Triazines

It has been suggested that placebo analgesia involves both higher order cognitive networks and endogenous opioid systems. The rostral anterior cingulate cortex (rACC) and the brainstem are implicated in opioid analgesia, suggesting a similar role for these structures in placebo analgesia. Using positron emission tomography, we confirmed that both opioid and placebo analgesia are associated with increased activity in the rACC. We also observed a covariation between the activity in the rACC and the brainstem during both opioid and placebo analgesia, but not during the pain-only condition. These findings indicate a related neural mechanism in placebo and opioid analgesia.

Topics: Adult; Analgesia; Analgesics, Opioid; Brain Stem; Cerebrovascular Circulation; Gyrus Cinguli; Humans; Male; Nerve Net; Pain; Pain Measurement; Piperidines; Placebo Effect; Placebos; Receptors, Opioid; Remifentanil; Tomography, Emission-Computed

Topics: Analgesics, Opioid; Anesthetics, Intravenous; Fentanyl; Humans; Infusions, Intravenous; Pain; Pain Measurement; Piperidines; Propofol; Remifentanil

Colonoscopy is one of the most frequently performed outpatient procedures in the United States. This study was designed to test the hypothesis that a remifentanil infusion would be superior to boluses of meperidine in older patients undergoing ambulatory colonoscopy. One hundred ASA physical status I-IV patients undergoing colonoscopy were randomized in this double-blinded study to receive either remifentanil infusions (n = 49) or titrated boluses of meperidine (n = 51). Patient tolerance was assessed using physiologic variables and side effects associated with opioid analgesia. Verbal pain/anxiety and patient/operator satisfaction were also assessed. As a group, the physiologic characteristics demonstrated no significant differences in the response to the colonoscopy procedure. Although the patient and operator satisfaction surveys were similar between groups, the incidences of tachycardia, hypotension, and nausea were less and the adjusted verbal pain and anxiety scores were more in the Remifentanil group compared with the Meperidine group. This study demonstrates that remifentanil and meperidine were equally well tolerated in older patients undergoing ambulatory colonoscopy when administered by an anesthesia provider. The differences in the pharmakinetics of remifentanil and meperidine most likely account for the differences noted between the two treatment groups.. Remifentanil infusions and meperidine boluses are equally well tolerated in older patients undergoing ambulatory colonoscopy when administered by an anesthesia provider.

Topics: Adjuvants, Anesthesia; Aged; Ambulatory Care; Analgesics, Opioid; Anesthetics, Intravenous; Anxiety; Colonoscopy; Double-Blind Method; Female; Humans; Infusions, Intravenous; Injections, Intravenous; Male; Meperidine; Middle Aged; Pain; Pain Measurement; Piperidines; Remifentanil

Lanepitant selectively blocks substance P binding to the neurokinin-1 receptor, preventing neurogenic inflammation and pain transmission. Substance P is present in synovial fluid and in excess in cerebral spinal fluid. We investigated the effect of lanepitant on pain caused by osteoarthritis to evaluate the role of neurokinin-1 blockade.. Outpatients (n = 214) with moderate to severe lower-limb osteoarthritis pain were treated for 3 weeks in a parallel, randomized double-blind study with initial doses of 20, 60, 200, or 600 mg lanepitant, 375 mg naproxen, or placebo, followed by 10, 30, 100, or 300 mg lanepitant twice a day, 375 mg naproxen twice a day, or placebo twice a day in the multiple-dose period. Pain intensity, pain relief, patient global impression, and adjunctive analgesic use were compared across treatments. Safety was evaluated with adverse events, vital signs, and laboratory assessments.. There was no statistically significant difference in efficacy or safety across treatments for the initial dose assessment. After 1 week of therapy, naproxen was statistically significantly (P < .05) better than placebo and lanepitant in reducing average pain. During the second and third weeks of therapy, patients receiving naproxen continued to have statistically significantly (P < .05) less pain than those receiving placebo or lanepitant despite using significantly less adjunctive analgesic medication. There were no statistically significant differences in rates of discontinuation across treatments. Lanepitant treatment was associated with diarrhea, whereas naproxen treatment was associated with gastric discomfort. There were no clinically relevant changes in vital signs or laboratory analytes for any of the treatments.. Lanepitant was ineffective in relieving osteoarthritis pain, possibly because neurokinin-1 binding of substance P does not play a significant role in osteoarthritis pain or because lanepitant fails to adequately penetrate the blood-brain barrier to affect central pain perception.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Indoles; Male; Middle Aged; Naproxen; Neurokinin-1 Receptor Antagonists; Osteoarthritis; Pain; Pain Measurement; Piperidines

In experimental studies, drug-induced analgesia is usually assessed by cutaneous stimulation. If analgesics act differently on cutaneous and deep nociception, the results of these studies may not be entirely applicable to clinical pain involving deep structures. We tested the hypothesis that opioids have different abilities to inhibit cutaneous and muscular pain. Either the opioid remifentanil or placebo was infused in 12 healthy volunteers in a cross-over fashion. Repeated electrical stimulation (five impulses at 2 Hz) was applied to both skin and muscle. Pain thresholds were recorded. Remifentanil caused a higher increase in the muscular pain thresholds than in the cutaneous pain thresholds (P = 0.035). We conclude that opioids inhibit muscular pain more strongly than cutaneous pain in humans.

Topics: Adult; Analgesics, Opioid; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Electric Stimulation; Female; Humans; Male; Muscle, Skeletal; Organ Specificity; Pain; Pain Threshold; Piperidines; Remifentanil; Skin

To assess the incidence of adverse events in postmenopausal women treated with raloxifene compared with placebo, hormone replacement therapy (HRT), or unopposed estrogen.. Common treatment groups were pooled across eight randomized, parallel clinical trials (6-30 months' duration) of raloxifene to create the following three databases: placebo-controlled, HRT-controlled, and estrogen-controlled databases. Incidence and severity of all treatment-emergent adverse events, defined as events that first occurred or worsened during treatment, were compared among groups in each of the databases.. Discontinuation rates overall, and those related to adverse events, were not significantly different between treatment groups in any database. There was no significant difference in incidence of vaginal bleeding or breast discomfort between women treated with raloxifene (60 mg/d) or placebo. Both of these events were reported more frequently in women receiving HRT or estrogen. Vaginal bleeding was responsible for significantly more discontinuations from the HRT groups compared with the raloxifene group. Hot flashes was the only event common to all three databases that was significantly increased in the raloxifene group, but this event did not increase the discontinuation rates. The incidence of leg cramps was greater in raloxifene-treated women compared with placebo-treated women in the placebo-controlled database, but did not cause any discontinuations of therapy. Raloxifene had no effect on the incidence of vaginal symptoms or central nervous system events.. Raloxifene had an adverse event profile distinct from HRT and unopposed estrogen and was well tolerated by postmenopausal women.

Topics: Adult; Aged; Breast Diseases; Estrogen Antagonists; Estrogen Replacement Therapy; Female; Hot Flashes; Humans; Incidence; Middle Aged; Pain; Piperidines; Postmenopause; Raloxifene Hydrochloride; Uterine Hemorrhage

To test the hypothesis that remifentanil, because of its favorable pharmacokinetic properties, would be advantageous to use in combination with midazolam to provide analgesia and sedation during brief painful procedures.. Prospective observation and data collection.. University hospital.. Seventeen children aged 2 to 12 years, who underwent 20 brief, painful procedures.. Administration of intravenous midazolam hydrochloride, 0.05 mg/kg, and remifentanil hydrochloride, 1 microg/kg, followed by a remifentanil infusion at 0.1 microg x kg(-1) x min(-1). The dose was titrated at 5-minute intervals to levels of sedation and analgesia.. Successful remifentanil doses, times to discharge readiness, side effects, complications, and requirement for additional medications.. The technique was successful in 17 of 20 procedures. The mean +/- SD successful dose was 0.4 +/- 0.2 microg x kg(-1) x min(-1). Four children developed hypoxemia that abated with mild stimulation; 1 child became unresponsive and required positive-pressure ventilation. The mean +/- SD time to reach discharge criteria was 9.5 +/- 4.3 minutes. Hypoxemia was avoided in 10 of 13 patients by continuous stimulation throughout the procedure.. The use of remifentanil and midazolam during brief, painful procedures results in rapid times to discharge but is complicated by a high incidence of life-threatening respiratory depression at subtherapeutic levels.

Topics: Analgesics, Opioid; Biopsy; Bone Marrow Examination; Child; Child, Preschool; Conscious Sedation; Drug Therapy, Combination; Female; Fracture Fixation; Humans; Hypnotics and Sedatives; Infant; Infusions, Intravenous; Male; Midazolam; Pain; Piperidines; Prospective Studies; Remifentanil; Statistics, Nonparametric

Transvaginal puncture for oocyte retrieval is a short-lasting but painful procedure. We hypothesized that a sole infusion of the ultra-short acting mu-agonist remifentanil may be a suitable and well-controllable single-agent analgesic technique that can dose-dependently be applied to spontaneously breathing patients.. Fifty consenting adult women were enrolled in this prospective trial. A sedative premedication was omitted, all patients received 3 L/min of inhaled oxygen, and a sole remifentanil infusion was started with 0.25 microg/kg/min. Remifentanil was adjusted as needed for pain relief (in steps of 0.05 microg/kg/min) and finished after the last puncture. Dosage requirements, vital functions, oxygen saturation (as achieved by pulse oximetry, psO(2)), adverse drug effects and the level of sedation (LOS 1-5; 1 = asleep/unarousable, 4 = calm/awake) were recorded. Remifentanil plasma concentrations were achieved by STANPUMP pharmacokinetic simulation. Data are presented as mean +/- SD.. A total of 50 women (31.8 +/- 5.1 yr, 67.3 +/- 14. ASA I or II ) were investigated. Follicular aspiration lasted 10.8+/-5.2 min, and remifentanil was infused for 19.7+/-8.3 min. Dosage requirements were 0.25 microg/kg/min in 70% of all patients, 0.3 microg/kg/min in 22%, 0.2 microg/kg/min in 6%, and 0.4 microg/kg/min in 2% of all cases. Vital signs (baseline, after 1(st) puncture, end of surgery) nearly remained unchanged: heart frequency = 85 +/- 15, 87 +/- 17, 90 +/- 17 bpm, systolic blood pressure = 129 +/- 12, 132 +/- 13, 131 +/- 14 mmHg; respiratory rate = 116 +/- 4, 15 +/- 4 breaths/min; psO(2) = 99 +/- 1, 99 +/- 1, 99 +/- 2%. LOS was 4.0 (all), 3.9 +/- 0.3, 3.9 +/- 0.3. Remifentanil plasma concentrations were 5.0 +/- 1.3 ng/mL at the start, 6.6 +/- 1.3 at the end of surgery and 1.2 +/- 0.5 at PACU arrival. Adverse drug effects: 54% itching, no muscle rigidity. 94% of all women would choose this technique again.. The sole infusion of remifentanil is a suitable and satisfying single-agent monitored anaesthesia care technique for oocyte retrieval. However, close anaesthetic observation - especially of the respiratory function - is mandatory.

Topics: Adult; Analgesics, Opioid; Female; Fertilization in Vitro; Humans; Infusions, Intravenous; Oocyte Donation; Pain; Piperidines; Prospective Studies; Remifentanil; Respiratory Function Tests

We performed a prospective, randomized study comparing the efficacy and safety of remifentanil, propofol or both for conscious sedation during eye surgery under retrobulbar blockade. Forty-five unpremedicated patients were assigned to receive remifentanil (group R) (n = 15, mean dosage: 0.05 +/- 0.03 microgram kg-1 min-1), propofol (group P) (n = 15, 1.5 +/- 0.5 mg kg-1 h-1) or a combination (group RP) (n = 15, R: 0.03 +/- 0.01 microgram kg-1 min-1; P: 0.7 +/- 0.2 mg kg-1 h-1). Haemodynamic responses were comparable among all groups. Minimum values for respiratory rate were lower in R patients (R: 7 vs. P and RP: 10 breaths min-1). Perioperative blood gas analysis showed differences in maximum carbon dioxide tensions (R: 51.5 vs. P: 48.3 vs. RP: 45.5 mmHg) and decrease in minimum pH values (R: -0.06 vs. P: -0.0 vs. RP: -0.01). All group P patients reported mild to intense pain during retrobulbar block, while 53% of the group R patients were free from pain. In group RP, 60% of patients experienced no pain and the remaining 40% reported mild pain only. Remifentanil, applied as the sole agent, provided superior pain relief and patient comfort when compared with propofol, but produced greater respiratory depression and postoperative nausea. The combination of remifentanil and propofol provided haemodynamic stability, adequate spontaneous respiration and pain relief, with a low risk of untoward side effects.

Topics: Adult; Aged; Anesthesia, Conduction; Anesthetics, Intravenous; Conscious Sedation; Female; Hemodynamics; Humans; Male; Middle Aged; Ophthalmologic Surgical Procedures; Oxygen; Pain; Pain Measurement; Piperidines; Propofol; Prospective Studies; Remifentanil; Respiratory Mechanics

A-3665 is a new short-acting synthetic opioid of the piperidine class. We conducted a double-blind, escalating dose comparison of A-3665 to alfentanil and placebo. Analgesic efficacy was assessed after the administration of A-3665 in increasing intravenous doses (0.25, 0.5, 1, 2, 4, 8, 16, 32, and 64 micrograms/kg) to nine groups of volunteers. At the lower doses (0.25, 0.5, 1, and 2 micrograms/kg), five volunteers were in each group; four received A-3665 and one received placebo in a double-blind manner. There were nine volunteers in each of the next three groups; four received A-3665 (4, 8, or 16 micrograms/kg), four received alfentanil (4, 8, or 16 micrograms/kg), and one received placebo. At the 32 micrograms/kg and 64 micrograms/kg dose levels, five subjects each were to be enrolled (four to receive A-3665 and one to receive placebo); however, the study was terminated after two subjects in the 64 micrograms/kg group had significant respiratory depression. Both drugs caused potent analgesia, compared with placebo, with peak effect occurring 3 min after injection. There was no significant difference in analgesic potency of A-3665 and alfentanil as measured by tolerance to tibial pressure at 3 min. At the dose of 16 micrograms/kg, both drugs significantly increased pain tolerance to tibial pressure compared with placebo at 3 min, but alfentanil continued to display significant analgesic effect versus placebo and versus A-3665 at 6, 11, and 15 min after injection. A-3665 caused significant respiratory depression at doses of 32 micrograms/kg and 64 micrograms/kg, but alfentanil did not induce significant respiratory depression at the doses tested.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Adult; Alfentanil; Analgesics; Carbon Dioxide; Cardiovascular System; Dose-Response Relationship, Drug; Double-Blind Method; Histamine; Humans; Oxygen; Pain; Partial Pressure; Piperidines; Respiration; Tetrazoles

A comparative, randomized, double-blind study of diclofenac sodium 75 mg im versus Baralgin (a combination drug composed of dipyrone and two spasmolytics) 5 mL iv was performed on 57 patients with renal colic. Both groups were comparable as to age, sex, pain evolution time before treatment, and no treatment for renal colic in the six hours preceding trial drug administration. No significant differences were found between the two groups with respect to the evolution of pain after the first dose or in the frequency of administration of a second dose. Tolerability was good in both groups, but sweating and pain throughout the vein were observed in one patient in the Baralgin group. We concluded that diclofenac sodium constitutes an excellent alternative to pyrazolone analgesics, with the advantages of being monotherapy and having good tolerability, when used as intramuscular injection in ambulatory patients.

Topics: Adult; Aminopyrine; Benzophenones; Blood Pressure; Colic; Diclofenac; Dipyrone; Double-Blind Method; Drug Combinations; Female; Humans; Injections, Intramuscular; Injections, Intravenous; Kidney Diseases; Male; Middle Aged; Pain; Parasympatholytics; Piperidines; Randomized Controlled Trials as Topic

In a randomized, double-blind, placebo-controlled study, 32 patients with nonulcer dyspepsia received 5 mg of cisapride or placebo three times daily for four weeks after a two-week run-in phase on placebo. Limited antacid use was allowed. Cisapride was superior to placebo in reducing the intensity of epigastric pain at two weeks (P = 0.03) and four weeks (P = 0.01). At the end of treatment, 82% of the cisapride-treated patients and 43% of the controls had no or only mild pain. Minor, gastrointestinal side effects were observed in two cisapride-treated patients and in one control.

Topics: Adult; Antacids; Cisapride; Clinical Trials as Topic; Double-Blind Method; Dyspepsia; Female; Humans; Male; Pain; Piperidines; Random Allocation; Serotonin Antagonists; Time Factors

A randomised multicentre double-blind study was conducted to compare the efficacy and safety of roxatidine acetate 75 mg twice daily and ranitidine 150 mg twice daily in 295 patients with endoscopically confirmed gastric ulcers. Substantial reductions in ulcer diameters and healing rates of 85.6 and 88.2% for roxatidine acetate and ranitidine, respectively, were obtained after 8 weeks of treatment. There was no difference in healing rates between smokers and non-smokers in either group. The relief of day and night-time epigastric pain was comparable for both treatment groups, as was antacid tablet consumption, with the majority of patients pain-free at the end of the study. The incidence of side effects was low, with 3 patients treated with roxatidine acetate, compared with 4 ranitidine-treated patients, reporting adverse reactions. There were no clinically significant changes in laboratory values. The present study suggests that 8 weeks of treatment with roxatidine acetate 75 mg twice a day produces effective and safe acute management of gastric ulcers which is comparable to that seen with ranitidine.

Topics: Adolescent; Adult; Aged; Female; Histamine H2 Antagonists; Humans; Male; Middle Aged; Pain; Piperidines; Ranitidine; Stomach Ulcer

Topics: Acute Disease; Adult; Aged; Clinical Trials as Topic; Double-Blind Method; Female; Humans; Ketanserin; Male; Middle Aged; Pain; Piperidines; Random Allocation; Serotonin Antagonists; Thrombophlebitis

An evaluation was carried out of the effect of domperidone on gastro-intestinal symptoms in patients with irritable bowel syndrome. Ninety-eight patients were included; 32 in an open pilot study and 66 in a double-blind placebo-controlled study. Domperidone was taken at a dosage of 10 mg tablets 4-times daily. At the end of the 4-week treatment, symptoms had disappeared or were at least markedly improved in about 80% of the domperidone-treated patients. Significant superiority of domperidone to the placebo was observed for the symptom clusters 'post-prandial flatulence', 'abdominal pain' and 'abnormal bowel habit'. No side-effects were reported.

Topics: Abdomen; Adult; Aged; Benzimidazoles; Clinical Trials as Topic; Colonic Diseases, Functional; Defecation; Domperidone; Double-Blind Method; Female; Flatulence; Humans; Male; Middle Aged; Pain; Pilot Projects; Piperidines; Placebos

Topics: Aminopyrine; Clinical Trials as Topic; Dipyrone; Drug Combinations; Drug Evaluation; Humans; Muscle Cramp; Pain; Piperidines; Spinal Diseases

Topics: Adolescent; Adult; Aged; Chronic Disease; Clinical Trials as Topic; Colitis, Ulcerative; Diarrhea; Dimethylamines; Female; Gastrointestinal Agents; Humans; Male; Middle Aged; Pain; Piperidines; Placebos

Topics: Administration, Oral; Amides; Analgesics; Analysis of Variance; Aspirin; Caffeine; Clinical Trials as Topic; Codeine; Differential Threshold; Drug Evaluation; Electric Stimulation; Fumarates; Humans; Pain; Phenacetin; Phenobarbital; Piperidines; Placebos; Propionates; Pyridines; Toothache

Topics: Analgesics; Benzimidazoles; Clinical Trials as Topic; Dextromoramide; Female; Humans; Male; Middle Aged; Pain; Pentazocine; Piperidines; Postoperative Complications

Topics: Adolescent; Adult; Aged; Blood Pressure; Cholecystectomy; Female; Humans; Isonipecotic Acids; Male; Meperidine; Middle Aged; Morphinans; Nausea; Nitriles; Pain; Piperidines; Pulse; Respiration; Vomiting

Topics: Adolescent; Child; Child, Preschool; Clinical Trials as Topic; Gastrointestinal Diseases; Humans; Infant; Pain; Parasympatholytics; Piperidines; Recurrence; Vomiting

Topics: Adult; Animals; Colic; Dioxolanes; Dose-Response Relationship, Drug; Drug Evaluation; Female; Humans; Kidney Calculi; Male; Pain; Parasympatholytics; Piperidines; Rats; Spasm; Suppositories; Time Factors

Topics: Administration, Oral; Aged; Analgesics; Animals; Chemistry, Organic; Chronic Disease; Dogs; Humans; Male; Middle Aged; Organic Chemistry Phenomena; Pain; Piperidines; Placebos; Rats; Rats, Inbred Strains

Topics: Adult; Analgesics; Benzimidazoles; Clinical Trials as Topic; Dextromoramide; Female; Humans; Intervertebral Disc Displacement; Laminectomy; Male; Middle Aged; Pain; Piperidines; Postoperative Care; Respiration

Topics: Aminopyrine; Analgesics; Clinical Trials as Topic; Humans; Morphine; Pain; Piperidines; Postoperative Care

Topics: Adult; Analgesia; Analgesics; Animals; Chemical Phenomena; Chemistry; Dogs; Female; Guinea Pigs; Humans; Lethal Dose 50; Male; Mice; Middle Aged; Pain; Piperidines; Placebos; Rats; Time Factors

Topics: Analgesics; Animals; Benzimidazoles; Clinical Trials as Topic; Female; Humans; Mice; Pain; Piperidines; Rats

Topics: Aminopyrine; Analgesics; Barbiturates; Chlordiazepoxide; Female; Humans; Imidazoles; Italy; Ketones; Male; Pain; Perphenazine; Piperidines; Placebos; Postoperative Complications; Rural Population; Surgical Procedures, Operative; Urban Population

The safety of anaesthesia has improved as a result of better control of anaesthetic depth. However, conventional monitoring does not inform on the nature of nociceptive processes during unconsciousness. A means of inferring the quality of potentially painful experiences could derive from analysis of brain activity using neuroimaging. We have evaluated the dose effects of remifentanil on brain response to noxious stimuli during deep sedation and spontaneous breathing.. Optimal data were obtained in 26 healthy subjects. Pressure stimulation that proved to be moderately painful before the experiment was applied to the thumbnail. Functional MRI was acquired in 4-min periods at low (0.5 ng ml. At low remifentanil doses, we observed partial activation in brain areas processing sensory-discriminative and emotional-affective aspects of pain. At medium doses, relevant changes were identified in structures highly sensitive to general brain arousal, including the brainstem, cerebellum, thalamus, auditory and visual cortices, and the frontal lobe. At high doses, no significant activation was observed.. The response to moderately intense focal pressure in pain-related brain networks is effectively eliminated with safe remifentanil doses. However, the safety margin in deep sedation-analgesia would be narrowed in minimising not only nociceptive responses, but also arousal-related biological stress.

Topics: Anesthetics, Intravenous; Brain; Electroencephalography; Humans; Pain; Piperidines; Propofol; Remifentanil; Unconsciousness

Whether pinocembrin (PCN) could be used to alleviate hip fracture-induced pain is investigated in this research. Aged rats with hip fractures were treated with vehicle or 80 mg/kg/day PCN from

Topics: Aging; Animals; Disease Models, Animal; Flavanones; Hip Fractures; Indoles; Male; Neurokinin-1 Receptor Antagonists; Nociceptive Pain; Pain; Piperidines; Rats; Rats, Sprague-Dawley; Signal Transduction; Substance P

There is evidence for the involvement of peroxisome proliferator-activated receptors (PPARs) in pain, cognition, and anxiety. However, their role in pain-fear interactions is unknown. The amygdala plays a key role in pain, conditioned fear, and fear-conditioned analgesia (FCA). We investigated the effects of intra-basolateral amygdala (BLA) administration of PPARα, PPARβ/δ, and PPARγ antagonists on nociceptive behaviour, FCA, and conditioned fear in the presence or absence of nociceptive tone. Male Sprague-Dawley (SD) rats received footshock (FC) or no footshock (NFC) in a conditioning arena. Twenty-three and a half hours later, rats received an intraplantar injection of formalin or saline and, 15 min later, intra-BLA microinjections of vehicle, PPARα (GW6471) PPARβ/δ (GSK0660), or PPARγ (GW9662) antagonists before arena re-exposure. Pain and fear-related behaviour were assessed, and neurotransmitters/endocannabinoids measured post-mortem. Intra-BLA administration of PPARα or PPARγ antagonists potentiated freezing in the presence of nociceptive tone. Blockade of all PPAR subtypes in the BLA increased freezing and BLA dopamine levels in NFC rats in the absence of nociceptive tone. Administration of intra-BLA PPARα and PPARγ antagonists increased levels of dopamine in the BLA compared with the vehicle-treated counterparts. In conclusion, PPARα and PPARγ in the BLA play a role in the expression or extinction of conditioned fear in the presence or absence of nociceptive tone.

Topics: Analgesia; Animals; Basolateral Nuclear Complex; Conditioning, Psychological; Fear; Formaldehyde; Male; Nociception; Pain; Peroxisome Proliferator-Activated Receptors; Piperidines; Rats; Rats, Sprague-Dawley

Pain is influenced by various factors, such as fear, anxiety, and memory. We previously reported that pain-like behaviors in mice can be induced by environmental cues in which a pain stimulus was previously presented, and that pain was reduced using fentanyl (an opioid). Although opioid analgesics are currently used to treat persistent pain, their inappropriate use causes a significant number of deaths in the United States. Thus, alternative medicines to opioids are needed. Here, we reported that SR 57227A, a serotonin type-3 receptor agonist, significantly reduced pain-like behaviors. The number of c-Fos positive cells increased by environmental cues in PFC was decreased by SR 57227A. Moreover, SR 57227A reduced pain-like behaviors of the formalin test, and restored reductions in paw withdrawal thresholds by acidic saline intramuscular injection and sciatic nerve ligation. Unlike opioids, SR 57227A induced no preference behaviors as measured by the conditioned place preference test. These data suggested that SR 57227A is an effective alternative pain reliever to opioids that targets chronic pain.

Topics: Analgesics; Analgesics, Opioid; Animals; Mice; Pain; Piperidines; Rats; Rats, Sprague-Dawley; Serotonin; Serotonin Receptor Agonists

Nano-carbon is often used as a tracer in thyroidectomy, to improve the accuracy of the operation. Remifentanil is the most commonly used anesthetic during thyroidectomy, but the use of remifentanil can sometimes cause patients with anesthesia hyperalgesia. Therefore, auxiliary anesthetics are often used in surgery to prevent remifentanil from causing anesthesia hyperalgesia. The purpose of this article is to explore the specific application effect of the fusion agent of hydromorphone and parecoxib sodium after thyroidectomy based on nano-carbon in the prevention of remifentanil-induced anesthesia hyperalgesia. Taking 60 patients who underwent thyroidectomy based on carbon nanotechnology in our hospital as the research object, the patients were divided into the parecoxib sodium group, hydromorphone control group and hydromorphone and parecoxib sodium fusion agent group. All patients were injected with remifentanil before surgery for general paralysis. Ten minutes before the end of the operation, the parecoxib sodium group was injected with quantitative parecoxib sodium, and the hydromorphone control group was injected with quantitative hydromorphone, hydromorphone and the parecoxib sodium fusion medicament group was injected with a quantitative combination of parecoxib sodium and hydromorphone. The patient's comfort, calmness, pain, adverse reactions and recovery time of consciousness were counted. The results of the study showed that the sedation score of the hydromorphone and parecoxib sodium fusion drug group was (15.8±1.5), the pain degree score was (1.9±0.5), lower than the other two groups, and the postoperative recovery time was (38±5.0) )min, lower than the other two groups. It can be seen that the use of a fusion agent of hydromorphone and parecoxib sodium after thyroidectomy based on nano-carbon is effective in preventing and reducing remifentanil-induced anesthesia hyperalgesia.

Topics: Analgesics, Opioid; Anesthesia; Humans; Hydromorphone; Hyperalgesia; Isoxazoles; Pain; Piperidines; Remifentanil; Thyroidectomy

Significant individual differences have been observed in pain sensitivity and analgesic effect of opioids. Previous studies have shown that genetic factors contributed to analgesics requirement obviously. Therefore, we investigated the role of genetic polymorphisms in the sensitivity to the analgesic effect of remifentanil in this study.. One hundred thirty-seven patients undergoing gynaecological surgery were observed. Before procedures, we measured the basal pain threshold of each patient, including the pressure pain threshold and pressure pain tolerance threshold. Subsequently, patients received a continuous remifentanil infusion for 15 min at a constant rate of 0.2 μg/(kg min). The pain thresholds were measured again after the remifentanil infusion. Moreover, respiratory depression was estimated using oxygen saturation during infusion. DNA was extracted from peripheral venous blood and genotyped using SNaPshot technology.. Polymorphisms were found in genes associated with the individual variation in analgesia. Participants carrying OPRM1 rs9397685 AA, ADRB1 rs1801253 CC, and GCH1 rs8007267 CC polymorphisms showed higher sensitivity to analgesic effect induced by remifentanil, and the participants carrying the OPRD1 rs2234918 TT showed lower sensitivity to remifentanil-related respiratory depression. Moreover, individual susceptibility to remifentanil increases with age.. Gene variation in OPRM1 rs9397685 AA, ADRB1 rs1801253 CC, GCH1 rs8007267 CC, and OPRD1 rs2234918 TT were related to the conspicuous interindividual differences in the analgesia and respiratory depression of remifentanil, mainly by affecting the target protein receptors and relative metabolic enzymes.

Topics: Analgesics, Opioid; China; Female; Humans; Pain; Piperidines; Remifentanil; Respiratory Insufficiency

The sigma 1 receptor is a multifunctional receptor with wide distribution in the nervous system and its function has been implicated with a number of neurological disorders including dementia and Alzheimer's disease (AD) and other neurodegenerative disorders. In addition, modulators of σ1 have been advanced into clinical trials for the treatment of pain. Starting from our previously disclosed piperidine scaffold, we have identified a class of potent sigma 1 modulators. This work highlights the key SAR components that lead to the divergence in D

Topics: Alzheimer Disease; Animals; Dopamine; Ligands; Pain; Piperidines; Receptors, sigma

Seven new hydrazinyl thiazole derivatives of piperidin-4-one (PE3-PE9) have been synthesized by cyclization of intermediate thiosemicarbazone derivative (PE2). Parent molecule (PE1) was synthesized by one pot total synthesis using Mannich condensation reaction. Percent yield of most of the compounds found in between 70-85%. Compounds were identified by spectroscopic analysis. In vivo analgesic activity was examined using tail flick method. One-way ANOVA was used to compare the mean latency time of synthesized derivatives with control and standard. Analgesic activity was discussed in terms of structural differences between compounds. Among allthe derivatives thiosemicarbazone derivative showed good analgesic activity (195.24%). Methoxy (-OCH3) and bromo (-Br) containing thiazole derivative also showed good pain reducing property (167.62%, 203%) at a dose of 30mg/kg.

Topics: Analgesics; Animals; Molecular Structure; Pain; Piperidines; Structure-Activity Relationship; Thiazoles

The present study has explored the hypothesis that neurokinin1 receptors (NK1Rs) in medial septum (MS) modulate nociception evoked on hind paw injection of formalin. Indeed, the NK1Rs in MS are localized on cholinergic neurons which have been implicated in nociception. In anaesthetized rat, microinjection of L-733,060, an antagonist at NK1Rs, into MS antagonized the suppression of CA1 population spike (PS) evoked on peripheral injection of formalin or on intraseptal microinjection of substance P (SP), an agonist at NK1Rs. The CA1 PS reflects the synaptic excitability of pyramidal cells in the region. Furthermore, microinjection of L-733,060 into MS, but not LS, attenuated formalin-induced theta activation in both anaesthetized and awake rat, where theta reflects an oscillatory information processing by hippocampal neurons. The effects of L-733,060 on microinjection into MS were nociceptive selective as the antagonist did not block septo-hippocampal response to direct MS stimulation by the cholinergic receptor agonist, carbachol, in anaesthetized animal or on exploration in awake animal. Interestingly, microinjection of L-733,060 into both MS and LS attenuated formalin-induced nociceptive flinches. Collectively, the foregoing novel findings highlight that transmission at NK1R provide an affective valence to septo-hippocampal information processing and that peptidergic transmission in the septum modulates nociceptive behaviours.

Topics: Animals; Disinfectants; Formaldehyde; Hippocampus; Inflammation; Male; Nociception; Pain; Piperidines; Prosencephalon; Rats; Rats, Sprague-Dawley; Receptors, Neurokinin-1; Septal Nuclei

Ampreloxetine is a novel norepinephrine reuptake inhibitor in development for the treatment of symptomatic neurogenic orthostatic hypotension. The objectives of this analysis were to define the pharmacokinetics of once-daily oral ampreloxetine and provide dose recommendations for clinical development.. We fitted a population pharmacokinetic model to ampreloxetine plasma concentrations from single- and multiple-ascending dose trials in healthy subjects and two phase II studies in adult subjects with attention-deficit/hyperactive disorder or fibromyalgia at doses of 2-50 mg.. Ampreloxetine pharmacokinetics was best described by a two-compartment model with first-order absorption and elimination. The terminal half-life was 30-40 h, resulting in sustained drug concentrations for the entire 24-h dosing interval at steady state. Covariates of age, weight, or renal impairment did not impact ampreloxetine exposure. Cytochrome P450 2D6 phenotype had no influence on ampreloxetine exposure. Sex and smoking status were identified as statistically significant covariates, suggesting a role for cytochrome P450 1A2 in the elimination of ampreloxetine. Despite statistical significance, differences in ampreloxetine exposure in male vs female subjects and smokers vs non-smokers were not clinically meaningful at the recommended dose. At the 10-mg dose, > 75% norepinephrine transporter inhibition and < 50% serotonin transporter inhibition are anticipated for adult subjects.. The population pharmacokinetic model effectively described the plasma concentration-time profile of ampreloxetine after single and multiple doses. Population pharmacokinetic/pharmacodynamic analysis justified using a fixed dosing regimen with no dose adjustments across a broad population and can be used to inform dosing strategies in future clinical studies.. ClinicalTrials.gov identifier numbers NCT01693692 (fibromyalgia); NCT01458340 (attention-deficit/hyperactive disorder).

Topics: Adult; Attention Deficit Disorder with Hyperactivity; Case-Control Studies; Female; Fibromyalgia; Humans; Male; Norepinephrine; Pain; Phenyl Ethers; Piperidines

To review the pharmacology, pharmacokinetics, efficacy, safety, and place in therapy of rimegepant for treatment of migraine.. A comprehensive PubMed and Cochrane search (1985 to May 2020) was performed utilizing the keywords. All English-language trials evaluating oral rimegepant were included for this review.. Rimegepant orally disintegrating tablet (ODT) is Food and Drug Administration approved for the treatment of migraine. According to data from 3 phase 3 randomized controlled trials, rimegepant has been shown to significantly improve freedom from pain at 2 hours after the dose and freedom from the most bothersome symptom 2 hours postdose. Additional outcomes improved include freedom from photophobia and phonophobia at 2 hours postdose and pain relief 2 hours after the dose. Adverse effects of rimegepant include nausea, urinary tract infection, and dizziness.. Orally disintegrating rimegepant provides a novel mechanism of action for the treatment of acute migraine. When patients experience inadequate relief from other therapies, have contraindications to triptans, or are unable to tolerate the adverse effects of triptans, rimegepant is a promising therapeutic option.. Rimegepant ODT is an efficacious migraine treatment option with a novel mechanism of action, convenient dosage form, and limited adverse effect profile.

Topics: Acute Disease; Administration, Oral; Calcitonin Gene-Related Peptide; Calcitonin Gene-Related Peptide Receptor Antagonists; Clinical Trials as Topic; Humans; Migraine Disorders; Nausea; Pain; Pain Management; Piperidines; Pyridines; Solubility; Tablets; Treatment Outcome

Topics: Adenine; Aged; Blood Cell Count; Central Nervous System Neoplasms; Cerebrospinal Fluid; Diagnosis, Differential; Eye Diseases; Eye Pain; Humans; Magnetic Resonance Imaging; Male; Optic Disk; Optic Nerve; Pain; Piperidines; Tomography, X-Ray Computed; Vision Disorders; Waldenstrom Macroglobulinemia

T-type voltage-gated calcium channels are an emerging therapeutic target for neurological disorders including epilepsy and pain. Inhibition of T-type channels reduces the excitability of peripheral nociceptive sensory neurons and reverses pain hypersensitivity in male rodent pain models. However, administration of peripherally restricted T-type antagonists failed to show efficacy in multiple clinical and preclinical pain trials, suggesting that inhibition of peripheral T-type channels alone may be insufficient for pain relief.. We utilized the selective and CNS-penetrant T-type channel antagonist, Z944, in electrophysiological, calcium imaging and behavioural paradigms to determine its effect on lamina I neuron excitability and inflammatory pain behaviours.. Voltage-clamp recordings from lamina I spinal neurons of adult rats revealed that approximately 80% of neurons possess a low threshold T-type current, which was blocked by Z944. Due to this highly prevalent T-type current, Z944 potently blocked action-potential evoked somatic and dendritic calcium transients in lamina I neurons. Moreover, application of Z944 to spinal cord slices attenuated action potential firing rates in over half of laminae I/II neurons. Finally, we found that intraperitoneal injection of Z944 (1-10 mg·kg. T-type calcium channels critically shape the excitability of lamina I pain processing neurons and inhibition of these channels by the clinical stage antagonist Z944 potently reverses pain hypersensitivity across sexes.

Topics: Animals; Calcium Channel Blockers; Calcium Channels, T-Type; Female; Male; Pain; Piperidines; Rats; Spinal Cord Dorsal Horn

Pain is a core domain of psoriatic arthritis (PsA). This post hoc analysis evaluated time to pain improvement and the impact of baseline pain severity on pain response in patients with PsA receiving tofacitinib.. Data from two trials (NCT01877668; NCT01882439) in patients receiving tofacitinib 5 mg twice daily, placebo switching to tofacitinib 5 mg twice daily at month 3 (placebo-to-tofacitinib) or adalimumab (NCT01877668 only) were included. Improvement in pain (≥30%/≥50% decrease from baseline in Visual Analogue Scale pain score) was assessed; median time to initial (first post-baseline visit)/continued (first two consecutive post-baseline visits) pain improvement was estimated (Kaplan-Meier) for all treatment arms. A parametric model was used to determine the relationship between baseline pain severity and time to pain response in patients receiving tofacitinib.. At month 3, more patients experienced pain improvements with tofacitinib/adalimumab versus placebo. Median days (95% CI) to initial/continued pain improvements of ≥30% and ≥50%, respectively, were 55 (29-57)/60 (57-85) and 85 (57-92)/171 (90-not estimable (NE)) for tofacitinib, versus 106 (64-115)/126 (113-173) and 169 (120-189)/NE (247-NE) for placebo-to-tofacitinib. Pain improvements were also experienced more quickly for adalimumab versus placebo. Predicted time to ≥30%/≥50% pain improvement was shorter in patients with higher baseline pain versus lower baseline pain (tofacitinib arm only).. In patients with PsA, pain improvements were experienced by more patients, and more rapidly, with tofacitinib and adalimumab versus placebo. In those receiving tofacitinib, higher baseline pain was associated with faster pain improvements.

Topics: Antirheumatic Agents; Arthritis, Psoriatic; Humans; Pain; Piperidines; Pyrimidines; Treatment Outcome

Stress contributes to major depressive disorder (MDD) and chronic pain, which affect a significant portion of the global population, but researchers have not clearly determined how these conditions are initiated or amplified by stress. The chronic social defeat stress (CSDS) model is a mouse model of psychosocial stress that exhibits depressive-like behavior and chronic pain. We hypothesized that metabotropic glutamate receptor 5 (mGluR5) expressed in the nucleus accumbens (NAc) normalizes the depressive-like behaviors and pain following CSDS. Here, we show that CSDS induced both pain and social avoidance and that the level of mGluR5 decreased in susceptible mice. Overexpression of mGluR5 in the NAc shell and core prevented the development of depressive-like behaviors and pain in susceptible mice, respectively. Conversely, depression-like behaviors and pain were exacerbated in mice with mGluR5 knockdown in the NAc shell and core, respectively, compared to control mice subjected to 3 days of social defeat stress. Furthermore, (RS)-2-chloro-5-hydroxyphenylglycine (CHPG), an mGluR5 agonist, reversed the reduction in the level of the endocannabinoid (eCB) 2-arachidonoylglycerol (2-AG) in the NAc of susceptible mice, an effect that was blocked by 3-((2-methyl-1, 3-thiazol-4-yl) ethynyl) pyridine hydrochloride (MTEP), an mGluR5 antagonist. In addition, the injection of CHPG into the NAc shell and core normalized depressive-like behaviors and pain, respectively, and these effects were inhibited by AM251, a cannabinoid type 1 receptor (CB1R) antagonist. Based on these results, mGluR5-mediated eCB production in the NAc relieves stress-induced depressive-like behaviors and pain.

Topics: Animals; Cannabinoid Receptor Antagonists; Chronic Disease; Depressive Disorder, Major; Endocannabinoids; Male; Mice; Mice, Inbred C57BL; Microinjections; Nucleus Accumbens; Pain; Piperidines; Pyrazoles; Pyridines; Receptor, Metabotropic Glutamate 5; Signal Transduction; Social Defeat; Stress, Psychological; Thiazoles

Medications that improve pain threshold can be useful in the pharmacotherapy of Parkinson's disease (PD). Pain is a prevalent PD's non-motor symptom with a higher prevalence of analgesic drugs prescription for patients. However, specific therapy for PD-related pain are not available. Since the endocannabinoid system is expressed extensively in different levels of pain pathway, drugs designed to target this system have promising therapeutic potential in the modulation of pain. Thus, we examined the effects of the 6-hydroxydopamine- induced PD on nociceptive responses of mice and the influence of cannabidiol (CBD) on 6-hydroxydopamine-induced nociception. Further, we investigated the pathway involved in the analgesic effect of the CBD through the co-administration with a fatty acid amide hydrolase (FAAH) inhibitor, increasing the endogenous anandamide levels, and possible targets from anandamide, i.e., the cannabinoid receptors subtype 1 and 2 (CB1 and CB2) and the transient receptor potential vanilloid type 1 (TRPV1). We report that 6-hydroxydopamine- induced parkinsonism decreases the thermal and mechanical nociceptive threshold, whereas CBD (acute and chronic treatment) reduces this hyperalgesia and allodynia evoked by 6-hydroxydopamine. Moreover, ineffective doses of either FAAH inhibitor or TRPV1 receptor antagonist potentialized the CBD-evoked antinociception while an inverse agonist of the CB1 and CB2 receptor prevented the antinociceptive effect of the CBD. Altogether, these results indicate that CBD can be a useful drug to prevent the parkinsonism-induced nociceptive threshold reduction. They also suggest that CB1 and TRPV1 receptors are important for CBD-induced analgesia and that CBD could produce these analgesic effects increasing endogenous anandamide levels.

Topics: Amidohydrolases; Analgesics; Animals; Benzamides; Brain; Cannabidiol; Capsaicin; Carbamates; Celecoxib; Hyperalgesia; Male; Mice; Mice, Inbred C57BL; Morphine; Nociception; Oxidopamine; Pain; Parkinson Disease; Piperidines; Pyrazoles; Thienamycins

Clindamycin, a bacteriostatic semisynthetic lincosamide, is useful in the management of infections caused by aerobic and anaerobic Gram-positive cocci, including bacteremic pneumonia, streptococcal toxic shock syndrome and sepsis. It has been recently demonstrated that clindamycin inhibits in vitro and in vivo inflammatory cytokine production. In the present study, we investigated the effects of clindamycin in acute and chronic models of pain and inflammation in mice and the underlying mechanisms. Intraperitoneal (i.p.) administration of clindamycin (400 mg/kg) increased the animal's latency to exhibit the nociceptive behavior induced by noxious heat (hot plate model). Intrathecal injection of clindamycin (2, 10 and 50 µg) also increased the animals' latency to exhibit the nociceptive behavior. Tactile hypersensitivity and paw edema induced by intraplantar (i.pl.) injection of carrageenan were attenuated by previous administration of clindamycin (200 and 400 mg/kg, i.p.). Clindamycin (100, 200 and 400 mg/kg, i.p.) also attenuated ongoing tactile hypersensitivity and paw edema induced by i.pl. injection of complete Freund's adjuvant (CFA). The antinociceptive activity of clindamycin (400 mg/kg, i.p.) in the hot plate model was attenuated by previous administration of naltrexone (5 and 10 mg/kg, i.p.), but not glibenclamide or AM251. CFA-induced production of TNF-α and CXCL-1 was reduced by clindamycin (400 mg/kg, i.p.). Concluding, clindamycin exhibits activities in acute and chronic models of pain and inflammation. These effects are associated with reduced production of TNF-α and CXCL-1 and activation of opioidergic mechanisms. Altogether, these results indicate that the clindamycin's immunomodulatory effects may contribute to a pharmacological potential beyond its antibiotic property.

Topics: Analgesics; Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents; Behavior, Animal; Carrageenan; Chemokine CXCL1; Clindamycin; Disease Models, Animal; Dose-Response Relationship, Drug; Edema; Inflammation; Male; Mice; Pain; Piperidines; Pyrazoles; Tumor Necrosis Factor-alpha

Topics: Analgesics; Animals; Female; Ligands; Mice; Models, Molecular; Pain; Piperidines; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Structure-Activity Relationship

Evidence indicates that periaqueductal gray matter (PAG) plays an important role in defensive responses and pain control. The activation of cannabinoid type-1 (CB1) or mu-opioid (MOR) receptors in the dorsal region of this structure (dPAG) inhibits fear and facilitates antinociception induced by different aversive stimuli. However, it is still unknown whether these two receptors work cooperatively in order to achieve these inhibitory actions. This study investigated the involvement and a likely interplay between CB1 and MOR receptors localized into the dPAG on the regulation of fear-like defensive responses and antinociception (evaluated in tail-flick test) evoked by dPAG chemical stimulation with N-methyl-d-aspartate (NMDA). Before the administration of NMDA, animals were first intra-dPAG injected with the CB1 agonist ACEA (0.5 pmol), or with the MOR agonist DAMGO (0.5 pmol) in combination with the respective antagonists AM251 (CB1 antagonist, 100 pmol) or CTOP (MOR antagonist, 1 nmol). To investigate the interplay between these receptors, microinjection of CTOP was combined with ACEA, or microinjection of AM251 was combined with DAMGO. Our results showed that both the intra-PAG treatments with ACEA or DAMGO inhibited NMDA-induced freezing expression, whereas only the treatment with DAMGO increased antinociception induced with NMDA, which are completely blocked by its respective antagonists. Interestingly, the inhibitory effects of ACEA or DAMGO on freezing was blocked by CTOP and AM251, respectively, indicating a functional interaction between these two receptors in the mediation of defensive behaviors. However, this cooperative interaction was not observed during the NMDA-induced antinociception. Our findings indicate that there is a cooperative action between the MOR and CB1 receptors within the dPAG and it is involved in the mediation of NMDA-induced defensive responses. Additionally, the MORs into the dPAG are involved in the modulation of the antinociceptive effects that follow a fear-like defense-reaction induced by dPAG chemical stimulation with NMDA.

Topics: Analgesics, Opioid; Animals; Arachidonic Acids; Behavior, Animal; Cannabinoid Receptor Agonists; Cannabinoid Receptor Antagonists; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Excitatory Amino Acid Agonists; Fear; Freezing Reaction, Cataleptic; Male; Microinjections; N-Methylaspartate; Nociception; Pain; Pain Measurement; Periaqueductal Gray; Piperidines; Pyrazoles; Rats; Receptor, Cannabinoid, CB1; Receptors, Opioid, mu; Somatostatin

4-Anilidopiperidine class of synthetic opioid analgesics, with it's representative fentanyl, are by far the most potent and clinically significant for the treatment of the severe chronic and surgical pain. However, side effects of μ-opioids are often quite serious. In order to improve the pharmacological profile of this class of opioid analgesics, a novel fentanyl analogs were designed, synthesized and evaluated in vivo for their antinociceptive activity.. The title compounds were prepared using known synthetic transformations, including N-bromoacetamide mediated Hofmann rearrangement, highly selective carbamate cleavage with trimethylsilyl iodide and dehydration of carboxamide group to nitrile in the presence of SOCl. The scalable synthetic route towards novel fentanyl analogs bearing nitrogen groups in position C. Of ten compounds tested for their antinociceptive activity, compound cis-4 is characterized by high potency, rapid beginning and short duration of action and due to this might be incorporated in different pharmaceutical forms.

Topics: Analgesics, Opioid; Animals; Dose-Response Relationship, Drug; Fentanyl; Mice; Pain; Pain Measurement; Piperidines

Topics: Benzamides; Freedom; Humans; Pain; Piperidines; Pyridines; Pyrroles

Topics: Benzamides; Freedom; Humans; Pain; Piperidines; Pyridines; Pyrroles

Interactions between multiple myeloma (MM) and bone marrow (BM) are well documented to support tumour growth, yet the cellular mechanisms underlying pain in MM are poorly understood. We have used in vivo murine models of MM to show significant induction of nerve growth factor (NGF) by the tumour-bearing bone microenvironment, alongside other known pain-related characteristics such as spinal glial cell activation and reduced locomotion. NGF was not expressed by MM cells, yet bone stromal cells such as osteoblasts expressed and upregulated NGF when cultured with MM cells, or MM-related factors such as TNF-α. Adiponectin is a known MM-suppressive BM-derived factor, and we show that TNF-α-mediated NGF induction is suppressed by adiponectin-directed therapeutics such as AdipoRON and L-4F, as well as NF-κB signalling inhibitor BMS-345541. Our study reveals a further mechanism by which cellular interactions within the tumour-bone microenvironment contribute to disease, by promoting pain-related properties, and suggests a novel direction for analgesic development.

Topics: Adiponectin; Animals; Bone Marrow; Cell Proliferation; Disease Models, Animal; Gene Expression Regulation, Neoplastic; Humans; Imidazoles; Mice; Multiple Myeloma; Nerve Growth Factor; Neuroglia; NF-kappa B; Osteoblasts; Pain; Peptides; Piperidines; Quinoxalines; Stromal Cells; Tumor Microenvironment; Tumor Necrosis Factor-alpha

Topics: Double-Blind Method; Freedom; Humans; Migraine Disorders; Pain; Piperidines; Pyridines; Tablets

Topics: Calcitonin Gene-Related Peptide Receptor Antagonists; Freedom; Humans; Migraine Disorders; Pain; Piperidines; Pyridines

The emotional processing and coordination of top-down responses to noxious and conditioned aversive stimuli involves the medial prefrontal cortex (mPFC). Evidence suggests that subregions of the mPFC [infralimbic (IfL), prelimbic (PrL) and anterior cingulate (ACC) cortices] differentially alter the expression of contextually induced fear and nociceptive behaviour. We investigated the role of the endocannabinoid system in the IfL, PrL and ACC in formalin-evoked nociceptive behaviour, fear-conditioned analgesia (FCA) and conditioned fear in the presence of nociceptive tone.. AM251 attenuated FCA when injected into the IfL or PrL and reduced contextually induced freezing behaviour when injected intra-IfL but not intra-PrL or intra-ACC. Intra-ACC administration of AM251 alone or in combination with URB597 had no effect on FCA or freezing. URB597 attenuated FCA and freezing behaviour when injected intra-IfL, prolonged the expression of FCA when injected intra-PrL and had no effect on these behaviours when injected intra-ACC.. These results suggest important and differing roles for FAAH substrates or CB

Topics: Animals; Behavior, Animal; Benzamides; Cannabinoid Receptor Modulators; Carbamates; Conditioning, Psychological; Endocannabinoids; Fear; Pain; Pain Measurement; Piperidines; Prefrontal Cortex; Pyrazoles; Rats

Commonly prescribed opioid analgesics produce tolerance upon chronic use due in part to induction of hyperalgesia. Given that two reported bivalent ligands (MMG22 and MCC22) produce potent antinociception without tolerance only in inflamed mice, we have investigated the possible cellular and receptor targets of these ligands. The selective microglia inhibitors, minocycline and SB290157, antagonized intrathecal (i.t.) MCC22 antinociception orders of magnitude more potently than MMG22, suggesting that MCC22 selectively targets activated microglia. The astrocyte toxin, l-α-aminoadipic acid antagonized MMG22 antinociception 126-fold without reducing the potency of MCC22, indicating that activated astrocytes are targets of MMG22. MK-801 and Ro25-6981 antagonism of MMG22 antinociception, but not MCC22, is consistent with selective inhibition of activated NMDAR in astrocytes. The antinociception produced by i.t. MMG22 or MCC22 were both antagonized by the selective mu opioid receptor antagonist, β-FNA, implicating interaction of these ligands with MOR in spinal afferent neurons. MCC22 antinociception was potently blocked by kainate or AMPA ion channel antagonists (LY382884; NBQX), in contrast to MMG22. It is concluded that i.t. MMG22 and MCC22 produce exceptional antinociception via potent inhibition of activated spinal glia, thereby leading to desensitization of spinal neurons and enhanced activation of neuronal MOR. Thus, the present study suggests a new approach to treatment of chronic inflammatory pain without tolerance through a single molecular entity that simultaneously inhibits activated glia and stimulates MOR in spinal neurons.

Topics: Analgesics, Opioid; Animals; Drug Tolerance; Isoquinolines; Male; Mice; Mice, Inbred ICR; Neuroglia; Pain; Pain Measurement; Piperidines; Receptors, Opioid

Protocatechuic acid is an antioxidant which is shown to have analgesic activity in limited studies. However, the mechanisms of action remain unclear.. It is aimed to investigate the possible contribution of cannabinoid system that supresses the nociceptive process by the activation of CB1 and CB2 receptors in central and peripheral levels of pain pathways, to the analgesic activity of protocatechuic acid.. The analgesic activity of protocatechuic acid was determined at the doses of 75, 150 and 300 mg/kg (i.p.) by acetic acid-induced writhing and tail-immersion tests in mice. The results were compared to the analgesic effect of 300 mg/kg (i.p.) dipyrone and non-specific CB receptor agonist 5 mg/kg (i.p.) WIN 55,212-2. For investigating the contribution of cannabinoid system to protocatechuic acid analgesia; pre-treatment with 8 mg/kg (i.p.) CB1 antagonist AM251 and 8 mg/kg (i.p.) CB2 antagonist AM630 were performed separately before 300 mg/kg protocatechuic acid administration.. It was determined that protocatechuic acid has dose-dependent analgesic effect independently from locomotor activity and is comparable with effects of dipyrone and WIN 55,212-2. Pre-treatment with CB1 receptor antagonist AM251 significantly antagonized the protocatechuic acid-induced analgesia in the tail-immersion and writhing tests, whereas pre-treatment of CB2 receptor antagonist AM630 was found to be effective only in the tail-immersion test.. It is concluded that cannabinoid modulation contributes to the analgesic effect of protocatechuic acid in spinal level rather than peripheral. CB1 receptor stimulation rather than CB2 receptor stimulation mediates the analgesic effect of protocatechuic acid in both levels, especially peripheral. Graphical abstract Protocatechuic acid inhibits pain response via cannabinoidergic system.

Topics: Acetic Acid; Analgesics; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Hydroxybenzoates; Indoles; Male; Mice; Pain; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Receptors, Cannabinoid

 Opioids are widely used as effective analgesics, but opioid sensitivity is well known to vary widely among individuals. We explored the genetic factors that contribute to individual differences in intraoperative opioid sensitivity by performing a genome-wide association study.. We conducted a multistage genome-wide association study in subjects who underwent laparoscopic-assisted colectomy.. A nonsynonymous SNP, rs199670311, within the TMEM8A gene region and intronic SNPs, including rs4839603, within the SLC9A9 gene region were significantly associated with intraoperative opioid requirements (p = 3.409 × 10. Our findings provide valuable information for personalized pain treatment during laparoscopic-assisted colectomy.

Topics: Adult; Aged; Aged, 80 and over; Alleles; Analgesics, Opioid; Colectomy; Female; Genetic Loci; Genome-Wide Association Study; Humans; Intraoperative Care; Laparoscopy; Male; Membrane Glycoproteins; Middle Aged; Pain; Pain Measurement; Piperidines; Polymorphism, Single Nucleotide; Remifentanil; Sodium-Hydrogen Exchangers; Young Adult

Cannabinoids (CBs) play important roles in pain modulation. Recently, VD-hemopressin(β) [VD-Hpβ], a 12-residue β-hemoglobin-derived peptide, was reported to activate both CB

Topics: Acetic Acid; Analgesics; Animals; Area Under Curve; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Routes; Indoles; Male; Mice; Mice, Inbred Strains; Oligopeptides; Pain; Pain Measurement; Piperidines; Pyrazoles; Rotarod Performance Test; Spinal Cord

Oral ulcer is the most common oral disease and leads to pain during meals and speaking, reducing the quality of life of patients. Recent evidence using animal models suggests that oral ulcers induce cyclooxygenase-dependent spontaneous pain and cyclooxygenase-independent mechanical allodynia. Endothelin-1 is upregulated in oral mucosal inflammation, although it has not been shown to induce pain in oral ulcers. In the present study, we investigated the involvement of endothelin-1 signaling with oral ulcer-induced pain using our proprietary assay system in conscious rats. Endothelin-1 was significantly upregulated in oral ulcers experimentally induced by topical acetic acid treatment, while endothelin-1 production was suppressed by antibacterial pretreatment. Spontaneous nociceptive behavior in oral ulcer model rats was inhibited by swab applications of BQ-788 (ET

Topics: Acetanilides; Anilides; Animals; Bridged Bicyclo Compounds; Caproates; Cinnamates; Disease Models, Animal; Endothelin-1; Male; Oligopeptides; Oral Ulcer; Pain; Peptides, Cyclic; Piperidines; Purines; Rats; Rats, Wistar; Signal Transduction; Sulfonamides; TRPV Cation Channels

Topics: Administration, Oral; Analgesics; Animals; Epoxide Hydrolases; HEK293 Cells; Humans; Inflammation; Lipopolysaccharides; Male; Molecular Structure; Pain; Phosphodiesterase 4 Inhibitors; Piperidines; Rats, Sprague-Dawley

Eicosanoids play a crucial role in inflammatory pain. However, there is very little knowledge about the contribution of oxidized linoleic acid metabolites in inflammatory pain and peripheral sensitization. Here, we identify 12,13-dihydroxy-9Z-octadecenoic acid (12,13-DiHOME), a cytochrome P450-derived linoleic acid metabolite, as crucial mediator of thermal hyperalgesia during inflammatory pain. We found 12,13-DiHOME in increased concentrations in peripheral nervous tissue during acute zymosan- and complete Freund's Adjuvant-induced inflammatory pain. 12,13-DiHOME causes calcium transients in sensory neurons and sensitizes the transient receptor potential vanilloid 1 (TRPV1)-mediated intracellular calcium increases via protein kinase C, subsequently leading to enhanced TRPV1-dependent CGRP-release from sensory neurons. Peripheral injection of 12,13-DiHOME in vivo causes TRPV1-dependent thermal pain hypersensitivity. Finally, application of the soluble epoxide hydrolase (sEH)-inhibitor TPPU reduces 12,13-DiHOME concentrations in nervous tissue and reduces zymosan- and CFA-induced thermal hyperalgesia in vivo. In conclusion, we identify a novel role for the lipid mediator 12,13-DiHOME in mediating thermal hyperalgesia during inflammatory pain and propose a novel mechanism that may explain the antihyperalgesic effects of sEH inhibitors in vivo.

Topics: Analgesics; Animals; Behavior, Animal; Disease Models, Animal; Enzyme Inhibitors; Epoxide Hydrolases; Female; Freund's Adjuvant; Hot Temperature; Humans; Hyperalgesia; Inflammation; Linoleic Acid; Male; Mice; Oleic Acids; Oxidation-Reduction; Pain; Phenylurea Compounds; Piperidines; Protein Kinase C; Sensory Receptor Cells; TRPV Cation Channels; Zymosan

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

Pain accompanies rheumatoid arthritis and other chronic inflammatory conditions and is difficult to manage. Although opioids provide potent analgesia, chronic opioid use can cause tolerance and addiction. Recent studies have demonstrated functional interactions between chemokine and opioid receptor signaling pathways. Reported heterodimerization of chemokine and opioid receptors led our group to develop bivalent compounds that bind both types of receptors, with the goal of targeting opioids to sites of inflammation. MCC22 is a novel bivalent compound containing a CCR5 antagonist and mu opioid receptor (MOR) agonist pharmacophores linked through a 22-atom spacer. We evaluated the efficacy of MCC22 in the K/B.g7 T-cell receptor transgenic mouse model of spontaneous inflammatory arthritis.. MCC22 or morphine was administered intraperitoneally at varying doses to arthritic K/B.g7 mice or nonarthritic control mice. Mechanical pain hypersensitivity was measured each day before and after drug administration, using the electronic von Frey test. The potency of MCC22 relative to that of morphine was calculated. Functional readouts of pain included grip strength and nesting behavior. A separate dosing regimen was used to determine whether the drugs induced pharmacologic tolerance.. MCC22 provided ~ 3000-fold more potent analgesia than morphine in this model. Daily treatment with MCC22 also led to a cumulative analgesic effect, reducing the daily baseline pain level. MCC22 produced no observable analgesic effect in nonarthritic control mice. Importantly, repeated administration of MCC22 did not induce pharmacologic tolerance, whereas a similar regimen of morphine did. Both grip strength and nesting behaviors improved among arthritic mice treated with MCC22. Ankle thickness and arthritis scores were not affected by MCC22. The analgesic effect of MCC22 was abolished in K/B.g7 mice genetically lacking CCR5, demonstrating the receptor specificity of the antagonist pharmacophore.. MCC22 is a novel bivalent ligand that targets CCR5 and MOR. Our findings demonstrate that MCC22 provides highly potent analgesia and improved functional outcomes in a model of inflammatory arthritis, without inducing typical opioid tolerance. These findings suggest that MCC22 or similar compounds could be used to treat the pain associated with inflammatory arthritis and related conditions, while minimizing the risks typically associated with chronic opioid use.

Topics: Analgesics; Animals; Arthritis, Experimental; Arthritis, Rheumatoid; Drug Tolerance; Isoquinolines; Mice; Mice, Inbred C57BL; Mice, Transgenic; Pain; Piperidines; Receptors, CCR5; Receptors, Opioid, mu

Topics: Analgesics; Animals; Antipruritics; Arachidonic Acids; Brain; Cell Line, Tumor; Cyclooxygenase Inhibitors; Endocannabinoids; Enzyme Inhibitors; Glycerides; Humans; Hydrolysis; Male; Mice; Mice, Inbred ICR; Monoacylglycerol Lipases; Pain; PC-3 Cells; Piperidines; Prostaglandins; Rats; Rats, Sprague-Dawley; Rodentia

Although the muscarinic receptor family has long been a source of potentially compelling targets for small molecule drug discovery, it was difficult to achieve agonist selectivity within the family. A new class of M1 muscarinic agonists has emerged, and these compounds have been characterized as agonists that activate the receptor at an allosteric site. Members of this class of M1 agonists have been shown to be selective across the muscarinic receptors. However, upon introduction of a novel pharmacologic mechanism, it is prudent to ensure that no new off-target activities have arisen, particularly within the context of in vivo experiments. Reported here, is the in vitro and in vivo characterization of a novel M1 agonist tool compound, PPBI, and demonstrations that the primary biological effects of PPBI are mediated through M1. PPBI reverses d-amphetamine locomotor activity, but fails to do so in transgenic mice that do not express M1. PPBI also reverses a natural deficit in a rat cognition model at a level of exposure which also activates cortical circuitry. Most notably, PPBI is analgesic in a variety of rat and mouse models and the analgesic effect of PPBI is reversed by an M1-preferring antagonist and an M1-selective toxin. Finally, the pharmacokinetic/pharmacodynamic measures of PPBI are compared across multiple endpoints which highlights that activity in models of psychosis and pain require higher exposures than that required in the cognition model.

Topics: Amphetamine; Analgesics; Animals; Benzimidazoles; Brain; Central Nervous System Stimulants; CHO Cells; Cognition; Cricetulus; Disease Models, Animal; Humans; Male; Mice, Inbred C57BL; Mice, Knockout; Molecular Structure; Motor Activity; Muscarinic Agonists; Nootropic Agents; Pain; Piperidines; Pyrrolidines; Random Allocation; Rats, Sprague-Dawley; Receptor, Muscarinic M1; Transfection

This study was conducted to identify the brain regions corresponding to mechanical noxious stimulation in cats using functional magnetic resonance imaging (fMRI) and to investigate the modulatory effect of remifentanil on the activation of these regions. Six healthy cats were anesthetized using a constant-rate infusion of alfaxalone. Cats were allocated to one of three treatment groups: remifentanil 0 (saline), 0.25, and 0.5μg/kg/min. A 3.0-T MRI unit was used to collect fMRI data. During the fMRI scanning, mechanical noxious stimulation was applied by tail clamping. The brain regions activated by the stimulation were identified based on blood oxygenation level-dependent (BOLD) responses. The modulatory effects of remifentanil were evaluated using a region of interest (ROI) analysis comparing signal changes in each brain region. Increased activity from noxious stimulation was observed in the somatosensory area (the postcruciatus gyrus, the anterior part of the marginalis gyrus, and the anterior part of the ectomarginalis gyrus), the parietal association area (the middle part of the marginalis gyrus and the middle part of the ectomarginalis gyrus), the cingulate cortex, the hippocampus, and the cerebellum. The results of the ROI analysis indicated that activations in the somatosensory area, the cingulate cortex, the hippocampus, and the cerebellum were significantly modulated (P<0.05) by remifentanil. In cats, activation patterns evoked by mechanical noxious stimulation were observed in several brain regions thought to be involved in various aspects of pain processing, including sensory discrimination and integration, affect, and motor response. These brain responses were modulated by remifentanil.

Topics: Analgesics, Opioid; Animals; Brain; Cats; Dose-Response Relationship, Drug; Female; Magnetic Resonance Imaging; Male; Pain; Piperidines; Random Allocation; Remifentanil

Lysophosphatidic acid (LPA) is a bioactive lipid that acts via at least six G protein-coupled receptors, LPA receptors 1-6 (LPA1-6), for various physiological functions. We examined (1) whether LPA5 is involved in pain signaling in the spinal cord; and (2) the pharmacological effects of a novel LPA5 antagonist on intrathecal prostaglandin (PG)- and (S)-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-induced allodynia, and neuropathic and inflammatory pain in rodents. Intrathecal injection of a selective LPA5 agonist, geranylgeranyl diphosphate, and a non-selective agonist, LPA, induced allodynia in wild type, but not in LPA5 knockout mice. These novel results suggest that LPA5 is important for pain signal transmission in the spinal cord. AS2717638 (6,7-dimethoxy-2-(5-methyl-1,2-benzoxazol-3-yl)-4-(piperidin-1-ylcarbonyl)isoquinolin-1(2H)-one) bound to the LPA-binding site on LPA5 and selectively inhibited LPA-induced cyclic adenosine monophosphate accumulation in human LPA5-but not LPA1-, 2-, or 3-expressing cells. Further, oral administration of AS2717638 inhibited LPA5 agonist-induced allodynia in mice. AS2717638 also significantly improved PGE

Topics: Analgesics; Animals; Benzoxazoles; Cells, Cultured; Cyclic AMP; Female; Hyperalgesia; Inflammation; Injections, Spinal; Isoquinolines; Lysophospholipids; Male; Mice, Inbred C57BL; Mice, Knockout; Neuralgia; Pain; Pain Threshold; Piperidines; Polyisoprenyl Phosphates; Rats, Inbred Lew; Rats, Sprague-Dawley; Receptors, Lysophosphatidic Acid

The discovery and selection of a highly potent and selective Na

Topics: Animals; Binding Sites; Dogs; Half-Life; Hepatocytes; Humans; Infusions, Intravenous; Inhibitory Concentration 50; Mice; Microsomes, Liver; Molecular Docking Simulation; NAV1.7 Voltage-Gated Sodium Channel; Pain; Piperidines; Protein Binding; Protein Structure, Tertiary; Pyridines; Rats; Structure-Activity Relationship; Sulfonamides; Thiadiazoles; Voltage-Gated Sodium Channel Blockers

Current studies indicate that the cholinergic and opioid systems interact to modulate pain. In the present work, we investigated the influence of the cholinesterase inhibitors, donepezil (0.5; 1 or 3mg/kg, i.p.) and rivastigmine (0.03; 0.5 or 1mg/kg, i.p.), on the acute antinociceptive effects of morphine (5mg/kg, i.p.) in the hot plate test in mice. Herein, both inhibitors were found to enhance and prolong the analgesic effects of morphine without affecting latencies themselves. In an extension of this work, we determined which cholinergic receptors subtype mediates the enhancement of analgesic effects of morphine, following inhibition of cholinesterases. In this part of the study, scopolamine (0.5mg/kg, i.p.), a muscarinic cholinergic receptors antagonist, but not mecamylamine (3mg/kg, i.p.), a nicotinic cholinergic receptors antagonist, reversed the enhancing effects of donepezil (3mg/kg, i.p.) and rivastigmine (1mg/kg, i.p.) on the morphine antinociception. Moreover, both cholinesterase inhibitors attenuated the development of tolerance to the antinociceptive effects of morphine. In contrast, acute administration of donepezil (3mg/kg, i.p.) or rivastigmine (1mg/kg, i.p.) on the day of expression of tolerance, had no effect on the already developed morphine tolerance. What is more, in both set of experiments, rivastigmine was slightly more potent than donepezil due to the broader inhibitory spectrum of this drug on acetylcholine degradation. Thus, our results suggest that the cholinesterase inhibitors, donepezil and rivastigmine, may be administered with morphine in order to enhance the latter's analgesic effects for the treatment of acute and chronic pain.

Topics: Acetylcholine; Analgesics, Opioid; Analysis of Variance; Animals; Area Under Curve; Cholinesterase Inhibitors; Disease Models, Animal; Donepezil; Dose-Response Relationship, Drug; Drug Synergism; Indans; Male; Mice; Morphine; Pain; Pain Measurement; Piperidines; Rivastigmine; Time Factors

Orexin plays an important role in pain modulation. Orexin-1 and orexin-2 receptors (Ox1r and Ox2r) are found at high density in the ventrolateral periaqueductal gray matter (vlPAG). Our previous study showed that chemical stimulation of the lateral hypothalamus with carbachol induces antinociception in the tail-flick test, a model of acute pain, and Ox1r-mediated antinociception in the vlPAG is modulated by the activity of vlPAG CB1 receptors. In the current study, TCS OX2 29, an Ox2r antagonist (5, 15, 50, 150, and 500 nmol/l), was microinjected into the vlPAG 5 min before the administration of carbachol (125 nmol/l). TCS OX2 29 dose dependently reduced carbachol-induced antinociception. In a second set of experiments, animals were treated with carbachol 5 min after intra-vlPAG administration of 15 nmol/l TCS OX2 29 and 1 nmol/l AM251 (a selective CB1 receptor antagonist), or 150 nmol/l TCS OX2 29 and 10 nmol/l AM251. The findings showed that the antinociceptive effect of orexin is partially mediated by activation of vlPAG Ox2 receptors. Furthermore, the administration of ineffective doses of Ox2 and CB1 receptor antagonists reduced the lateral hypothalamus-induced antinociception. It seems that Ox2 and CB1 receptors act through different pathways and Ox2r-mediated antinociception is not dependent on CB1 receptor activity.

Topics: Animals; Carbachol; Disease Models, Animal; Dose-Response Relationship, Drug; Hypothalamic Area, Lateral; Isoquinolines; Male; Orexin Receptor Antagonists; Orexin Receptors; Orexins; Pain; Periaqueductal Gray; Piperidines; Pyrazoles; Pyridines; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1

Phenylpiperidines are a chemical class of drugs with a phenyl moiety directly attached to piperidine. These agents have an important role in many aspects of medicine including anesthesia and pain medicine. After the development of meperidine, fentanyl, which is a second generation synthetic phenylpiperidine series opioid, was synthesized and introduced into clinical anesthesia practice as fentanyl citrate in 1968. Fentanyl-mediated or modulated responses involve action at the mu-opioid receptor as an agonist at the dorsal horn inhibiting ascending pain pathways in the rostral ventral medulla, increasing pain threshold, and producing both analgesic and sedative effects. Clinicians should appreciate that since fentanyl is metabolized mainly via CYP3A4, potential adverse effects can occur with concomitant use of any drug which affects CYP3A4 activity. Discontinuation of CYP3A4 inducers can also result in an increase in fentanyl plasma concentration. We describe the role of remifentanil, a short-acting, organ independent analgesic and sufentanil, including newer formulations of sufentanil currently being evaluated sublingually for pain management. We examine the routes of administration and clinical considerations, including the role of opioids such as fentanyl as a natural killer cell suppressive agent. Fentanyl and other opioids have been shown to potentiate propagation of infection or cancer. In recent years, fentanyl and other phenylpiperidine formulations have been developed and successfully marketed for chronic pain patients. Because all opioids have complex physiological responses and potential drug-drug interactions, the clinician should appreciate all aspects of this drug class and consider all available options in appropriate clinical settings. Key words: Fentanyl; Remifentanil, Sufentanil, opioids, analgesics, pain, perioperative, management.

Topics: Analgesics; Chronic Pain; Fentanyl; Humans; Pain; Piperidines; Sufentanil

By taking advantage of certain features in piperidine 4, we developed a novel series of cyclohexylamine- and piperidine-based benzenesulfonamides as potent and selective Na

Topics: Analgesics; Animals; Benzenesulfonamides; Drug Discovery; Ganglia, Spinal; HEK293 Cells; Humans; Male; Mice; NAV1.7 Voltage-Gated Sodium Channel; Pain; Piperidines; Sulfonamides; Voltage-Gated Sodium Channel Blockers

Paravertebral block (PVB) is feasible for postoperative analgesia in patients who undergo cardiac surgery with unilateral thoracotomy. Postoperative continuous PVB is as effective as thoracic epidural anesthesia and is less likely to cause hypotension. However, the intraoperative utility and safety of PVB remains unclear. Therefore, the present study was conducted to determine the efficacy and hemodynamic influence of intraoperative paravertebral bolus injection during cardiac surgery. We retrospectively compared intraoperative medication use and blood pressure measurements between patients who underwent transapical transcatheter aortic valve implantation (TA-TAVI) with (PVB group, n = 46) or without (non-PVB group, n = 15) intraoperative PVB. Remifentanil administration was lower by more than 40 % in the PVB group compared with that in the non-PVB group (728 ± 319 µg vs. 1240 ± 488 µg, P < 0.001). The average and variability of intraoperative blood pressure showed no significant differences between groups. The duration of hypotension (blood pressure less than 80 % of baseline) was 25.1 ± 21.5 % and 25.4 ± 18.1 % of the entire anesthesia time in the non-PVB and PVB groups, respectively (P = 0.74). The use of inotropic and vasopressor agents was comparable between groups. Intraoperative paravertebral bolus injection decreased remifentanil administration without causing hypotension during TA-TAVI in hemodynamically unstable patients. This result suggests the intraoperative utility of PVB in cardiac surgery.

Topics: Aged; Aged, 80 and over; Analgesics, Opioid; Anesthetics, Local; Aortic Valve; Blood Pressure; Bupivacaine; Cardiac Catheterization; Cardiotonic Agents; Female; Fentanyl; Heart Valve Prosthesis; Heart Valve Prosthesis Implantation; Humans; Hypotension; Levobupivacaine; Male; Nerve Block; Pain; Pain Measurement; Piperidines; Remifentanil; Retrospective Studies; Risk Factors; Time Factors; Treatment Outcome; Vasoconstrictor Agents

Topics: Analgesics; Cognition; Female; Humans; Male; Pain; Piperidines; Pregabalin; Respiration

N-Phenyl-N-(piperidin-2-ylmethyl)propionamide based bivalent ligands are unexplored for the design of opioid based ligands. Two series of hybrid molecules bearing N-phenyl-N-(piperidin-2-ylmethyl)propionamide derived small molecules conjugated with an enkephalin analogues with and without a linker (β-alanine) were designed and synthesized. Both bivalent ligand series exhibited remarkable binding affinities from nanomolar to subnanomolar range at both μ and δ opioid receptors and displayed potent agonist activities as well. The replacement of Tyr with Dmt and introduction of a linker between the small molecule and enkephalin analogue resulted in highly potent ligands. Both series of ligands showed excellent binding affinities at both μ (0.6-0.9nM) and δ (0.2-1.2nM) opioid receptors respectively. Similarly, these bivalent ligands exhibited potent agonist activities in both MVD and GPI assays. Ligand 17 was evaluated for in vivo antinociceptive activity in non-injured rats following spinal administration. Ligand 17 was not significantly effective in alleviating acute pain. The most likely explanations for this low intrinsic efficacy in vivo despite high in vitro binding affinity, moderate in vitro activity are (i) low potency suggesting that higher doses are needed; (ii) differences in experimental design (i.e. non-neuronal, high receptor density for in vitro preparations versus CNS site of action in vitro); (iii) pharmacodynamics (i.e. engaging signalling pathways); (iv) pharmacokinetics (i.e. metabolic stability). In summary, our data suggest that further optimisation of this compound 17 is required to enhance intrinsic antinociceptive efficacy.

Topics: Amides; Analgesics; Animals; Dose-Response Relationship, Drug; Enkephalins; Guinea Pigs; Humans; Ileum; Ligands; Mice; Molecular Structure; Pain; Piperidines; Rats; Receptors, Opioid, delta; Receptors, Opioid, mu; Structure-Activity Relationship

Pain greatly affects the quality of life of people worldwide. Despite their demonstrated efficacy, currently used opioid drugs and nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently associated with several adverse events. The identification of new therapeutic targets and the development of corresponding analgesics may represent novel approaches for effectively treating pain. SY0916 is a novel compound that was designed and synthesized by the Institute of Materia Medica, Chinese Academy of Medical Sciences. As demonstrated by the hot plate test, tail-flick test and the formalin test, SY0916 exerted strong peripheral and central antinociceptive effects. Western blot, immunohistochemistry and enzyme-linked immunosorbent assay (ELISA) results indicate that SY0916 induces its peripheral antinociceptive effect by suppressing the peripheral activity of inflammatory mediators such as prostaglandin E2 (PGE2), tumor necrosis factor-alpha (TNF-α) and 5-hydroxytryptamine (5-HT). Moreover, its central antinociceptive effect might be mediated by the down-regulation of PGE2 and TNF-α expression and the inhibition of p-p38 and NF-κB pathway signaling in glial cells. These findings demonstrate that SY0916 may serve as a promising analgesic candidate drug.

Topics: Analgesics; Animals; Brain Stem; Cell Line; Dinoprostone; Female; Formaldehyde; Hot Temperature; Ketones; Mice; Mitogen-Activated Protein Kinases; NF-kappa B; Pain; Piperidines; Rats, Sprague-Dawley; Serotonin; Tumor Necrosis Factor-alpha

Bispectral index (BIS) is considered very useful to guide anesthesia care in elderly patients, but its use is controversial for the evaluation of the adequacy of analgesia. This study compared the BIS changes in response to loss of consciousness (LOC) and loss of somatic response (LOS) to nociceptive stimuli between elderly and young patients receiving intravenous target-controlled infusion (TCI) of propofol and remifentanil.. This study was performed on 52 elderly patients (aged 65-78 years) and 52 young patients (aged 25-58 years), American Society of Anesthesiologists physical status I or II. Anesthesia was induced with propofol administered by TCI. A standardized noxious electrical stimulus (transcutaneous electrical nerve stimulation, [TENS]) was applied (50 Hz, 80 mA, 0.25 ms pulses for 4 s) to the ulnar nerve at increasing remifentanil predicted effective-site concentration (Ce) until patients lost somatic response to TENS. Changes in awake, prestimulus, poststimulus BIS, heart rate, mean arterial pressure, pulse oxygen saturation, predicted plasma concentration, Ce of propofol, and remifentanil at both LOC and LOS clinical points were investigated.. BISLOCin elderly group was higher than that in young patient group (65.4 ± 9.7 vs. 57.6 ± 12.3) (t = 21.58, P < 0.0001) after TCI propofol, and the propofol Ce at LOC was 1.6 ± 0.3 μg/ml in elderly patients, which was significantly lower than that in young patients (2.3 ± 0.5 μg/ml) (t = 7.474, P < 0.0001). As nociceptive stimulation induced BIS to increase, the mean of BIS maximum values after TENS was significantly higher than that before TENS in both age groups (t = 8.902 and t = 8.019, P < 0.0001). With increasing Ce of remifentanil until patients lost somatic response to TENS, BISLOSwas the same as the BISLOCin elderly patients (65.6 ± 10.7 vs. 65.4 ± 9.7), and there were no marked differences between elderly and young patient groups in BISawake, BISLOS, and Ce of remifentanil required for LOS.. In elderly patients, BIS can be used as an indicator for hypnotic-analgesic balance and be helpful to guide the optimal administration of propofol and remifentanil individually.. CTRI Reg. No: ChiCTR-OOC-14005629; http://www.chictr.org.cn/showproj.aspx?proj=9875.

Topics: Adult; Aged; Electroencephalography; Female; Humans; Male; Middle Aged; Movement Disorders; Pain; Piperidines; Propofol; Remifentanil; Transcutaneous Electric Nerve Stimulation; Unconsciousness

Prostaglandin E2 (PGE2), one of the terminal products in the cyclooxygenase pathway, plays an important role in various inflammatory responses. To determine whether selective inhibition of PGE2 may relieve these inflammatory symptoms, we synthesized a selective PGE2 synthesis inhibitor, compound A [1-(6-fluoro-5,7-dimethyl-1,3-benzothiazol-2-yl)-N-[(1S,2R)-2-(hydroxymethyl)cyclohexyl]piperidine-4-carboxamide], then investigated the effects on pyrexia, arthritis and inflammatory pain in guinea pigs. In LPS-stimulated guinea pig macrophages, compound A selectively inhibited inducible PGE2 biosynthesis in a dose-dependent manner whereas enhanced the formation of thromboxane B2 (TXB2). Compound A suppressed yeast-evoked PGE2 production selectively and enhanced the production of TXB2 and 6-keto PGF1αin vivo. In addition, compound A relieved yeast-induced pyrexia and also suppressed paw swelling in an adjuvant-induced arthritis model. The effect on gastrointestinal (GI) ulcer formation was also evaluated and compound A showed a lower GI adverse effect than indomethacin. However, compound A failed to relieve yeast-induced thermal hyperalgesia. These results suggest that selective inhibition of PGE2 synthesis may have anti-pyretic and anti-inflammatory properties without GI side effect, but lack the analgesic efficacy.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Experimental; Benzothiazoles; Depression, Chemical; Dinoprostone; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Fever; Guinea Pigs; Imidazoles; Indomethacin; Inflammation; Macrophages; Pain; Peptic Ulcer; Phenanthrenes; Piperidines; Stimulation, Chemical; Thromboxane B2

Single-nucleotide polymorphisms in genes involved in pain control might predispose to exaggerated sensitivity or difference in opioid analgesic effect. The relevance of the KCNJ6 -1250G>A (rs6517442, c.-1787G>A) and the catecholamine-O-methyltransferase (COMT) c.472G>A (rs4680, ValMet) single-nucleotide polymorphisms were studied in preterm infants needing intubation and randomized to a premedication strategy including remifentanil (n = 17) or morphine (n = 17).. Pain was scored with Astrid Lindgren and Lund Children's Hospital Pain Assessment Scale every 30 minutes for 6 hours. The pain relief provided by the opioids was compared between the different KCNJ6 and COMT genotypes.. Infants homozygous for the KCNJ6 -1250A allele had an increased duration after intubation to achieve a score indicating no pain compared with infants with the A/G or G/G genotypes (182 ± 30, 109 ± 29, and 60 ± 21 minutes, respectively; Logrank = 7.5, P = 0.006). Similarly, the duration was increased in individuals with the COMT Val/Val alleles compared with Val/Met and Met/Met (285 ± 37, 137 ± 25, and 63 ± 15 minutes, respectively; Logrank = 14.4, P = 0.0021). Cox proportional hazards analysis confirmed that the variation in both genes was independently associated with susceptibility to respond to therapy.. We conclude that the KCNJ6 -1250A and COMT Val alleles are predisposing preterm newborns to diminished opioid-induced pain relief.

Topics: Alleles; Analgesics, Opioid; Catechol O-Methyltransferase; G Protein-Coupled Inwardly-Rectifying Potassium Channels; Genetic Predisposition to Disease; Genotype; Humans; Infant, Newborn; Infant, Premature; Intubation, Intratracheal; Morphine; Pain; Pain Management; Pain Measurement; Piperidines; Polymorphism, Single Nucleotide; Remifentanil

Fatty acid amide hydrolase (FAAH) is a membrane anchored serine hydrolase that has a principle role in the metabolism of the endogenous cannabinoid anandamide. Docking studies using representative FAAH crystal structures revealed that compounds containing a novel piperidinyl thiazole isoxazoline core fit within the ligand binding domains. New potential FAAH inhibitors were designed and synthesized incorporating urea, carbamate, alkyldione and thiourea reactive centers as potential pharmacophores. A small library of candidate compounds (75) was then screened against human FAAH leading to the identification of new carbamate and urea based inhibitors (Ki=pM and nM, respectively). Representative carbamate and urea based chemotypes displayed slow, time dependent inhibition kinetics leading to enzyme inactivation which was slowly reversible. However, evidence indicated that features of the mechanism of inactivation differ between the two pharmacophore types. Selected compounds were also evaluated for analgesic activity in the mouse-tail flick test.

Topics: Amidohydrolases; Analgesics; Animals; Dose-Response Relationship, Drug; Enzyme Inhibitors; Humans; Isoxazoles; Kinetics; Male; Mice; Mice, Inbred ICR; Molecular Docking Simulation; Molecular Structure; Pain; Pain Measurement; Piperidines; Structure-Activity Relationship; Thiazoles

The matrine-type alkaloid 4-dimethylamino-1-pentanoylpiperidine (3a) has an antinociceptive effect through its impact on the κ-opioid receptor (KOR). Derivatives of 3a were synthesized by altering its amide and tertiary amine groups, and were evaluated for their antinociceptive effects. The results indicated that the distance between these groups on 3a was optimal for the antinociceptive effect. The effects obtained with compounds 8 and 9 indicated that the relative configuration of the 3- and 4-substituents influenced the effect mediated through the KOR.

Topics: Alkaloids; Analgesics; Animals; Dose-Response Relationship, Drug; Drug Design; Injections, Subcutaneous; Mice; Models, Molecular; Molecular Structure; Pain; Piperidines; Receptors, Opioid, kappa; Structure-Activity Relationship

A series of new κ opioid receptor (KOR) agonists were developed from the lead compound 4-dimethylamino-1-pentanoylpiperidine (3), a matrine-type alkaloid. Derivatives of 3 were synthesized with a variety of phenyl substituents and evaluated for their antinociceptive effects. Additionally, their selectivity for an opioid receptor was investigated for cis-4c and d, and trans-4g, all of which had high activity exerted through the KOR.

Topics: Alkaloids; Analgesics; Animals; Dose-Response Relationship, Drug; Injections, Subcutaneous; Mice; Molecular Structure; Pain; Piperidines; Receptors, Opioid, kappa; Structure-Activity Relationship

Experiences of social rejection represent a major source of distress and in particular peer rejection during adolescence has been implicated in various psychiatric disorders. Moreover, experimentally induced acute social rejection alters pain perception in humans, implicating overlapping neurocircuits for social and physical pains. We recently demonstrated that rearing of adolescent Wistar rats with inadequate, less playful play partners (Fischer 344) persistently decreases pain sensitivity, although the detailed mechanisms mediating the aversiveness during the social encounter remained unsettled. With the present study we examined the behavioral performance during acute interaction of female adolescent Wistar rats with either age-matched same-strain partners or rats from the Fischer 344 strain. We here identify the low responsiveness upon playful attacks, which appears to be characteristic for social play in the Fischer 344 strain, as one of the main aversive components for adolescent Wistar animals during cross-strain encounters, which subsequently diminishes thermal pain reactivity. A detailed behavioral analysis further revealed increased ultrasonic vocalization at 50kHz and an increased frequency of playful attacks for adolescent Wistar animals paired with a Fischer 344 rat compared to same-strain control pairs. Finally, an acute injection of a subthreshold dose of the cannabinoid type 1 receptor inverse agonist/antagonist SR141716 before the social encounter abolished enhanced play-soliciting behavior in Wistar/Fischer 344 pairs as well as the behavioral consequences of the rejection experience in adolescent Wistar rats, further emphasizing an important modulatory role of the endocannabinoid system in mediating the effects of social behavior and social pain.

Topics: Animals; Cannabinoid Receptor Antagonists; Cohort Studies; Female; Hot Temperature; Motor Activity; Pain; Pain Perception; Piperidines; Psychological Distance; Pyrazoles; Random Allocation; Rats, Inbred F344; Rats, Wistar; Receptor, Cannabinoid, CB1; Rimonabant

Fatty-acid amide hydrolase (FAAH) is the major enzyme responsible for degradation of anandamide, an endocannabinoid. Pharmacological inhibition or genetic deletion of FAAH (FAAH KO) produces antinociception in preclinical pain models that is largely attributed to anandamide-induced activation of cannabinoid receptors. However, FAAH metabolizes a wide range of structurally related, biologically active lipid signaling molecules whose functions remain largely unknown. Some of these endogenous lipids, including anandamide itself, may exert pro-nociceptive effects under certain conditions. In our study, FAAH KO mice exhibited a characteristic analgesic phenotype in the tail flick test and in both formalin and carrageenan models of inflammatory nociception. Nonetheless, intradermal injection of the transient receptor potential channel V1 (TRPV1) agonist capsaicin increased nocifensive behavior as well as mechanical and heat hypersensitivity in FAAH KO relative to wild-type mice. This pro-nociceptive phenotype was accompanied by increases in capsaicin-evoked Fos-like immunoreactive (FLI) cells in spinal dorsal horn regions implicated in nociceptive processing and was attenuated by CB1 (AM251) and TRPV1 (AMG9810) antagonists. When central sensitization was established, FAAH KO mice displayed elevated levels of anandamide, other fatty-acid amides, and endogenous TRPV1 agonists in both paw skin and lumbar spinal cord relative to wild-type mice. Capsaicin decreased spinal cord 2-AG levels and increased arachidonic acid and prostaglandin E2 levels in both spinal cord and paw skin irrespective of genotype. Our studies identify a previously unrecognized pro-nociceptive phenotype in FAAH KO mice that was unmasked by capsaicin challenge. The heightened nociceptive response was mediated by CB1 and TRPV1 receptors and accompanied by enhanced spinal neuronal activation. Moreover, genetic deletion of FAAH has a profound impact on the peripheral and central lipidome. Thus, genetic deletion of FAAH may predispose animals to increased sensitivity to certain types of pain. More work is necessary to determine whether such changes could explain the lack of efficacy of FAAH inhibitors in clinical trials.

Topics: Acrylamides; Amidohydrolases; Analgesia; Animals; Arachidonic Acid; Bridged Bicyclo Compounds, Heterocyclic; Capsaicin; Carrageenan; Disease Models, Animal; Ethanolamines; Formaldehyde; Genotype; Hyperalgesia; Inflammation; Injections, Intraperitoneal; Ligands; Lumbar Vertebrae; Mice, Inbred C57BL; Mice, Knockout; Nociception; Pain; Pain Threshold; Phenotype; Piperidines; Proto-Oncogene Proteins c-fos; Pyrazoles; Receptor, Cannabinoid, CB1; Skin; Spinal Cord Dorsal Horn; TRPV Cation Channels

Chemical stimulation of the lateral hypothalamus (LH) with carbachol induces antinociception which is antagonized by blockade of orexin receptors in some pain modulatory sites in the tail-flick test. In this study, we evaluated the role of orexin-1 and CB1 receptors in the periaqueductal gray matter (PAG), a critical pain modulatory site, in mediation of antinociceptive responses induced by LH stimulation in rats.. One hundred thirty-two adult male albino Wistar rats weighing 180-250 g were unilaterally implanted with two separate cannulae into the LH and ventrolateral PAG (vlPAG). Intra-vlPAG administration of SB334867, as a selective orexin-1 receptor antagonist (0.5, 1.5, 5, 15 and 50 nM), or AM251, as a selective CB1 receptor antagonist (1, 3, 10, 30 and 100 nM), was performed just 5 min before carbachol (125 nM) microinjection into the LH.. Our findings showed that SB334867 or AM251 administration dose dependently prevented the development of LH-induced antinociception in rats. Treatment with two antagonists at the same time could not intensify their effects in comparison with separate administration of antagonists.. It seems that antinociceptive effect of intra-LH administration of carbachol is mediated, at least partially, through the activation of orexin-1 and CB1 receptors in the vlPAG.. This work demonstrates a pain modulatory role of the orexinergic system via the PAG in hypothalamic-mediated analgesia suggesting that orexins can be advantageously targeted to achieve analgesia. WHAT DOES THIS STUDY ADD?: OX1 receptor antagonist (SB334867) administration into the ventrolateral periaqueductal gray matter (vlPAG) dose dependently blocked the carbachol-induced antinociception. CB1 receptor antagonist (AM251) microinjection in the vlPAG prevented carbachol-induced antinociception in a dose-dependent manner. Concurrent administration of SB334867 and AM251 into the vlPAG did not reinforce the antinociceptive responses.

Topics: Animals; Benzoxazoles; Carbachol; Disease Models, Animal; Hypothalamic Area, Lateral; Male; Microinjections; Naphthyridines; Orexin Receptors; Orexins; Pain; Pain Measurement; Periaqueductal Gray; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Stimulation, Chemical; Urea

Neurotensin receptor type 2 (NTS2) compounds display analgesic activity in animal pain models. We have identified the first high-affinity NTS2-selective antagonist (8) that is active in vivo. This study also revealed that the NTS2 FLIPR assay designation for a compound, agonist, partial agonist, and so forth, did not correlate with its in vivo activity as observed in the thermal tail-flick acute model of pain. This suggests that calcium mobilization is not the signaling pathway involved in NTS2-mediated analgesia as assessed by the thermal tail-flick model. Finally, we found a significant bias between rat and human for compound 9 in the NTS2 binding assay.

Topics: Analgesics; Analysis of Variance; Animals; Bridged Bicyclo Compounds, Heterocyclic; Calcium; Carboxylic Acids; Disease Models, Animal; Dose-Response Relationship, Drug; Hindlimb Suspension; Humans; Injections, Spinal; Male; Neurotransmitter Agents; Pain; Piperidines; Protein Binding; Pyrazoles; Radioligand Assay; Rats; Rats, Sprague-Dawley; Reaction Time; Receptors, Neurotensin

Complex regional pain syndrome type 1 (CRPS-I) remains one of the most clinically challenging neuropathic pain syndromes and its mechanism has not been fully characterized. Cannabinoid receptor 2 (CB2) has emerged as a promising target for treating different neuropathic pain syndromes. In neuropathic pain models, activated microglia expressing CB2 receptors are seen in the spinal cord. Chemokine fractalkine receptor (CX3CR1) plays a substantial role in microglial activation and neuroinflammation. We hypothesized that a CB2 agonist could modulate neuroinflammation and neuropathic pain in an ischemia model of CRPS by regulating CB2 and CX3CR1 signaling. We used chronic post-ischemia pain (CPIP) as a model of CRPS-I. Rats in the CPIP group exhibited significant hyperemia and edema of the ischemic hindpaw and spontaneous pain behaviors (hindpaw shaking and licking). Intraperitoneal administration of MDA7 (a selective CB2 agonist) attenuated mechanical allodynia induced by CPIP. MDA7 treatment was found to interfere with early events in the CRPS-I neuroinflammatory response by suppressing peripheral edema, spinal microglial activation and expression of CX3CR1 and CB2 receptors on the microglia in the spinal cord. MDA7 also mitigated the loss of intraepidermal nerve fibers induced by CPIP. Neuroprotective effects of MDA7 were blocked by a CB2 antagonist, AM630. Our findings suggest that MDA7, a novel CB2 agonist, may offer an innovative therapeutic approach for treating neuropathic symptoms and neuroinflammatory responses induced by CRPS-I in the setting of ischemia and reperfusion injury.

Topics: Animals; Benzofurans; CX3C Chemokine Receptor 1; Disease Models, Animal; Encephalitis; Epidermis; Hyperalgesia; Ischemia; Male; Microglia; Pain; Piperidines; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB2; Receptors, Chemokine; Reflex Sympathetic Dystrophy; Spinal Cord Dorsal Horn

Neuroplastic changes in the amygdala account for emotional-affective aspects of pain and involve neuropeptides such as calcitonin gene-related peptide and corticotropin-releasing factor. Another neuropeptide system, central arginine vasopressin, has been implicated in neuropsychiatric disorders, but its role in pain-related emotional expression and neuroplasticity remains to be determined. Here, we tested the hypothesis that arginine vasopressin in the amygdala contributes to pain-related emotional-affective responses, using stereotaxic applications of arginine vasopressin and antagonists for G-protein coupled vasopressin V1A and oxytocin receptors in adult male Sprague-Dawley rats. In normal animals, arginine vasopressin increased audible and ultrasonic vocalizations and anxiety-like behavior (decreased open-arm preference in the elevated plus maze). The facilitatory effects were blocked by a selective V1A antagonist (SR 49059, Relcovaptan) but not by an oxytocin receptor antagonist (L-371,257). L-371,257 had some facilitatory effects on vocalizations. Arginine vasopressin had no effect in arthritic rats (kaolin/carrageenan knee joint pain model). SR 49059 inhibited vocalizations and anxiety-like behavior (elevated plus maze) in arthritic, but not normal, rats and conveyed anxiolytic properties to arginine vasopressin. Arginine vasopressin, SR 49059, and L-371,257 had no significant effects on spinal reflexes. We interpret the data to suggest that arginine vasopressin through V1A in the amygdala contributes to emotional-affective aspects of pain (arthritis model), whereas oxytocin receptors may mediate some inhibitory effects of the vasopressin system.

Topics: Amygdala; Animals; Arthritis; Benzoxazines; Carrageenan; Disease Models, Animal; Hormone Antagonists; Indoles; Kaolin; Male; Maze Learning; Microdialysis; Pain; Piperidines; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptors, Oxytocin; Receptors, Vasopressin; Reflex; Vocalization, Animal

The G-protein coupled receptor 55 (GPR55) is activated by cannabinoids and non-cannabinoid molecules and has been speculated to play a modulatory role in a large variety of physiological and pathological processes, including in metabolically perturbed states. We therefore generated male mice deficient in the gene coding for the cannabinoid/lysophosphatidylinositol (LPI) receptor Gpr55 and characterized them under normal dietary conditions as well as during high energy dense diet feeding followed by challenge with the CB1 receptor antagonist/GPR55 agonist rimonabant. Gpr55 deficient male mice (Gpr55 KO) were phenotypically indistinguishable from their wild type (WT) siblings for the most part. However, Gpr55 KO animals displayed an intriguing nocturnal pattern of motor activity and energy expenditure (EE). During the initial 6 hours of the night, motor activity was significantly elevated without any significant effect observed in EE. Interestingly, during the last 6 hours of the night motor activity was similar but EE was significantly decreased in the Gpr55 KO mice. No significant difference in motor activity was detected during daytime, but EE was lower in the Gpr55 KO compared to WT mice. The aforementioned patterns were not associated with alterations in energy intake, daytime core body temperature, body weight (BW) or composition, although a non-significant tendency to increased adiposity was seen in Gpr55 KO compared to WT mice. Detailed analyses of daytime activity in the Open Field paradigm unveiled lower horizontal activity and rearing time for the Gpr55 KO mice. Moreover, the Gpr55 KO mice displayed significantly faster reaction time in the tail flick test, indicative of thermal hyperalgesia. The BW-decreasing effect of rimonabant in mice on long-term cafeteria diet did not differ between Gpr55 KO and WT mice. In conclusion, Gpr55 deficiency is associated with subtle effects on diurnal/nocturnal EE and motor activity behaviours but does not appear per se critically required for overall metabolism or behaviours.

Topics: Animals; Behavior, Animal; Body Temperature; Calorimetry; Cannabinoid Receptor Antagonists; Diet, High-Fat; Energy Metabolism; Gene Deletion; Longitudinal Studies; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Motor Activity; Pain; Piperidines; Pyrazoles; Receptors, Cannabinoid; Rimonabant; Thermosensing

Monitoring the levels of sedation-analgesia may be helpful for managing patient stress on minimally invasive medical procedures. Monitors based on EEG analysis and designed to assess general anesthesia cannot distinguish reliably between a light and deep sedation. In this work, the Poincaré plot is used as a nonlinear technique applied to EEG signals in order to characterize the levels of sedation-analgesia, according to observed categorical responses that were evaluated by means of Ramsay Sedation Scale (RSS). To study the effect of high frequencies due to EMG activity, three different frequency ranges (FR1=0.5-110 Hz, FR2=0.5-30 Hz and FR3=30-110 Hz) were considered. Indexes from power spectral analysis and plasma concentration of propofol and remifentanil were also compared with the bispectral index BIS. An adaptive Neurofuzzy Inference System was applied to model the interaction of the best indexes with respect to RSS score for each analysis, and leave-one-out cross validation method was used. The ability of the indexes to describe the level of sedation-analgesia, according with the RSS score, was evaluated using the prediction probability (Pk). The results showed that the ratio SD1/SD2FR3 contains useful information about the sedation level, and SD1FR2 and SD2FR2 had the best performance classifying response to noxious stimuli. Models including parameters from Poincaré plot emerge as a good estimator of sedation-analgesia levels.

Topics: Anesthesia, General; Electroencephalography; Hypnotics and Sedatives; Nonlinear Dynamics; Pain; Piperidines; Propofol; Remifentanil; Signal Processing, Computer-Assisted

Distraction is used clinically to relieve and manage pain. It is hypothesized that pain demands attention and that exposure to another attention-demanding stimulus causes withdrawal of attention away from painful stimuli, thereby reducing perceived pain. We have recently developed a rat model that provides an opportunity to investigate the neurobiological mechanisms mediating distraction-induced analgesia, as these mechanisms are, at present, poorly understood. Given the well-described role of the endogenous cannabinoid (endocannabinoid; EC) system in the modulation of pain and attentional processing, the present study investigated its role in distraction-induced antinociception in rats.. Animals received the CB1 receptor antagonist/inverse agonist, rimonabant or vehicle intraperitoneally, 30 min prior to behavioural evaluation. Formalin-evoked nociceptive behaviour was measured in the presence or absence of a novel-object distractor. Liquid chromatography-tandem mass spectrometry was used to determine the levels of the endogenous cannabinoids anandamide and 2-arachidonoylglycerol (2-AG) in the ventral hippocampus (vHip).. Exposure to a novel object distractor significantly reduced formalin-evoked nociceptive behaviour. The novel object-induced reduction in nociceptive behaviour was attenuated by rimonabant. Novel object exposure was also associated with increased tissue levels of anandamide and 2-AG in the vHip.. These data suggest that the reduction in formalin-evoked nociceptive behaviour that occurs as a result of exposure to a novel object may be mediated by engagement of the EC system, in particular in the vHip. The results provide evidence that the EC system may be an important neural substrate subserving attentional modulation of pain.

Topics: Animals; Arachidonic Acids; Attention; Behavior, Animal; Cannabinoid Receptor Antagonists; Endocannabinoids; Exploratory Behavior; Fear; Glycerides; Hippocampus; Male; Nociception; Pain; Pain Measurement; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Rats; Receptor, Cannabinoid, CB1; Rimonabant

Monoacylglycerol lipase (MAGL) represents a primary degradation enzyme of the endogenous cannabinoid (eCB), 2-arachidonoyglycerol (2-AG). This study reports a potent covalent MAGL inhibitor, SAR127303. The compound behaves as a selective and competitive inhibitor of mouse and human MAGL, which potently elevates hippocampal levels of 2-AG in mice. In vivo, SAR127303 produces antinociceptive effects in assays of inflammatory and visceral pain. In addition, the drug alters learning performance in several assays related to episodic, working and spatial memory. Moreover, long term potentiation (LTP) of CA1 synaptic transmission and acetylcholine release in the hippocampus, two hallmarks of memory function, are both decreased by SAR127303. Although inactive in acute seizure tests, repeated administration of SAR127303 delays the acquisition and decreases kindled seizures in mice, indicating that the drug slows down epileptogenesis, a finding deserving further investigation to evaluate the potential of MAGL inhibitors as antiepileptics. However, the observation that 2-AG hydrolysis blockade alters learning and memory performance, suggests that such drugs may have limited value as therapeutic agents.

Topics: Acetylcholine; Administration, Oral; Analgesics; Animals; Arachidonic Acids; Binding Sites; Brain; Cannabinoid Receptor Antagonists; Carbamates; Chromatography, High Pressure Liquid; Crystallography, X-Ray; Disease Models, Animal; Electric Stimulation; Endocannabinoids; Enzyme Inhibitors; Glycerides; Hippocampus; Humans; Hydrolysis; In Vitro Techniques; Learning; Long-Term Potentiation; Mass Spectrometry; Memory, Short-Term; Mice; Mice, Inbred C57BL; Mice, SCID; Monoacylglycerol Lipases; Pain; Piperidines; Protein Structure, Tertiary; Pyrazoles; Rimonabant; Seizures; Sulfonamides

A novel class of potent cannabinoid receptor 2 (CB2) agonists based on a (S)-piperidine scaffold was identified using ligand-based pharmacophore models. Optimization of solubility and metabolic stability led to the identification of several potent CB2 agonists (e.g., 30) that displayed selectivity over cannabinoid receptor 1 (CB1) and acceptable drug like properties. In rats, compound 30 demonstrated a favorable pharmacokinetic profile and efficacy in a Streptozotocin-induced diabetic neuropathy model, with full reversal of mechanical hyperalgesia.

Topics: Animals; Diabetic Neuropathies; Half-Life; Humans; Ligands; Male; Microsomes, Liver; Pain; Pipecolic Acids; Piperidines; Protein Binding; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Solubility; Structure-Activity Relationship; Thiazines

The pharmacological inhibition of anandamide (AEA) hydrolysis by fatty acid amide hydrolase (FAAH) attenuates pain in animal models of osteoarthritis (OA) but has failed in clinical trials. This may have occurred because AEA also activates transient receptor potential vanilloid type 1 (TRPV1), which contributes to pain development. Therefore, we investigated the effectiveness of the dual FAAH-TRPV1 blocker OMDM-198 in an MIA-model of osteoarthritic pain. We first investigated the MIA-induced model of OA by (1) characterizing the pain phenotype and degenerative changes within the joint using X-ray microtomography and (2) evaluating nerve injury and inflammation marker (ATF-3 and IL-6) expression in the lumbar dorsal root ganglia of osteoarthritic rats and differences in gene and protein expression of the cannabinoid CB1 receptors FAAH and TRPV1. Furthermore, we compared OMDM-198 with compounds acting exclusively on FAAH or TRPV1. Osteoarthritis was accompanied by the fragmentation of bone microstructure and destroyed cartilage. An increase of the mRNA levels of ATF3 and IL-6 and an upregulation of AEA receptors and FAAH in the dorsal root ganglia were observed. OMDM-198 showed antihyperalgesic effects in the OA model, which were comparable with those of a selective TRPV1 antagonist, SB-366,791, and a selective FAAH inhibitor, URB-597. The effect of OMDM-198 was attenuated by the CB1 receptor antagonist, AM-251, and by the nonpungent TRPV1 agonist, olvanil, suggesting its action as an "indirect" CB1 agonist and TRPV1 antagonist. These results suggest an innovative strategy for the treatment of OA, which may yield more satisfactory results than those obtained so far with selective FAAH inhibitors in human OA.

Topics: Activating Transcription Factor 3; Amidohydrolases; Anilides; Animals; Arachidonic Acids; Benzamides; Capsaicin; Carbamates; Cinnamates; Disease Models, Animal; Endocannabinoids; Ganglia, Spinal; Gene Expression; Hyperalgesia; Inflammation; Interleukin-6; Lumbar Vertebrae; Male; Osteoarthritis; Pain; Pain Management; Pain Measurement; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; TRPV Cation Channels

Pain-related functional impairment and behavioral depression are diagnostic indicators of pain and targets for its treatment. Nesting is an innate behavior in mice that may be sensitive to pain manipulations and responsive to analgesics. The goal of this study was to develop and validate a procedure for evaluation of pain-related depression of nesting in mice. Male ICR mice were individually housed and tested in their home cages. On test days, a 5- × 5-cm Nestlet was subdivided into 6 pieces, the pieces were evenly distributed on the cage floor, and Nestlet consolidation was quantified during 100-minute sessions. Baseline nesting was stable within and between subjects, and nesting was depressed by 2 commonly used inflammatory pain stimuli (intraperitoneal injection of dilute acid; intraplantar injection of complete Freund adjuvant). Pain-related depression of nesting was alleviated by drugs from 2 classes of clinically effective analgesics (the nonsteroidal anti-inflammatory drug ketoprofen and the μ-opioid receptor agonist morphine) but not by a drug from a class that has failed to yield effective analgesics (the centrally acting kappa opioid agonist U69,593). Neither ketoprofen nor morphine alleviated depression of nesting by U69,593, which suggests that ketoprofen and morphine effects were selective for pain-related depression of nesting. In contrast to ketoprofen and morphine, the kappa opioid receptor antagonist JDTic blocked depression of nesting by U69,593 but not by acid or complete Freund adjuvant. These results support utility of this procedure to assess expression and treatment of pain-related depression in mice.

Topics: Analgesics, Opioid; Analysis of Variance; Animals; Anti-Inflammatory Agents, Non-Steroidal; Benzeneacetamides; Depression; Dose-Response Relationship, Drug; Freund's Adjuvant; Ketoprofen; Male; Mice; Mice, Inbred ICR; Morphine; Nesting Behavior; Pain; Piperidines; Pyrrolidines; Receptors, Opioid, kappa; Tetrahydroisoquinolines

Over the past decade, pharmacological manipulation of cannabinoid 1 receptor (CB1R) has become an interesting approach for the management of food ingestion disorders, among other physiological functions. Searching for new substances with similar desirable effects, but fewer side-effects we have synthesized a SR141716A (a cannabinoid receptor inverse agonist also called Rimonabant) analog, 1-(2,4-Difluorophenyl)-4-methyl-N-(1-piperidinyl)-5-[4-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxamide, ENP11, that so far, as we have previously shown, has induced changes in glucose availability, i.e. hypoglycemia, in rats. In this study we tested the effects, if any, of ENP11 (0.5, 1.0, and 3.0mg/kg) in food ingestion, core temperature, pain perception and motor control in adult Wistar rats. Results showed that ENP11 reduced food ingestion during the first hour immediately after administration. Likewise, ENP11 (1.0mg/kg) blocked anandamide (AEA)-induced hyperphagia during the first 4h of the dark phase of the light-dark cycle, and it also blocked AEA-induced hypothermia. However, none of the ENP11 doses used affected pain perception or motor control. We believe that ENP11 is a potential useful CB1R antagonist that reduces food ingestion and regulates core temperature.

Topics: Animals; Appetite Depressants; Arachidonic Acids; Body Temperature; Body Weight; Cannabinoid Receptor Antagonists; Eating; Endocannabinoids; Feeding Behavior; Hyperphagia; Male; Pain; Pain Perception; Piperidines; Polyunsaturated Alkamides; Postural Balance; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1

The present study focused on the interactive effects of (Mpa(6))-γ2-MSH-6-12 (Mpa, spinal level) and endokinin A/B (EKA/B, supraspinal level) on pain regulation in mice. EKA/B (30 pmol) only weakened 100 pmol Mpa-induced hyperalgesia at 5 min, but could enhance it during 20-30 min. However, EKA/B (100 pmol) antagonized all dose levels of Mpa significantly at 5 min and blocked them completely at 10 min. EKA/B (3 nmol) co-injected with Mpa presented marked analgesia at 5 min and enduring hyperalgesia within 20-60 min. To investigate the underlying mechanisms between Mpa and EKA/B, SR140333B and SR142801 (NK1 and NK3 receptor antagonists, respectively) were utilized. SR140333B had no influence on Mpa, while SR142801 potentiated it during 20-30 min. Whereas, SR140333B and SR142801 could block the co-administration of Mpa and EKA/B (30 pmol) separately at 5 min and 30 min. These phenomena might attribute to that these two antagonists promoted the antagonism of EKA/B (30 pmol) at the early stage, while antagonized EKA/B preferentially in the latter period. SR140333B weakened the analgesia of EKA/B (3 nmol), but produced no effect on Mpa. However, SR140333B failed to affect the co-injection of Mpa and EKA/B, which implied that EKA/B cooperated with Mpa prior to SR140333B. These results could potentially help to better understand the interaction of NK and MrgC receptors in pain regulation in mice.

Topics: Animals; Dose-Response Relationship, Drug; gamma-MSH; Hyperalgesia; Injections, Intraventricular; Injections, Spinal; Male; Mice; Neurokinin A; Neurokinin B; Neurokinin-1 Receptor Antagonists; Pain; Pain Measurement; Piperidines; Receptors, Neurokinin-3; Tropanes

Previously, we had shown that donepezil provides anti-apoptotic effects associated with the prevention of morphine tolerance to the analgesic effect. In this regard, the present study aimed to evaluate the molecular mechanisms involved in this effect considering the possible role of Toll-like receptor (TLR) 2,4, and the balance between pre-apoptotic and anti-apoptotic Bcl family proteins. To this end, male Wistar rats received daily morphine in combination with either normal saline or donepezil (0.5, 1, or 1.5 mg/kg, ip). The analgesic effect was assessed by the plantar test apparatus. The latency was recorded when the animal responded to the light stimulus. On the 15th day, when no significant difference was observed between morphine and saline groups in terms of analgesia, the frontal cortex and lumbar spinal cord of the animals were dissected. Then, TLR2 and 4, Bcl2, and Bax mRNA fold changes were calculated using Real-time PCR method. The results indicated no significant analgesic effect in the morphine group compared with the saline treated animals after 15 days of injection, while daily co-administration of donepezil with morphine preserved significant analgesia. Moreover, Quantitative PCR showed that morphine significantly increased TLRs and Bax gene expressions and decreased the anti-apoptotic Bcl2. In contrast, donepezil prevented these morphine induced changes in the mentioned gene expressions. Taken together, the results suggest that the neuroprotective effects of donepezil in attenuating morphine-induced tolerance and apoptosis are mediated by preventing morphine-induced changes in TLR2 and 4 gene expressions.

Topics: Analgesics, Opioid; Animals; Apoptosis; bcl-2-Associated X Protein; Donepezil; Drug Tolerance; Frontal Lobe; Gene Expression; Indans; Lumbar Vertebrae; Male; Morphine; Neuroprotective Agents; Pain; Piperidines; Proto-Oncogene Proteins c-bcl-2; Rats, Wistar; RNA, Messenger; Spinal Cord; Toll-Like Receptors

Locus coeruleus (LC) nucleus is involved in noradrenergic descending pain modulation. LC receives dense orexinergic projections from the lateral hypothalamus. Orexin-A and -B are hypothalamic peptides which modulate a variety of brain functions via orexin type-1 (OX1) and orexin type-2 (OX2) receptors. Previous studies have shown that activation of OX1 receptors induces endocannabinoid synthesis and alters synaptic neurotransmission by retrograde signaling via affecting cannabinoid type-1 (CB1) receptors. In the present study the interaction of orexin-A and endocannabinoids was examined at the LC level in a rat model of inflammatory pain. Pain was induced by formalin (2%) injection into the hind paw. Intra-LC microinjection of orexin-A decreased the nociception score during both phases of formalin test. Furthermore, intra-LC microinjection of either SB-334867 (OX1 receptor antagonist) or AM251 (CB1 receptor antagonist) increased flinches and also the nociception score during phase 1, 2 and the inter-phase of formalin test. The analgesic effect of orexin-A was diminished by prior intra-LC microinjection of either SB-334867 or AM251. This data show that, activation of OX1 receptors in the LC can induce analgesia and also the blockade of OX1 or CB1 receptors is associated with hyperalgesia during formalin test. Our findings also suggest that CB1 receptors may modulate the analgesic effect of orexin-A. These results outline a new mechanism by which orexin-A modulates the nociceptive processing in the LC nucleus.

Topics: Analgesics; Analysis of Variance; Animals; Benzoxazoles; Carrier Proteins; Dose-Response Relationship, Drug; Formaldehyde; Locus Coeruleus; Male; Microinjections; Naphthyridines; Orexins; Pain; Pain Measurement; Piperidines; Pyrazoles; Rats; Rats, Wistar; Urea

The interstitial cells of Cajal (ICCs) are the pacemaker cells in the gastrointestinal (GI) tract. In the present study, the effects of Dangkwisoo‑san (DS) on pacemaker potentials in cultured ICCs from the small intestine of the mouse were investigated. The whole‑cell patch‑clamp configuration was used to record pacemaker potentials from cultured ICCs and the increase in intracellular Ca2+ concentration ([Ca2+i) was analyzed in cultured ICCs using fura‑2‑acetoxymethyl ester. The generation of pacemaker potentials in the ICCs was observed. DS produced pacemaker depolarizations in a concentration dependent manner in current clamp mode. The 4‑diphenylacetoxy‑N‑methyl‑piperidine methiodide muscarinic M3 receptor antagonist inhibited DS‑induced pacemaker depolarizations, whereas methoctramine, a muscarinic M2 receptor antagonist, did not. When guanosine 5'‑[β‑thio] diphosphate (GDP‑β‑S; 1 mM) was in the pipette solution, DS marginally induced pacemaker depolarizations, whereas low Na+ solution externally eliminated the generation of pacemaker potentials and inhibited the DS‑induced pacemaker depolarizations. Additionally, the nonselective cation channel blocker, flufenamic acid, inhibited the DS‑induced pacemaker depolarizations. Pretreatment with Ca2+‑free solution and thapsigargin, a Ca2+‑ATPase inhibitor in the endoplasmic reticulum, also eliminated the generation of pacemaker currents and suppressed the DS‑induced pacemaker depolarizations. In addition, [Ca2+]i analysis revealed that DS increased [Ca2+]i. These results suggested that DS modulates pacemaker potentials through muscarinic M3 receptor activation in ICCs by G protein‑dependent external and internal Ca2+ regulation and external Na+. Therefore, DS were observed to affect intestinal motility through ICCs.

Topics: Animals; Calcium-Transporting ATPases; Cells, Cultured; Diamines; Female; Gastrointestinal Motility; Guanosine Diphosphate; Interstitial Cells of Cajal; Intestine, Small; Male; Mice; Mice, Inbred BALB C; Pain; Phytotherapy; Piperidines; Plants, Medicinal; Receptor, Muscarinic M2; Receptor, Muscarinic M3; Thapsigargin; Thionucleotides

Treatment of pain with morphine and its congeners in sickle cell anemia is suboptimal, warranting the need for analgesics devoid of side effects, addiction and tolerance liability. Small-molecule nociceptin opioid receptor ligands show analgesic efficacy in acute and chronic pain models. We show that AT-200, a high affinity nociceptin opioid receptor agonist with low efficacy at the mu opioid receptor, ameliorated chronic and hypoxia/reoxygenation-induced mechanical, thermal and deep tissue/musculoskeletal hyperalgesia in HbSS-BERK sickle mice. The antinociceptive effect of AT-200 was antagonized by SB-612111, a nociceptin opioid receptor antagonist, but not naloxone, a non-selective mu opioid receptor antagonist. Daily 7-day treatment with AT-200 did not develop tolerance and showed a sustained anti-nociceptive effect, which improved over time and led to reduced plasma serum amyloid protein, neuropeptides, inflammatory cytokines and mast cell activation in the periphery. These data suggest that AT-200 ameliorates pain in sickle mice via the nociceptin opioid receptor by reducing inflammation and mast cell activation without causing tolerance. Thus, nociceptin opioid receptor agonists are promising drugs for treating pain in sickle cell anemia.

Topics: Anemia, Sickle Cell; Animals; Cycloheptanes; Mast Cells; Mice; Mice, Transgenic; Nociceptin Receptor; Pain; Piperidines; Receptors, Opioid

Epoxyeicosatrienoic acids (EETs) are potent endogenous analgesic metabolites produced from arachidonic acid by cytochrome P450s (P450s). Metabolism of EETs by soluble epoxide hydrolase (sEH) reduces their activity, while their stabilization by sEH inhibition decreases both inflammatory and neuropathic pain. Here, we tested the complementary hypothesis that increasing the level of EETs through induction of P450s by omeprazole (OME), can influence pain related signaling by itself, and potentiate the anti-hyperalgesic effect of sEH inhibitor. Rats were treated with OME (100mg/kg/day, p.o., 7 days), sEH inhibitor TPPU (3mg/kg/day, p.o.) and OME (100mg/kg/day, p.o., 7 days)+TPPU (3mg/kg/day, p.o., last 3 days of OME dose) dissolved in vehicle PEG400, and their effect on hyperalgesia (increased sensitivity to pain) induced by PGE2 was monitored. While OME treatment by itself exhibited variable effects on PGE2 induced hyperalgesia, it strongly potentiated the effect of TPPU in the same assay. The significant decrease in pain with OME+TPPU treatment correlated with the increased levels of EETs in plasma and increased activities of P450 1A1 and P450 1A2 in liver microsomes. The results show that reducing catabolism of EETs with a sEH inhibitor yielded a stronger analgesic effect than increasing generation of EETs by OME, and combination of both yielded the strongest pain reducing effect under the condition of this study.

Topics: Analgesics; Animals; Cytochrome P-450 Enzyme System; Dinoprostone; Enzyme Inhibitors; Epoxide Hydrolases; Epoxy Compounds; Hyperalgesia; Male; Microsomes, Liver; Omeprazole; Pain; Phenylurea Compounds; Piperidines; Rats; Rats, Sprague-Dawley

Psychological processes such as expectancy, attention, and affect directly influence clinical outcomes. These factors are grouped together as "nonspecific" factors, or placebo effects, in the medical literature, and their individual contributions are rarely considered. The pain-reducing effects of analgesic treatments may reflect changes in these psychological factors, rather than pure drug effects on pain. Furthermore, drug effects may not be isolated by drug vs. placebo comparisons if drugs interact with relevant psychological processes.. We sought to determine whether the analgesic effects of opioid and placebo treatment are mediated by changes in attention, expectancy, or affect.. We crossed intravenous administration of a potent opioid analgesic, remifentanil, with information about drug delivery (treatment expectancy or placebo) using a balanced placebo design. We measured drug and treatment expectancy effects on pain, attention, and responses to emotional images. We also examined interactions with cue-based expectations about noxious stimulation or stimulus expectancy.. Pain was additively influenced by treatment expectancy, stimulus expectancy, and drug concentration. Attention performance showed a small but significant interaction between drug and treatment expectancy. Finally, remifentanil enhanced responses to both positive and negative emotional images.. The pain-relieving effects of opioid drugs are unlikely to be mediated by changes in threat or affective processing. Standard open-label opioid administration influences multiple clinically relevant cognitive and emotional processes. Psychological factors can combine with drug effects to influence multiple outcomes in distinct ways. The influence of specific psychological factors should be considered when developing and testing pharmacological treatments.

Topics: Adult; Affect; Analgesics, Opioid; Anticipation, Psychological; Attention; Female; Humans; Male; Pain; Piperidines; Placebo Effect; Randomized Controlled Trials as Topic; Remifentanil; Young Adult

The analgesic efficacy of cannabinoids in chronic pain models is limited by side-effects. It has been proposed that this might be overcome by using agents which indirectly activate the endocannabinoid system. We examined the analgesic and side-effect profile of the dual FAAH/MAGL inhibitor JZL195 in an inflammatory pain model. The effect of systemic injections of a range of doses of JZL195 and the pan-cannabinoid receptor agonist WIN55212 were performed 1 day following intraplantar injection of CFA in C57BL/6 mice. JZL195 and WIN55212 both reduced mechanical allodynia and thermal hyperalgesia, and produced catalepsy and sedation in a dose dependent manner. Unlike WIN55212, JZL195 reduced allodynia at doses below those at which side-effects were observed. The effects of JZL195 and WIN55212 were abolished by co-application with the CB1 antagonist AM251. The CB2 antagonist also reduced the JZL195 anti-allodynia, and reversed the WIN55212 anti-allodynia. The reduction in allodynia produced by JZL195 was greater than that produced individually by the FAAH and MAGL inhibitors, URB597 and JZL184. These findings suggest that JZL195 reduces inflammation induced allodynia at doses below those which produce side-effects, and displays greater efficacy that FAAH or MAGL inhibitors. Thus, dual FAAH/MAGL inhibition has the potential to alleviate inflammatory pain with reduced cannabinoid-like side-effects.

Topics: Amidohydrolases; Analgesics; Analysis of Variance; Animals; Arthritis, Experimental; Benzamides; Benzoxazines; Carbamates; Disease Models, Animal; Dose-Response Relationship, Drug; Exploratory Behavior; Male; Mice; Mice, Inbred C57BL; Morpholines; Motor Activity; Naphthalenes; Pain; Pain Measurement; Piperazines; Piperidines; Pyrazoles; Time Factors

Alzheimer's disease is an advanced dementia. In this disease, little by little the brain loses most of its functions. Pain is a prevalent complaint. It seems easing the pain had the better recovery to antipsychotic drug in controlling agitation in dementia patients. Donepezil is a drug that is used to treat Alzheimer's disease. This brief report describes an 83-year-old woman with Alzheimer's disease who experienced boredom and changes in attitude for about 1 year and complained about general pain in her extremity. Starting donepezil controlled the patient's symptoms. As soon as the treatment started, all pain was dramatically eliminated and her behavior improved. Donepezil may be effective in controlling the pain and improve the outcome of these patients.

Topics: Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Female; Humans; Indans; Pain; Piperidines

The endogenous cannabinoid (endocannabinoid) system plays a key role in the modulation of aversive and nociceptive behaviour. The components of the endocannabinoid system are expressed throughout the hippocampus, a brain region implicated in both conditioned fear and pain. In light of evidence that pain can impact on the expression of fear-related behaviour, and vice versa, we hypothesised that exogenous administration of the endocannabinoid 2-arachidonoyl glycerol (2-AG) into the ventral hippocampus (vHip) would differentially regulate fear responding in the absence vs. the presence of formalin-evoked nociceptive tone. Fear-conditioned rats showed significantly increased freezing and a reduction in formalin-evoked nociceptive behaviour upon re-exposure to a context previously paired with footshock. Bilateral microinjection of 2-AG into the vHip significantly reduced contextually induced freezing in non-formalin-treated rats, and reduced formalin-evoked nociceptive behaviour in non-fear-conditioned rats. In contrast, 2-AG microinjection had no effect on fear responding in formalin-treated rats, and no effect on nociceptive behaviour in fear-conditioned rats. The inhibitory effect of 2-AG on fear-related behaviour, but not pain-related behaviour, was blocked by co-administration of the cannabinoid receptor 1 (CB1) antagonist/inverse agonist rimonabant. Tissue levels of the endocannabinoids N-arachidonoylethanolamide (anandamide, AEA) and 2-AG were similar in the vHip of fear-conditioned rats receiving formalin injection and the vHip of fear-conditioned rats receiving saline injection. However, the levels of AEA and 2-AG were significantly lower in the contralateral ventrolateral periaqueductal grey of formalin-treated fear-conditioned rats than in that of their saline-treated counterparts. These data suggest that 2-AG-CB1 receptor signalling in the vHip has an anti-aversive effect, and that this effect is abolished in the presence of a persistent pain state.

Topics: Animals; Arachidonic Acids; Cannabinoid Receptor Agonists; Cannabinoid Receptor Antagonists; Conditioning, Classical; Endocannabinoids; Fear; Freezing Reaction, Cataleptic; Glycerides; Hippocampus; Injections, Intraventricular; Mice; Nociception; Pain; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Rats; Receptor, Cannabinoid, CB1; Rimonabant

Epidemiological studies demonstrate that pain frequently occurs comorbid with depression. Gentiopicroside (Gent) is a secoiridoid compound isolated from Gentiana lutea that exhibits analgesic properties and inhibits the expression of GluN2B-containing N-methyl-D-aspartate (NMDA) receptors in the anterior cingulate cortex of mice. However, the effects of Gent on the reserpine-induced pain/depression dyad and its underlying mechanisms are unclear. Reserpine administration (1 mg/kg subcutaneous daily for 3 days) caused a significant decrease in the nociceptive threshold as evidenced by the reduced paw withdrawal latency in response to a radiant heat source and mechanical allodynia. Behavioral detection indicated a significant increase in immobility time during a forced swim test, as well as decreased time in the central area and total travel distance in an open field test. Furthermore, reserpinized animals exhibited increased oxidative stress. Systemic Gent administration dose-dependently ameliorated the behavioral deficits associated with reserpine-induced pain/depression dyad. At the same time, the decrease in biogenic amine levels (norepinephrine, dopamine, and serotonin) was integrated with the increase in caspase-3 levels and GluN2B-containing NMDA receptors in the amygdala of the reserpine-injected mice. Gent significantly reversed the changes in the levels of biogenic amines, caspase-3, and GluN2B-containing NMDA receptors in amygdala. However, Gent did not affect the expression of GluN2A-containing NMDA receptors. The inhibitory effects of Gent on oxidative stress were occluded by simultaneous treatment of GluN2B receptors antagonist Ro25-6981. Our study provides strong evidence that Gent inhibits reserpine-induced pain/depression dyad by downregulating GluN2B receptors in the amygdala.

Topics: Amygdala; Analgesics; Animals; Biogenic Amines; Brain Chemistry; Caspase 3; Chronic Pain; Depression; Disease Models, Animal; Down-Regulation; Excitatory Amino Acid Antagonists; Exploratory Behavior; Hot Temperature; Hyperalgesia; Iridoid Glucosides; Male; Mice; Mice, Inbred C57BL; Nerve Tissue Proteins; Oxidative Stress; Pain; Pain Threshold; Phenols; Piperidines; Receptors, N-Methyl-D-Aspartate; Reserpine; Stress, Mechanical; Swimming

The nociceptin opioid receptor (NOP) and its endogenous peptide ligand nociceptin/orphanin FQ have been shown to modulate the pharmacological effects of the classical opioid receptor system. Suppression of opioid-induced reward associated with mu-opioid receptor (MOP)-mediated analgesia, without decreasing anti-nociceptive efficacy, can potentially be achieved with NOP agonists having bifunctional agonist activity at MOP, to afford 'non-addicting' analgesics. In Part II of this series, we describe a continuing structure-activity relationship (SAR) study of the NOP-selective piperidin-4-yl-1,3-dihydroindol-2-one scaffold, to obtain bifunctional activity at MOP, and a suitable ratio of NOP/MOP agonist activity that produces a non-addicting analgesic profile. The SAR reported here is focused on the influence of various piperidine nitrogen aromatic substituents on the ratio of binding affinity and intrinsic activity at both the NOP and MOP receptors.

Topics: Analgesics; Animals; Ligands; Mice; Models, Animal; Nociceptin Receptor; Pain; Piperidines; Protein Binding; Receptors, Opioid; Receptors, Opioid, mu; Structure-Activity Relationship

Topics: Analgesics, Opioid; Female; Humans; Male; Pain; Piperidines; Remifentanil

Monoacylglycerol lipase (MGL) is the main enzyme responsible for degradation of the endocannabinoid 2-arachidonoylglycerol (2-AG). Selective inhibitors of MGL have antinociceptive effects upon acute administration and, therefore, hold promise as analgesics. To gain insight into the possible consequences of their prolonged administration, genetically modified mice with the knocked-out MGL gene were tested in several models of acute (phasic, tonic) and chronic (inflammatory, neuropathic) pain. MGL knockout mice showed normal acute phasic pain perception (pain thresholds) and no alleviation of pain perception in models of inflammatory and neuropathic pain. However, compared with wild-type controls, they showed significantly augmented nociceptive behavior in models of acute somatic and visceral tonic pain (formalin and acetic acid tests). The observed proalgesic changes in perception of tonic pain in MGL knockouts could have resulted from desensitization of cannabinoid receptors (known to occur after genetic inactivation of MGL). Supporting this notion, chronic pretreatment with the selective CB1 receptor antagonist AM 251 (employed to re-sensitize cannabinoid receptors in MGL knockouts) resulted in normalization of their tonic pain-related behaviors. Similar augmentation of tonic pain-related behaviors was replicated in C57BL/6N mice pretreated chronically with the selective MGL inhibitor JZL 184 (employed to pharmacologically desensitize CB1 receptors). These findings imply that prolonged use of MGL inhibitors, at doses causing close to complete inhibition of MGL enzymatic activity, not only have no beneficial analgesic effects, they may lead to exacerbation of some types of pain (particularly those with a tonic component).

Topics: Animals; Arachidonic Acids; Benzodioxoles; Cannabinoid Receptor Modulators; Endocannabinoids; Glycerides; Inflammation; Male; Mice; Mice, Inbred C57BL; Mice, Inbred CBA; Mice, Knockout; Neuralgia; Pain; Pain Threshold; Phosphotransferases (Alcohol Group Acceptor); Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1

A novel series of N-(N-methylpiperazinoacetyl)-2,6-diarylpiperidin-4-one derivatives (1c-3c and 5c) were synthesized, via base catalyzed nucleophilic substitution of N-chloroacetyl-2,6-diarylpiperidin-4-ones (1b-6b) with N-methyl piperazine. The newly synthesized compounds were characterized by FTIR, Mass and NMR spectral studies. All the compounds were screened for their possible analgesic and antipyretic activities. The compound 2c exhibited promising antipyretic activity, comparable to that of paracetamol at 60 mg/kg dose. The compounds 2b and 2c showed significant analgesic profile at a dose of 60 mg/kg and were also found to be more potent than the reference drug, diclofenac sodium. Thus, it can be concluded that the synthesized 2,6-diarylpiperidin-4-ones exhibit promising antipyretic and analgesic activities and could be potential drug candidates.

Topics: Acetic Acid; Analgesics; Animals; Antipyretics; Body Temperature; Dose-Response Relationship, Drug; Fever; Male; Mice; Pain; Pain Measurement; Piperazines; Piperidines; Rats; Rats, Wistar; Rectum

The objective of the present study was to validate the qCON index of hypnotic effect and the qNOX index of nociception. Both indices are derived from the frontal electroencephalogram (EEG) and implemented in the qCON 2000 monitor (Quantium Medical, Barcelona, Spain).. The study was approved by the local ethics committee, including data from 60 patients scheduled for ambulatory surgery undergoing general anaesthesia with propofol and remifentanil, using TCI. The Bis (Covidien, Boulder, CO, USA) was recorded simultaneously with the qCON. Loss of eyelash reflex [loss of consciousness (LOC)] was recorded, and prediction probability for Bis and qCON was calculated. Movement as a response to noxious stimulation [laryngeal mask airway (LMA) insertion, laryngoscopy and tracheal intubation] was registered. The correlation coefficient between qCON and Bis was calculated. The patients were divided into movers/non-movers as a response to noxious stimulation. A paired t-test was used to assess significant difference for qCON and qNOX for movers/non-movers.. The prediction probability (Pk) and the standard error (SE) for qCON and Bis for detecting LOC was 0.92 (0.02) and 0.94 (0.02) respectively (t-test, no significant difference). The R between qCON and Bis was 0.85. During the general anaesthesia (Ce propofol > 2 μg/ml, Ce remifentanil > 2 ng/ml), the mean value and standard deviation (SD) for qCON was 45 (8), while for qNOX it was 40 (6). The qNOX pre-stimuli values were significantly different (P < 0.05) for movers/non-movers as a response to LMA insertion [62.5 (24.0) vs. 45.5 (24.1)], tracheal intubation [58.7 (21.8) vs. 41.4 (20.9)], laryngoscopy [54.1 (21.4) vs. 41.0 (20.8)]. There were no significant differences in remifentanil or propofol effect-site concentrations for movers vs. non-movers.. The qCON was able to reliably detect LOC during general anaesthesia with propofol and remifentanil. The qNOX showed significant overlap between movers and non-movers, but it was able to predict whether or not the patient would move as a response to noxious stimulation, although the anaesthetic concentrations were similar.

Topics: Ambulatory Surgical Procedures; Analgesics; Anesthesia, General; Anesthetics, General; Consciousness Monitors; Dyskinesias; Electroencephalography; Humans; Hypnotics and Sedatives; Intraoperative Awareness; Intubation, Intratracheal; Laryngeal Masks; Laryngoscopy; Monitoring, Intraoperative; Nociception; Pain; Piperidines; Propofol; Reflex; Remifentanil; Unconsciousness

Endogenous cannabinoids (endocannabinoids) in the periaqueductal grey (PAG) play a vital role in mediating stress-induced analgesia. This analgesic effect of endocannabinoids is enhanced by pharmacological inhibition of their degradative enzymes. However, the specific effects of endocannabinoids and the inhibitors of their degradation are largely unknown within this pain-modulating region.. In vitro electrophysiological recordings were conducted from PAG neurons in rat midbrain slices. The effects of the major endocannabinoids and their degradation inhibitors on inhibitory GABAergic synaptic transmission were examined.. Exogenous application of the endocannabinoid, anandamide (AEA), but not 2-arachidonoylglycerol (2-AG), produced a reduction in inhibitory GABAergic transmission in PAG neurons. This AEA-induced suppression of inhibition was enhanced by the fatty acid amide hydrolase (FAAH) inhibitor, URB597, whereas a 2-AG-induced suppression of inhibition was unmasked by the monoacylglycerol lipase (MGL) inhibitor, JZL184. In addition, application of the CB1 receptor antagonist, AM251, facilitated the basal GABAergic transmission in the presence of URB597 and JZL184, which was further enhanced by the dual FAAH/MGL inhibitor, JZL195.. Our results indicate that AEA and 2-AG act via disinhibition within the PAG, a cellular action consistent with analgesia. These actions of AEA and 2-AG are tightly regulated by their respective degradative enzymes, FAAH and MGL. Furthermore, individual or combined inhibition of FAAH and/or MGL enhanced tonic disinhibition within the PAG. Therefore, the current findings support the therapeutic potential of FAAH and MGL inhibitors as a novel pharmacotherapy for pain.

Topics: Amidohydrolases; Animals; Arachidonic Acids; Benzamides; Benzodioxoles; Carbamates; Endocannabinoids; Female; Glycerides; In Vitro Techniques; Inhibitory Postsynaptic Potentials; Male; Monoacylglycerol Lipases; Neurons; Pain; Periaqueductal Gray; Piperidines; Polyunsaturated Alkamides; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Synaptic Transmission

Topics: Acetamides; Administration, Oral; Benzamides; Calcium Channel Blockers; Capsaicin; Clinical Trials, Phase I as Topic; Dose-Response Relationship, Drug; Evoked Potentials, Somatosensory; Humans; Lasers; Male; Pain; Piperidines; Time Factors

The basolateral amygdala (BLA) is a key substrate facilitating the expression of fear-conditioned analgesia (FCA). However, the neurochemical mechanisms in the BLA which mediate this potent suppression of pain responding during fear remain unknown. The present study investigated the role of cannabinoid1 (CB1) receptors and interactions with GABAergic (GABAA receptor) and glutamatergic (metabotropic glutamate receptor type 5; mGluR5) signalling in the BLA in formalin-evoked nociceptive behaviour and FCA in rats. Reexposure to a context previously paired with foot shock significantly reduced formalin-evoked nociceptive behaviour. Systemic or intra-BLA microinjection of the CB1 receptor antagonist/inverse agonist AM251 prevented this expression of FCA, while injection of AM251 into the central nucleus of the amygdala did not. The suppression of FCA by systemic AM251 administration was partially attenuated by intra-BLA administration of either the GABAA receptor antagonist bicuculline or the mGluR5 antagonist 2-methyl-6-(phenylethynyl) pyridine, (MPEP). Bilateral microinjection of MPEP, but not bicuculline, alone into the BLA enhanced formalin-evoked nociceptive behaviour. Postmortem analyses revealed that FCA was associated with a significant increase in tissue levels of anandamide in the BLA side contralateral to intraplantar formalin injection. In addition, fear-conditioned rats exhibited a robust formalin-induced increase in levels of 2-arachidonyl glycerol and N-palmitoylethanolamide in the ipsilateral and contralateral BLA, respectively. These data suggest that CB1 receptors in the BLA facilitate the expression of FCA, through a mechanism which is likely to involve the modulation of GABAergic and glutamatergic signalling.

Topics: Amygdala; Analgesia; Animals; Arachidonic Acids; Cannabinoid Receptor Agonists; Conditioning, Psychological; Dose-Response Relationship, Drug; Endocannabinoids; Ethanolamines; Excitatory Amino Acid Agents; Fear; Functional Laterality; GABA Agents; Glycerides; Injections, Intraventricular; Male; Pain; Pain Measurement; Piperidines; Pyrazoles; Rats; Receptor, Cannabinoid, CB1; Receptors, GABA; Receptors, Glutamate; Signal Transduction

Ventilatory depression is a serious side-effect of opioid analgesics. Naloxone, an antagonist of opioid receptors, eliminates not only ventilatory depression but also analgesic effect of opioids. Pharmacological dissociation of adverse reactions from the main action is important clinically and basically. Cholinergic and serotonergic mechanisms are suggested to counteract the opioid-induced ventilatory disturbances, but their influence on analgesia is still controversial. The present study evaluated the effects of cholinesterase inhibitors and serotonin-1A (5-HT1A) receptor agonists on morphine (1.0mg/kg, i.v.)-induced ventilatory depression and analgesia in rats. In anesthetized animals, spontaneous ventilation and hind leg withdrawal reflexes against nociceptive thermal stimuli were measured simultaneously. Physostigmine (0.1 and 0.2mg/kg, i.v.) and donepezil (0.5 and 1.0mg/kg, i.v.) relieved the morphine-induced ventilatory depression and enhanced its antinociception. On the other hand, (±)-8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT, 0.03 and 0.1mg/kg, i.v.) and buspirone (0.1 and 0.3mg/kg, i.v.) did not influence antinociception of morphine while they restored the decreased ventilation. In unanesthetized animals, hypercapnic ventilatory response was measured by using whole-body plethysmography. Physostigmine (0.3mg/kg, i.p.), donepezil (1.0mg/kg, i.p.), 8-OH-DPAT (0.3mg/kg, i.p.) and buspirone (3.0mg/kg, i.p.) all recovered the morphine (10mg/kg, i.p.)-induced depression of hypercapnic ventilatory response. The present study suggests that activation of cholinergic or serotonergic (5-HT1A) mechanisms may be a useful therapeutic approach for morphine-induced ventilatory depression without loss of its analgesic action.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Analgesia; Animals; Buspirone; Cholinesterase Inhibitors; Donepezil; Indans; Male; Morphine; Pain; Physostigmine; Piperidines; Rats; Rats, Wistar; Respiratory Insufficiency; Serotonin 5-HT1 Receptor Agonists

The in vivo preclinical pharmacodynamic profile of TD-1211, a selective opioid receptor antagonist currently under development for the treatment of opioid-induced constipation, was compared to that of the clinically studied opioid antagonists, naltrexone, alvimopan, and ADL 08-0011 (the primary active metabolite of alvimopan). The oral activity of TD-1211 was evaluated in models of gastrointestinal (GI) and central nervous system (CNS) function in the rat and dog. Oral administration of TD-1211, naltrexone, and ADL 08-0011 reversed loperamide-induced inhibition of gastric emptying and castor oil-induced diarrhea in rats and nonproductive GI circular smooth muscle contractility in dogs. Alvimopan was only efficacious in the castor oil model. Oral administration of naltrexone and ADL 08-0011, but not TD-1211 or alvimopan, was associated with a CNS withdrawal response in morphine-dependent mice, inhibition of morphine-induced anti-nociception in rat and dog hot plate tests, and hypothermia and sedation in dogs. It is concluded that TD-1211 has potent in vivo GI activity, consistent with opioid receptor antagonism, but has no significant CNS activity. The data from these studies support the clinical development of TD-1211 as a novel treatment for opioid-induced GI dysfunction.

Topics: Administration, Oral; Analgesics, Opioid; Animals; Benzamides; Central Nervous System; Dogs; Female; Gastrointestinal Tract; Male; Mice; Morphine; Naltrexone; Narcotic Antagonists; Pain; Piperidines; Rats; Rats, Sprague-Dawley; Substance Withdrawal Syndrome; Tropanes

Persistent pain is measured by means of self-report, the sole reliance on which hampers diagnosis and treatment. Functional magnetic resonance imaging (fMRI) holds promise for identifying objective measures of pain, but brain measures that are sensitive and specific to physical pain have not yet been identified.. In four studies involving a total of 114 participants, we developed an fMRI-based measure that predicts pain intensity at the level of the individual person. In study 1, we used machine-learning analyses to identify a pattern of fMRI activity across brain regions--a neurologic signature--that was associated with heat-induced pain. The pattern included the thalamus, the posterior and anterior insulae, the secondary somatosensory cortex, the anterior cingulate cortex, the periaqueductal gray matter, and other regions. In study 2, we tested the sensitivity and specificity of the signature to pain versus warmth in a new sample. In study 3, we assessed specificity relative to social pain, which activates many of the same brain regions as physical pain. In study 4, we assessed the responsiveness of the measure to the analgesic agent remifentanil.. In study 1, the neurologic signature showed sensitivity and specificity of 94% or more (95% confidence interval [CI], 89 to 98) in discriminating painful heat from nonpainful warmth, pain anticipation, and pain recall. In study 2, the signature discriminated between painful heat and nonpainful warmth with 93% sensitivity and specificity (95% CI, 84 to 100). In study 3, it discriminated between physical pain and social pain with 85% sensitivity (95% CI, 76 to 94) and 73% specificity (95% CI, 61 to 84) and with 95% sensitivity and specificity in a forced-choice test of which of two conditions was more painful. In study 4, the strength of the signature response was substantially reduced when remifentanil was administered.. It is possible to use fMRI to assess pain elicited by noxious heat in healthy persons. Future studies are needed to assess whether the signature predicts clinical pain. (Funded by the National Institute on Drug Abuse and others.).

Topics: Adult; Analgesics, Opioid; Artificial Intelligence; Brain; Brain Mapping; Female; Hot Temperature; Humans; Magnetic Resonance Imaging; Male; Pain; Pain Measurement; Piperidines; Remifentanil; ROC Curve; Sensitivity and Specificity; Young Adult

Cannabinoid CB1 receptors have been implicated in the antinociceptive effect of paracetamol. In the current study, we examined whether blockade of CB1 receptors prevent the analgesic activity of dipyrone, in a similar way to paracetamol. Hot-plate and tail-flick tests were used to assess the antinociceptive activity in mice. Dipyrone and WIN 55,212-2, a cannabinoid agonist, exerted significant antinociceptive effects in both hot-plate and tail flick tests. The CB1 receptor antagonist, AM-251 (3 mg/kg), at a dose which had no effect when used alone, did not alter the antinociceptive effect of dipyrone, whereas completely prevented the antinociceptive activity of WIN 55,212-2 in both thermal antinociceptive tests. Our findings suggest that, unlike paracetamol, cannabinoid CB1 receptors do not participate in the antinociceptive action of dipyrone when acute pain tests used.

Topics: Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Benzoxazines; Cannabinoid Receptor Agonists; Cannabinoid Receptor Antagonists; Dipyrone; Male; Mice; Mice, Inbred BALB C; Morpholines; Naphthalenes; Pain; Pain Measurement; Pain Threshold; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1

Topics: Analgesics; Animals; Brain; Inflammation; Male; Pain; Piperidines; Receptors, Metabotropic Glutamate; Receptors, Opioid, delta; Receptors, Opioid, mu

Despite common pathophysiological mechanisms, inflammatory and neuropathic pain do not respond equally to the analgesic effect of antidepressants, except for selective serotonin reuptake inhibitors (SSRIs), which show a limited efficacy in both conditions. We previously demonstrated that an interfering peptide (TAT-2ASCV) disrupting the interaction between 5-HT2A receptors and its associated PDZ proteins (e.g. PSD-95) reveals a 5-HT2A receptor-mediated anti-hyperalgesic effect and enhances the efficacy of fluoxetine (a SSRI) in diabetic neuropathic pain conditions in rats. Here, we have examined whether the same strategy would be useful to treat inflammatory pain. Sub-chronic inflammatory pain was induced by injecting λ-carrageenan (100 µl, 2%) into the left hind paw of the rat. Mechanical hyperalgesia was assessed after acute treatment with TAT-2ASCV or/and fluoxetine (SSRI) 2.5 h after λ-carrageenan injection. Possible changes in the level of 5-HT2A receptors and its associated PDZ protein PSD-95 upon inflammation induction were quantified by Western blotting in dorsal horn spinal cord. Administration of TAT-2ASCV peptide (100 ng/rat, intrathecally) but not fluoxetine (10 mg/kg, intraperitoneally) relieves mechanical hyperalgesia (paw pressure test) in inflamed rats. This anti-hyperalgesic effect involves spinal 5-HT2A receptors and GABAergic interneurons as it is abolished by a 5-HT2A antagonist (M100907, 150 ng/rat, intrathecally) and a GABAA antagonist, (bicuculline, 3 µg/rat, intrathecally). We also found a decreased expression of 5-HT2A receptors in the dorsal spinal cord of inflamed animals which could not be rescued by TAT-2ASCV injection, while the amount of PSD-95 was not affected by inflammatory pain. Finally, the coadministration of fluoxetine does not further enhance the anti-hyperalgesic effect of TAT-2ASCV peptide. This study reveals a role of the interactions between 5-HT2A receptors and PDZ proteins in the pathophysiological pathways of inflammatory pain and opens new perspectives in its control thanks to molecules disrupting 5-HT2A receptor/PDZ protein interactions.

Topics: Animals; Bicuculline; Carrageenan; Disks Large Homolog 4 Protein; Fluorobenzenes; Fluoxetine; Hyperalgesia; Inflammation; Injections; Intracellular Signaling Peptides and Proteins; Male; Membrane Proteins; Pain; Peptides; Piperidines; Posterior Horn Cells; Protein Binding; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2A; Serotonin 5-HT2 Receptor Antagonists

The level of sedation in patients undergoing medical procedures evolves continuously, such as the effect of the anesthetic and analgesic agents is counteracted by pain stimuli. The monitors of depth of anesthesia, based on the analysis of the electroencephalogram (EEG), have been progressively introduced into the daily practice to provide additional information about the state of the patient. However, the quantification of analgesia still remains an open problem. The purpose of this work is to analyze the capability of prediction of nociceptive responses based on the time-frequency representation (TFR) of EEG signal. Functions of spectral entropy, instantaneous power and instantaneous frequency were calculated in order to predict the presence or absence of the nociceptive responses to different stimuli during sedation in endoscopy procedure. Values of prediction probability of Pk above 0.75 and percentages of sensitivity and specificity above 70% and 65% respectively were achieved combining TFR functions with bispectral index (BIS) and with concentrations of propofol (CeProp) and remifentanil (CeRemi).

Topics: Consciousness Monitors; Electroencephalography; Endoscopy; Entropy; Humans; Hypnotics and Sedatives; Nociceptors; Pain; Piperidines; Propofol; Remifentanil

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 present study tested whether the selective monoacylglycerol lipase (MAGL) inhibitor JZL184 would reduce allodynia and paw edema in the carrageenan test.. The anti-edematous and anti-allodynic effects of JZL184 were compared to those of PF-3845, an inhibitor of fatty acid amide hydrolase (FAAH), and diclofenac, a non-selective cyclooxygenase inhibitor. Cannabinoid receptor involvement in the anti-edematous and anti-allodynic effects of JZL184 was evaluated by administration of the respective CB1 and CB2 receptor antagonists rimonabant and SR144528 as well as with CB1(-/-) and CB2(-/-) mice. JZL184 (1.6, 4, 16, or 40mg/kg) was administered for six days to assess tolerance.. JZL184 administered before or after carrageenan significantly attenuated carrageenan-induced paw edema and mechanical allodynia. Complementary genetic and pharmacological approaches revealed that the anti-allodynic effects of JZL184 required both CB1 and CB2 receptors, but only CB2 receptors mediated its anti-edematous actions. Importantly, both the anti-edematous and anti-allodynic effects underwent tolerance following repeated injections of high dose JZL184 (16 or 40mg/kg), but repeated administration of low dose JZL184 (4mg/kg) retained efficacy.. These results suggest that the MAGL inhibitor JZL184 reduces inflammatory nociception through the activation of both CB1 and CB2 receptors, with no evidence of tolerance following repeated administration of low doses.

Topics: Amidohydrolases; Animals; Anti-Inflammatory Agents, Non-Steroidal; Benzodioxoles; Carrageenan; Diclofenac; Edema; Hyperalgesia; Inflammation; Mice; Mice, Inbred C57BL; Mice, Knockout; Monoacylglycerol Lipases; Pain; Pain Measurement; Physical Stimulation; Piperidines; Pyridines; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2

Changes in skin conductance (SC), clinical stress score (CSS), the bispectral index spectroscopy (BIS) index and the variation in the BIS index may be used to monitor responses to nociceptive stimuli. We wanted to examine these methods during noxious stimulation during general anaesthesia and if the responses were associated with variability in genes related to pain.. Sixty patients, given propofol to a BIS level of 40-50, were stimulated with standardised tetanic electrical stimuli during propofol infusion, plasma level of 3 μg/ml alone, or together with remifentanil target plasma level of 3 ng/ml or 10 ng/ml. The CSS, SC, BIS index and the variability of the BIS index were registered. The inter-individual variation in nociceptive responses was analysed for co-variation with genotypes of 89 single nucleotide polymorphisms from 23 candidate genes.. During tetanic stimuli, CSS and SC increased significantly and were attenuated with increasing level of remifentanil, different from the BIS index and the variation in the BIS index. Polymorphisms in the P-glycoprotein (ABCB1), tachykinin 1 receptor (TACR1), dopamine receptor D3 (DRD3) and beta arrestin 2 (ARRB2) genes were associated with the co-variation in SC variables or CSS response or both during standardised nociceptive stimuli (P < 0.05). Because of no corrections for multiple testing, the genetic analyses are explorative, and associations must be tested in further studies.. This exploratory study suggests genes that may be tested further with relation to nociceptive response during anaesthesia. SC and CSS may be useful tools for monitoring nociceptive response during general anaesthesia.

Topics: Anesthesia, General; Anesthetics, Intravenous; Area Under Curve; Consciousness Monitors; Electric Stimulation; Female; Galvanic Skin Response; Genetic Variation; Genotype; Gynecologic Surgical Procedures; Humans; Individuality; Laparoscopy; Muscle Contraction; Nociception; Pain; Pain Measurement; Piperidines; Polymorphism, Single Nucleotide; Preanesthetic Medication; Remifentanil

There is currently no evidence about the genetic bases of postoperative pain variability in children.. We prospectively followed a cohort of 168 children after orthopedic or abdominal surgery, who were under morphine patient-controlled analgesia. The children and their parents were genotyped for 6 candidate-gene polymorphisms (single-nucleotide polymorphisms [SNPs]) implicated in nociception and opiate metabolism: ABCB1C3435T, COMTVal158Met, NTRK1His40Tyr, OPRMA118G, POMCArg236Gln, and a haplotype of CYP2D6. Postoperative pain was assessed using the Faces Pain Scale (FPS), at rest and during mobilization, 11 times during the first 24 postoperative hours.. At rest, and to a lesser extent, at mobilization, having at least 4 pain peaks of FPS score >6 in 24 hours was more frequent in children with ABCB1_CC than in children with ABCB1_CT and ABCB1_TT (adjusted risk ratio = 4.5; 95% confidence interval [CI],1.5-13.4; corrected CI for multiple comparisons, 0.98-20.55) and was more frequent in children with OPRM_GA than those with OPRM_AA (adjusted risk ratio = 3.5; 95% CI, 1.1-11.2; corrected CI, 0.70-17.30). After adjusting for parental mating type and correcting for multiple comparisons, mean FPS scores across the 24 postoperative hours were higher for OPRM_GA than for OPRM_AA at rest (P < 0.0002), higher for NTRK1_ CT or NTRK1_ TT than NTRK1_ CC during mobilization (P = 0.002), and lower for COMT_GG than COMT_AA and COMT_GA, during mobilization (P = 0.005).. ABCB1 and OPRM genotypes are associated with clinically meaningful pain variability, whereas NTRK1 and COMT are linked to subclinical effects. This first but small cohort study provides clues to further explore the genetic foundations of pediatric pain.

Topics: Adolescent; Analgesia; Analgesia, Patient-Controlled; Analgesics, Opioid; Anesthesia, General; Child; Child, Preschool; Cohort Studies; Female; Genetic Predisposition to Disease; Genotype; Humans; Longitudinal Studies; Male; Morphine; Pain; Pain Measurement; Pain, Postoperative; Piperidines; Polymorphism, Single Nucleotide; Prospective Studies; Remifentanil; Sufentanil; Switzerland; Treatment Outcome

Although electroencephalographic parameters and auditory evoked potentials (AEP) reflect the hypnotic component of anesthesia, there is currently no specific and mechanism-based monitoring tool for anesthesia-induced blockade of nociceptive inputs. The aim of this study was to assess visceral pain-evoked potentials (VPEP) and contact heat-evoked potentials (CHEP) as electroencephalographic indicators of drug-induced changes of visceral and somatosensory pain. Additionally, AEP and electroencephalographic permutation entropy were used to evaluate sedative components of the applied drugs.. In a study enrolling 60 volunteers, VPEP, CHEP (amplitude N2-P1), and AEP (latency Nb, amplitude Pa-Nb) were recorded without drug application and at two subanesthetic concentration levels of propofol, sevoflurane, remifentanil, or (s)-ketamine. Drug-induced changes of evoked potentials were analyzed. VPEP were generated by electric stimuli using bipolar electrodes positioned in the distal esophagus. For CHEP, heat pulses were given to the medial aspect of the right forearm using a CHEP stimulator. In addition to AEP, electroencephalographic permutation entropy was used to indicate level of sedation.. With increasing concentrations of propofol, sevoflurane, remifentanil, and (s)-ketamine, VPEP and CHEP N2-P1 amplitudes decreased. AEP and electroencephalographic permutation entropy showed neither clinically relevant nor statistically significant suppression of cortical activity during drug application.. Decreasing VPEP and CHEP amplitudes under subanesthetic concentrations of propofol, sevoflurane, remifentanil, and (s)-ketamine indicate suppressive drug effects. These effects seem to be specific for analgesia.

Topics: Adult; Analgesics, Opioid; Anesthetics, Dissociative; Anesthetics, Inhalation; Anesthetics, Intravenous; Electric Stimulation; Electroencephalography; Entropy; Evoked Potentials; Evoked Potentials, Auditory; Evoked Potentials, Somatosensory; Humans; Ketamine; Male; Methyl Ethers; Pain; Piperidines; Propofol; Remifentanil; Sevoflurane; Visceral Pain

Clinical trials frequently involve pairwise comparisons of different treatments to evaluate their relative efficacy. In this study, we examine methods for conducting pairwise tests of treatments with ordered categorical responses. A modified version of the Wilcoxon-Mann-Whitney test based on a logistic regression model assuming proportional odds is a popular choice for comparing two treatments. This paper discusses the extension of this test to pairwise comparisons involving more than two treatments. However, when the proportional odds assumption is not valid, the Wilcoxon-Mann-Whitney-type test procedure cannot control the overall type I error rate at the prespecified level of significance. We therefore propose a better strategy in which a latent normal model is employed. We presented a simulated comparative study of power and the overall type I error rate to illustrate the superiority of the latent normal model. Examples are also given for illustrative purposes.

Topics: Alfentanil; Child; Child, Preschool; Clinical Trials as Topic; Computer Simulation; Humans; Logistic Models; Pain; Piperidines; Propofol; Remifentanil

Endocannabinoids in the midbrain periaqueductal grey (PAG) modulate nociception and unconditioned stress-induced analgesia; however, their role in fear-conditioned analgesia (FCA) has not been examined. The present study examined the role of the endocannabinoid system in the dorsolateral (dl) PAG in formalin-evoked nociceptive behaviour, conditioned fear and FCA in rats.. Rats received intra-dlPAG administration of the CB(1) receptor antagonist/inverse agonist rimonabant, or vehicle, before re-exposure to a context paired 24 h previously with foot shock. Formalin-evoked nociceptive behaviour and fear-related behaviours (freezing and 22 kHz ultrasonic vocalization) were assessed. In a separate cohort, levels of endocannabinoids [2-arachidonoyl glycerol (2-AG) and N-arachidonoyl ethanolamide (anandamide; AEA)] and the related N-acylethanolamines (NAEs) [N-palmitoyl ethanolamide (PEA) and N-oleoyl ethanolamide (OEA)] were measured in dlPAG tissue following re-exposure to conditioned context in the presence or absence of formalin-evoked nociceptive tone.. Re-exposure of rats to the context previously associated with foot shock resulted in FCA. Intra-dlPAG administration of rimonabant significantly attenuated FCA and fear-related behaviours expressed in the presence of nociceptive tone. Conditioned fear without formalin-evoked nociceptive tone was associated with increased levels of 2-AG, AEA, PEA and OEA in the dlPAG. FCA was specifically associated with an increase in AEA levels in the dlPAG.. Conditioned fear to context mobilises endocannabinoids and NAEs in the dlPAG. These data support a role for endocannabinoids in the dlPAG in mediating the potent suppression of pain responding which occurs during exposure to conditioned aversive contexts.. This article is part of a themed section on Cannabinoids in Biology and Medicine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-8. To view Part I of Cannabinoids in Biology and Medicine visit http://dx.doi.org/10.1111/bph.2011.163.issue-7.

Topics: Analgesia; Animals; Cannabinoid Receptor Modulators; Conditioning, Psychological; Endocannabinoids; Fear; Formaldehyde; Male; Motor Activity; Pain; Periaqueductal Gray; Piperidines; Pyrazoles; Rats; Receptor, Cannabinoid, CB1; Rimonabant; Ultrasonics

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

2-Pentylpiperidine, named conmaculatin, a novel volatile alkaloid related to coniine was identified from the renowned toxic weed Conium maculatum L. (Apiaceae). The structure of conmaculatin was corroborated by synthesis (8 steps starting from cyclohexanol, overall yield 12%). Conmaculatin's strong peripheral and central antinociceptive activity in mice was observed in a narrow dose range (10-20mg/kg). It was found to be lethal in doses higher than 20mg/kg.

Topics: Acetylcholine; Alkaloids; Analgesics; Animals; Conium; Dose-Response Relationship, Drug; Hot Temperature; Male; Mice; Molecular Structure; Pain; Piperidines

Most of the modulating effects of cannabinoids on pain are through putative cannabinoid CB1 and CB2 receptors. However, the involvement of other receptors is also suggested. Cannabinoid compounds with analgesic activity such as palmitoylethanolamide (PEA) show low affinity to CB1 and CB2 receptors, yet selectively activate GPR55 receptors. The objective of the present study was to evaluate the possible role of spinal CB1 and GPR55 receptors on antinociceptive activity of PEA in formalin test as well as in the spinal expression of IL1-β in rat. Intrathecal (i.t.) administration of PEA (1, 10 μg) significantly decreased both pain-related scores in formalin test and IL1-β expression in rat spinal cord. Pretreatment of rats with low doses of CB1 receptor antagonist/GPR55 receptor agonist AM251 (10, 100 ng; i.t.), did not attenuated the effect of PEA, yet even significantly increased the effect of PEA on IL1-β expression in rat spinal cord. Interestingly, i.t. administration of low doses of AM251 per se significantly decreased both pain related behavior and spinal IL1-β expression in formalin test. These findings suggest the possible involvement of receptors other than CB1 receptors in spinal pain pathways, such as GPR55, in pain modulating activity of cannabinoids.

Topics: Amides; Animals; Drug Interactions; Endocannabinoids; Ethanolamines; Injections, Spinal; Interleukin-1beta; Male; Pain; Pain Measurement; Palmitic Acids; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Receptors, Cannabinoid; Receptors, G-Protein-Coupled; Spinal Cord

Spinal glial activation has been implicated in sustained morphine-mediated paradoxical pain sensitization. Since activation of glial CB2 cannabinoid receptors attenuates spinal glial activation in neuropathies, we hypothesized that CB2 agonists may also attenuate sustained morphine-mediated spinal glial activation and pain sensitization. Our data indicate that co-administration of a CB2-selective agonist (AM 1241) attenuates morphine (intraperitoneal; twice daily; 6 days)-mediated thermal hyperalgesia and tactile allodynia in rats. A CB2 (AM 630) but not a CB1 (AM 251) antagonist mitigated this effect. AM 1241 co-treatment also attenuated spinal astrocyte and microglial marker and pro-inflammatory mediator (IL-1β, TNFα) immunoreactivities in morphine-treated rats, suggesting that CB2 agonists may be useful to prevent the neuroinflammatory consequences of sustained morphine treatment.

Topics: Analgesics; Analgesics, Opioid; Animals; Cannabinoids; Hyperalgesia; Indoles; Inflammation; Interleukin-1beta; Male; Morphine; Neuroglia; Pain; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB2; Spinal Cord; Tumor Necrosis Factor-alpha

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

In this study we analyzed the mechanisms underlying celecoxib-induced analgesia in a model of inflammatory pain in rats, using the intracerebroventricular (i.c.v.) administration of selective opioid and cannabinoid antagonists.. Analgesic effects of celecoxib were prevented by selective μ-(β-funaltrexamine) and δ-(naltrindole), but not κ-(nor-binaltorphimine) opioid antagonists, given i.c.v. 30 min before celecoxib. Similar pretreatment with AM 251, but not SR 144528, cannabinoid CB(1) and CB(2) receptor antagonists, respectively, prevented celecoxib-induced analgesia. The fatty acid amide hydrolase inhibitor, URB 597, also prevented celecoxib-induced analgesia.. Our data provided further evidence for the involvement of endogenous opioids and revealed a new cannabinoid component of the mechanism(s) underlying celecoxib-induced analgesia.

Topics: Analgesics; Animals; Carrageenan; Celecoxib; Central Nervous System; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Inflammation; Male; Naltrexone; Pain; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Receptors, Opioid, delta; Receptors, Opioid, mu; Sulfonamides

Studies have shown that N-methyl-D-aspartate (NMDA) receptors play a critical role in pain processing at different levels of the central nervous system. In this study, we used female adult Wistar rats to examine the effects of antagonizing the NR2B subunit of the NMDA receptor in phasic and tonic pain processes. All the rats underwent stereotaxic surgery for cortical cannula implantation and after at least one week of recovery, rats performed behavioral tests. For evaluating the effects of drugs on motor coordination rats were tested in the rotarod apparatus. Moreover, rats were evaluated in the paw withdrawal latency (PWL) to a noxious thermal stimulus. Furthermore, rats were tested in the formalin-pain test. Rats that received the NR2B antagonist Ro 25-6981 before and after formalin injection showed significantly reduced pain responses in the formalin test, as compared with female control rats (p<0.05). In contrast, no differences among groups were found in the phasic pain test (Hargreaves) and the rotarod test. Taken together, these results suggest that cortical antagonism of the NR2B subunit of NMDA receptors is able to reduce inflammatory pain levels not only before, but after the formalin injection in females at different phases of the estrous cycle.

Topics: Animals; Drug Evaluation, Preclinical; Estrous Cycle; Excitatory Amino Acid Antagonists; Female; Formaldehyde; Gyrus Cinguli; Hot Temperature; Inflammation; Injections; Long-Term Potentiation; Pain; Pain Measurement; Phenols; Piperidines; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Rotarod Performance Test

Neurotensin (NT) analogs, NT69L, NT72, and NT79, differentially bind the two major neurotensin receptors, NTS1 and NTS2, to elicit effects similar to those of endogenous NT, including analgesia. Previous data strongly suggest NTS2 as the main receptor involved in NT- and NT analog-mediated visceral analgesia. However, this idea has yet to be confirmed with the use of mice lacking the NTS2 receptor. Here we use the writhing assay, a model of visceral pain, to investigate the analgesic effects of NT69L (binds NTS1 and NTS2 equally), NT79 (NTS2-selective), NT72 (NTS1 selective) and levocabastine (NTS2-selective) in WT, NTS1 knock-out, and NTS2 knock-out mice. Additionally, we investigate the role of NTS2 in the development of tolerance to NT69L-mediated visceral analgesia. All three NT analogs reduced writhing in the WT mice. NT79 and levocabsatine reduced writhing in the NTS1(-/-) mice while NT69L and NT72 showed significant analgesic effect in the NTS2(-/-) mice. In conclusion, the data shows that (1) both NTS1 and NTS2 are involved in mediating visceral analgesia and their respective roles appear to be NT analog-dependent; (2) NTS1 may inhibit NTS2-mediated analgesia; and (3) NTS2 is necessary for the development of tolerance to NT69L-mediated analgesia.

Topics: Acetic Acid; Analgesia; Analysis of Variance; Animals; Behavior, Animal; Histamine H1 Antagonists; Mice; Mice, Knockout; Neurotensin; Pain; Pain Measurement; Peptide Fragments; Piperidines; Receptors, Neurotensin

Placebo treatments and opiate drugs are thought to have common effects on the opioid system and pain-related brain processes. This has created excitement about the potential for expectations to modulate drug effects themselves. If drug effects differ as a function of belief, this would challenge the assumptions underlying the standard clinical trial. We conducted two studies to directly examine the relationship between expectations and opioid analgesia. We administered the opioid agonist remifentanil to human subjects during experimental thermal pain and manipulated participants' knowledge of drug delivery using an open-hidden design. This allowed us to test drug effects, expectancy (knowledge) effects, and their interactions on pain reports and pain-related responses in the brain. Remifentanil and expectancy both reduced pain, but drug effects on pain reports and fMRI activity did not interact with expectancy. Regions associated with pain processing showed drug-induced modulation during both Open and Hidden conditions, with no differences in drug effects as a function of expectation. Instead, expectancy modulated activity in frontal cortex, with a separable time course from drug effects. These findings reveal that opiates and placebo treatments both influence clinically relevant outcomes and operate without mutual interference.

Topics: Analgesics, Opioid; Anticipation, Psychological; Behavior; Brain Mapping; Dose-Response Relationship, Drug; Female; Hemodynamics; Hot Temperature; Humans; Image Processing, Computer-Assisted; Injections, Intravenous; Linear Models; Magnetic Resonance Imaging; Male; Pain; Pain Measurement; Piperidines; Remifentanil; Young Adult

Topics: Arteries; Artifacts; Cerebellum; Consciousness Monitors; Craniotomy; Decompression, Surgical; Diagnostic Errors; Electromyography; Facial Nerve; Humans; Intraoperative Complications; Male; Microsurgery; Middle Aged; Monitoring, Intraoperative; Pain; Piperidines; Propofol; Prostheses and Implants; Remifentanil; Trigeminal Nerve; Trigeminal Neuralgia

Acute stress reduces pain sensitivity by engaging an endocannabinoid signaling circuit in the midbrain. The neural mechanisms governing this process and molecular identity of the endocannabinoid substance(s) involved are unknown. We combined behavior, pharmacology, immunohistochemistry, RNA interference, quantitative RT-PCR, enzyme assays, and lipidomic analyses of endocannabinoid content to uncover the role of the endocannabinoid 2-arachidonoyl-sn-glycerol (2-AG) in controlling pain sensitivity in vivo. Here, we show that footshock stress produces antinociception in rats by activating type 5 metabotropic glutamate receptors (mGlu(5)) in the dorsolateral periaqueductal gray (dlPAG) and mobilizing 2-AG. Stimulation of mGlu(5) in the dlPAG with DHPG [(S)-3,5-dihydroxyphenylglycine] triggered 2-AG formation and enhanced stress-dependent antinociception through a mechanism dependent upon both postsynaptic diacylglycerol lipase (DGL) activity, which releases 2-AG, and presynaptic CB(1) cannabinoid receptors. Pharmacological blockade of DGL activity in the dlPAG with RHC80267 [1,6-bis(cyclohexyloximinocarbonylamino)hexane] and (-)-tetrahydrolipstatin (THL), which inhibit activity of DGL-α and DGL-β isoforms, suppressed stress-induced antinociception. Inhibition of DGL activity in the dlPAG with THL selectively decreased accumulation of 2-AG without altering levels of anandamide. The putative 2-AG-synthesizing enzyme DGL-α colocalized with mGlu(5) at postsynaptic sites of the dlPAG, whereas CB(1) was confined to presynaptic terminals, consistent with a role for 2-AG as a retrograde signaling messenger. Finally, virally mediated silencing of DGL-α, but not DGL-β, transcription in the dlPAG mimicked effects of DGL inhibition in suppressing both endocannabinoid-mediated stress antinociception and 2-AG formation. The results indicate that activation of the postsynaptic mGlu(5)-DGL-α cascade triggers retrograde 2-AG signaling in vivo. This pathway is required for endocannabinoid-mediated stress-induced analgesia.

Topics: Analgesia; Analysis of Variance; Animals; Arachidonic Acids; Cannabinoid Receptor Modulators; Cyclohexanones; Dose-Response Relationship, Drug; Electroconvulsive Therapy; Endocannabinoids; Excitatory Amino Acid Antagonists; Glycerides; Lipoprotein Lipase; Male; Methoxyhydroxyphenylglycol; Mice; Microscopy, Immunoelectron; Pain; Periaqueductal Gray; Piperidines; Protease Inhibitors; Pyrazoles; Pyridines; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate; Rimonabant; RNA, Messenger; RNA, Small Interfering; Synapses; Tandem Mass Spectrometry

Pitolisant (BF2.649) is a selective inverse agonist for the histamine H(3) receptor and was developed for the treatment of excessive daytime sleepiness in Parkinson disease, narcolepsy, and schizophrenia. Since H(3)-ligands can decrease inflammatory pain, we tested Pitolisant in inflammatory and neuropathic pain models. MATERIALS AND TREATMENTS: Behavioral effects of pitolisant and the structural different H(3) receptor inverse agonists ciproxifan and ST-889 were tested in zymosan-induced inflammation and the spared nerve injury model for neuropathic pain.. Responses to mechanical and thermal stimuli were determined. Calcium imaging was performed with primary neuronal cultures of dorsal root ganglions.. Clinically relevant doses of pitolisant (10 mg/kg) had no relevant effect on mechanical or thermal pain thresholds in all animal models. Higher doses (50 mg/kg) dramatically increased thermal but not mechanical pain thresholds. Neither ciproxifan nor ST-889 altered thermal pain thresholds. In peripheral sensory neurons high concentrations of pitolisant (30-500 μM), but not ciproxifan, partially inhibited calcium increases induced by capsaicin, a selective activator of transient receptor potential vanilloid receptor 1 (TRPV1). High doses of pitolisant induced a strong hypothermia.. The data show a dramatic effect of high dosages of pitolisant on the thermosensory system, which appears to be H(3) receptor-independent.

Topics: Animals; Behavior, Animal; Calcium; Cells, Cultured; Ganglia, Spinal; Histamine Agonists; Histamine H3 Antagonists; Hot Temperature; Hypothermia; Imidazoles; Mice; Pain; Pain Threshold; Piperidines; Psychomotor Performance

We studied in rats with a spinal nerve ligation-induced neuropathy whether dopamine D2 receptors (D2Rs) play a role in descending control of pain induced by stimulation of the primary motor cortex (M1). Noxious heat-evoked responses were determined in spinal dorsal horn wide-dynamic range (WDR) and nociceptive-specific (NS) neurons, with and without electrical M1 stimulation. A D2R antagonist, raclopride, was administered into the dorsal striatum or spinally in attempts to reverse spinal antinociception induced by M1 stimulation. Moreover, influence of M1 stimulation on the noxious heat-induced limb withdrawal reflex was determined following block of spinal D2Rs with raclopride or a lidocaine-induced block of the hypothalamic A11 cell group, the main source of spinal dopamine. Striatal administration of raclopride enhanced the heat-evoked baseline responses of WDR but not NS neurons and reversed the M1 stimulation-induced suppression of the heat response in WDR neurons. Following spinal administration of raclopride, M1 stimulation failed to suppress the heat response of WDR neurons, whereas the heat response of NS neurons was enhanced by M1-stimulation. After blocking the A11 with lidocaine or spinal D2Rs with raclopride, M1 stimulation failed to suppress the noxious heat-evoked withdrawal reflex. The results indicate that descending pain control induced by stimulation of the M1 cortex in neuropathic animals involves supraspinal (presumably striatal) and, through A11, spinal D2Rs. Supraspinal and spinal D2Rs have partly dissociative effects on spinal dorsal horn WDR and NS neurons, possibly reflecting differential roles and wirings that these sensory neurons have in pain-processing circuitries.

Topics: Analysis of Variance; Animals; Deep Brain Stimulation; Disease Models, Animal; Dopamine Antagonists; Functional Laterality; Hot Temperature; Indoles; Male; Motor Cortex; Motor Neurons; Nociceptors; Pain; Pain Measurement; Peripheral Nervous System Diseases; Piperidines; Raclopride; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2; Reflex; Spinal Cord

The cannabinoid receptor-mediated analgesic effects of 2-arachidonoylglycerol (2-AG) are limited by monoacylglycerol lipase (MAGL). 4-nitrophenyl 4-[bis (1,3-benzodioxol-5-yl) (hydroxy) methyl] piperidine-1-carboxylate (JZL184) is a potent inhibitor of MAGL in the mouse, though potency is reportedly reduced in the rat. Here we have assessed the effects of spinal inhibition of MAGL with JZL184 on nociceptive processing in rats.. In vivo spinal electrophysiological assays in anaesthetized rats were used to determine the effects of spinal administration of JZL184 on spinal nociceptive processing in the presence and absence of hindpaw inflammation. Contributions of CB(1) receptors to these effects was assessed with AM251. Inhibition of 2-oleoylglycerol hydrolytic activity and alterations of 2-AG in the spinal cord after JZL 184 were also assessed.. Spinal JZL184 dose-dependently inhibited mechanically evoked responses of wide dynamic range (WDR) neurones in naïve anaesthetized rats, in part via the CB(1) receptor. A single spinal administration of JZL184 abolished inflammation-induced expansion of the receptive fields of spinal WDR neurones. However, neither spinal nor systemic JZL184 altered levels of 2-AG, or 2-oleoylglycerol hydrolytic activity in the spinal cord, although JZL184 displayed robust inhibition of MAGL when incubated with spinal cord tissue in vitro.. JZL184 exerted robust anti-nociceptive effects at the level of the spinal cord in vivo and inhibited rat spinal cord MAGL activity in vitro. The discordance between in vivo and in vitro assays suggests that localized sites of action of JZL184 produce these profound functional inhibitory effects.. This article is part of a themed section on Cannabinoids. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.167.issue-8.

Topics: Amidohydrolases; Analgesics; Animals; Anti-Inflammatory Agents; Arachidonic Acids; Benzodioxoles; Carrageenan; Central Nervous System Sensitization; Drug Administration Routes; Endocannabinoids; Ethanolamines; Glycerides; Inflammation; Lipoprotein Lipase; Male; Mice; Mice, Inbred C57BL; Monoacylglycerol Lipases; Pain; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Species Specificity; Spinal Cord

The preprotachykinin A gene (ppt-A) codes for Substance P (SP), supports nociceptive sensitization, and modulates inflammatory responses after incision. Repeated opioid use produces paradoxical pain sensitization-termed opioid-induced hyperalgesia (OIH) -which can exacerbate pain after incision. Here the contribution of SP to peri-incisional nociceptive sensitization and nociceptive mediator production after opioid treatment was examined utilizing ppt-A knockout (-/-) mice and the neurokinin (NK1) receptor antagonist LY303870. Less mechanical allodynia was observed in ppt-A(-/-) mice compared to wild types (wt) after morphine treatment both before and after incision. Moreover, LY303870 administered with morphine reduced incisional hyperalgesia in wt mice. Incision after saline or escalating morphine treatment upregulated skin IL-1β, IL-6, G-CSF and MIP-1α levels in ppt-A(-/-) and wt mice similarly. However, chronic morphine treatment greatly exacerbated increases in skin nerve growth factor levels after incision, an effect entirely dependent upon intact SP signaling. Additionally, SP dependent upregulation of prodynorphin, NMDA1 and NK1 receptor expression in spinal cord was seen after morphine treatment and incision. A similar pattern was seen for 5-HT3 receptor expression in tissue from dorsal root ganglia. Therefore, SP may work at both central and peripheral sites to enhance nociceptive sensitization after morphine treatment and incision.. These studies show that SP signaling modulates enhanced nerve growth factor production and changes in neuronal gene expression seen after incision in mice previously exposed to morphine.

Topics: Analgesics, Opioid; Animals; Chemokine CCL3; Granulocyte Colony-Stimulating Factor; Hyperalgesia; Indoles; Interleukin-1beta; Interleukin-6; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Morphine; Neurokinin-1 Receptor Antagonists; Pain; Pain Measurement; Physical Stimulation; Piperidines; Protein Precursors; Skin; Spinal Cord; Tachykinins; Up-Regulation

Piperidine derivatives are known to exhibit analgesic activities and are likely to possess the ability to block the effects of prostaglandins through inhibition of downstream signaling pathways. The present study investigated the activity of five derivatives (PD2-6) of 4-(4'-bromophenyl)-4-piperidinol (PD1), against pain and platelet aggregation mediated by the release of prostaglandins and thromboxane A2, respectively. The results showed that compound PD1 and its two phenacyl derivatives PD3 and PD5 exhibited a highly significant analgesic effect (p < 0.01), whereas PD4 and PD6 also showed significant activity. PD3, the most active analgesic compound when docked to the opioid receptor, had interactions between the oxygen of its nitro group and the amino group of ARG 573, indicating a distance of 1.2563 Å. The antiplatelet data showed that compound PD5 (4-(4'-bromo-phenyl)-4-hydroxy-1-[2-(2″,4″-dimethoxyphenyl)-2-oxo-ethyl]-piperidinium bromide) had an IC(50) = 0.06 mM, which was the most active compound, whereas PD3 was the second most active compound against platelet aggregating factor-induced aggregation with an IC(50) = 80 mM. Acetyl salicylic acid (IC(50) = 150 μM) was used as a positive control.

Topics: Analgesics; Animals; Aspirin; Female; Humans; Inhibitory Concentration 50; Male; Mice; Pain; Piperidines; Platelet Aggregation; Platelet Aggregation Inhibitors; Prostaglandins; Receptors, Opioid; Structure-Activity Relationship; Thromboxane A2

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

BACKGROUND AND PURPOSE The endocannabinoid 2-arachidonoylglycerol (2-AG) is degraded primarily by monoacylglycerol lipase (MGL). We compared peripheral antinociceptive effects of JZL184, a novel irreversible MGL inhibitor, with the reversible MGL-preferring inhibitor URB602 and exogenous 2-AG in rats. EXPERIMENTAL APPROACH Nociception in the formalin test was assessed in groups receiving dorsal paw injections of vehicle, JZL184 (0.001-300 µg), URB602 (0.001-600 µg), 2-AG (ED(50)), 2-AG + JZL184 (at their ED(50)), 2-AG + URB602 (at their ED(50)), AM251 (80 µg), AM251 + JZL184 (10 µg), AM630 (25 µg) or AM630 + JZL184 (10 µg). Effects of MGL inhibitors on endocannabinoid accumulation and on activities of endocannabinoid-metabolizing enzymes were assessed. KEY RESULTS Intra-paw administration of JZL184, URB602 and 2-AG suppressed early and late phases of formalin pain. JZL184 and URB602 acted through a common mechanism. JZL184 (ED(50) Phase 1: 0.06 ± 0.028; Phase 2: 0.03 ± 0.011 µg) produced greater antinociception than URB602 (ED(50) Phase 1: 120 ± 51.3; Phase 2: 66 ± 23.9 µg) or 2-AG. Both MGL inhibitors produced additive antinociceptive effects when combined with 2-AG. Antinociceptive effects of JZL184, like those of URB602, were blocked by cannabinoid receptor 1 (CB(1)) and cannabinoid receptor 2 (CB(2)) antagonists. JZL184 suppressed MGL but not fatty-acid amide hydrolase or N-arachidonoyl-phosphatidylethanolamine phospholipase D activities ex vivo. URB602 increased hind paw 2-AG without altering anandamide levels. CONCLUSIONS AND IMPLICATIONS MGL inhibitors suppressed formalin-induced pain through peripheral CB(1) and CB(2) receptor mechanisms. MGL inhibition increased paw skin 2-AG accumulation to mediate these effects. MGL represents a target for the treatment of inflammatory pain.

Topics: Amidohydrolases; Animals; Arachidonic Acids; Benzodioxoles; Biphenyl Compounds; Cannabinoid Receptor Modulators; Drug Interactions; Drug Therapy, Combination; Endocannabinoids; Glycerides; Male; Monoacylglycerol Lipases; Pain; Pain Measurement; Phospholipase D; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2

Cricoid pressure has been shown to decrease the pressure in the lower esophageal sphincter (LES), increasing the risk of aspiration. Whether this reaction is due to pain associated with the application of cricoid pressure has not been studied. The aim of this study was to compare the effects of cricoid pressure with those of peripheral pain on pressures in the LES, and to study whether remifentanil influences these effects. Data from the upper esophageal sphincter (UES) are also described.. Continuous solid-state manometry was performed in 14 healthy volunteers. Initially, the effect of remifentanil (target-controlled infusion with a plasma target concentration of 5.0 ng/ml) was studied, and thereafter, the effects of cricoid pressure and peripheral pain stimulation (cold stimulation). Finally, these two interventions were repeated under ongoing remifentanil infusion.. Remifentanil decreased the LES pressure significantly [ΔP-6.5 mmHg, 95% confidence interval (95% CI) -1.7 to -11.2]. Cricoid pressure application decreased the LES pressure significantly (ΔP-3.7 mmHg, 95% CI -1.4 to 6.1), whereas peripheral pain did not (ΔP 1.2 mmHg, 95% CI -3.5 to 1.1). Under ongoing remifentanil infusion, no cricoid pressure-induced LES relaxation was observed. Cricoid pressure induced high pressures in the area of the UES, 215.7 (±91.2) mmHg without remifentanil vs. 219.4 (±74.2) mmHg with remifentanil.. Remifentanil as well as cricoid pressure per se induced decreases in LES pressure. However, cricoid pressure-induced changes of the barrier pressure were not significant whether induced with or without an infusion of remifentanil.

Topics: Adolescent; Adult; Blood Gas Analysis; Cold Temperature; Cricoid Cartilage; Esophageal Sphincter, Lower; Esophageal Sphincter, Upper; Female; Humans; Hypnotics and Sedatives; Male; Manometry; Pain; Piperidines; Pressure; Remifentanil; Young Adult

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

Cannabinoids have recently been identified as potential neuronal modulators of pruritic response, representing a potential target in the treatment of itch associated with a variety of pathophysiologic conditions. While the selective CB(1) receptor antagonist rimonabant is an established pruritic agent in both animal and clinical testing, its receptor mechanism of action and anatomical loci remain unclear.. The purpose of this study was to determine whether CB(1) receptor blockade is critical to rimonabant-induced scratching and to identify differences in scratching response based on different routes of administration. Furthermore, experiments were designed to elucidate any evidence as to whether rimonabant elicits scratching behavior through common immunologic hypersensitivity mechanisms.. Rimonabant was equally effective at producing scratching via intraperitoneal and local subcutaneous injection. This compound also produced an intense scratching response when administered intrathecally, but had no effects after intracerebroventricular administration. Repeated administration of rimonabant led to a decreased magnitude of scratching. While rimonabant-induced scratching was not attenuated either by pretreatment with the H(1) receptor antagonist loratadine or in mast cell-deficient mice, it lacked efficacy in CB(1) (-/-) mice.. Rimonabant is a potent and fully effective pruritogen when administered spinally or systemically and requires CB(1) receptors to induce scratching, suggesting an important spinal CB(1) receptor component of action. The lack of responsiveness to H(1) antagonism or mast cell deficiency supports previous findings that cannabinoids modulate itch through neuronal mechanisms, and not by traditional hypersensitivity activation.

Topics: Animals; Behavior, Animal; Disease Models, Animal; Dose-Response Relationship, Drug; Dronabinol; Female; Histamine H1 Antagonists; Hypersensitivity; Injections, Intraperitoneal; Injections, Intraventricular; Injections, Spinal; Injections, Subcutaneous; Loratadine; Male; Mast Cells; Mice; Mice, Inbred C57BL; Mice, Knockout; Pain; Piperidines; Pruritus; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant

Pharmacological manipulations of the type 1 cannabinoid receptor (CB1) suggest a role for CB1 in morphine-induced antinociception, but studies utilizing CB1 knockout (KO) mice do not support this conclusion. Since studies using CB1 KO mice to study morphine's antinociceptive effects have only examined thermal nociception, this study examines these interactions in models that employ a chemical stimulus.. To determine whether the findings obtained with thermal pain models extend to other models, the effects of morphine on acetic acid-induced writhing were examined in CB1 KO and wildtype (WT) mice. Behaviors that decrease in response to acid injection, feeding and wheel running, were also examined, and investigations were carried out in the thermal hotplate assay. The CB1 antagonist SR141716A was also examined in these assays.. Morphine completely blocked acid-induced writhing (1.0-10.0 mg/kg) and increased response latencies in the hotplate (10.0-32.0 mg/kg) in both genotypes. Morphine (3.2 mg/kg) significantly attenuated the suppression of wheel running but did not completely prevent this effect in either genotype. Morphine did not alter pain-suppressed feeding. In each of these assays, morphine's effects were not altered in CB1 KO mice compared with WT mice; however, SR141716A attenuated morphine's effects in C57BL/6 mice.. The effects of morphine do not differ in CB1 KO and WT mice in preclinical pain models using thermal and chemical stimuli. Since SR141716A did attenuate the effects of morphine, it is possible that CB1 KO mice undergo developmental changes that mask the role of CB1 receptors in morphine's antinociceptive effects.

Topics: Analgesics, Opioid; Animals; Behavior, Animal; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Morphine; Pain; Pain Measurement; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant

The endogenous cannabinoid (endocannabinoid) anandamide is principally degraded by the integral membrane enzyme fatty acid amide hydrolase (FAAH). Pharmacological blockade of FAAH has emerged as a potentially attractive strategy for augmenting endocannabinoid signaling and retaining the beneficial effects of cannabinoid receptor activation, while avoiding the undesirable side effects, such as weight gain and impairments in cognition and motor control, observed with direct cannabinoid receptor 1 agonists. Here, we report the detailed mechanistic and pharmacological characterization of N-pyridazin-3-yl-4-(3-{[5-(trifluoromethyl)pyridin-2-yl]oxy}benzylidene)piperidine-1-carboxamide (PF-04457845), a highly efficacious and selective FAAH inhibitor. Mechanistic studies confirm that PF-04457845 is a time-dependent, covalent FAAH inhibitor that carbamylates FAAH's catalytic serine nucleophile. PF-04457845 inhibits human FAAH with high potency (k(inact)/K(i) = 40,300 M(-1)s(-1); IC(50) = 7.2 nM) and is exquisitely selective in vivo as determined by activity-based protein profiling. Oral administration of PF-04457845 produced potent antinociceptive effects in both inflammatory [complete Freund's adjuvant (CFA)] and noninflammatory (monosodium iodoacetate) pain models in rats, with a minimum effective dose of 0.1 mg/kg (CFA model). PF-04457845 displayed a long duration of action as a single oral administration at 1 mg/kg showed in vivo efficacy for 24 h with a concomitant near-complete inhibition of FAAH activity and maximal sustained elevation of anandamide in brain. Significantly, PF-04457845-treated mice at 10 mg/kg elicited no effect in motility, catalepsy, and body temperature. Based on its exceptional selectivity and in vivo efficacy, combined with long duration of action and optimal pharmacokinetic properties, PF-04457845 is a clinical candidate for the treatment of pain and other nervous system disorders.

Topics: Amidohydrolases; Animals; Enzyme Inhibitors; Humans; Inflammation; Male; Mice; Mice, Inbred C57BL; Pain; Piperidines; Pyridazines; Rats; Rats, Sprague-Dawley; Urea

At low dose, the nonselective N-methyl-D-aspartate receptor antagonist ketamine produces potent analgesia. In humans, psychedelic side effects limit its use. To assess whether other N-methyl-D-aspartate receptor antagonist have an improved therapeutic utility index, we compared antinociceptive, side effect, and locomotor activity of three N-methyl-D-aspartate receptor antagonists.. Ketamine, its active metabolite norketamine, and the NR2B-selective antagonist traxoprodil (CP-101,606) were tested in rat models of acute antinociception (paw-withdrawal response to heat) and chronic neuropathic pain (spared nerve injury). Side effects (stereotypical behavior, activity level) were scored and locomotor function of the nerve-injured paw was assessed using computerized gait analysis. In the chronic pain model, treatment was given 7 days after surgery, for 3 h on 5 consecutive days.. All three N-methyl-D-aspartate receptor antagonists caused dose-dependent antinociception in the acute pain model and relief of mechanical and cold allodynia for 3-6 weeks after treatment in the chronic pain model (P < 0.05 vs. saline). In both tests, ketamine was most potent. Norketamine was as much as two times less potent and traxoprodil was up to 8 times less potent than ketamine (based on area under the curve measures). Nerve injury caused an inability to use the affected paw that either did not improve after treatment (ketamine, traxoprodil) or showed only a limited effect (norketamine). Traxoprodil, but not ketamine or norketamine, showed clear separation between effect and side effect.. The observation that traxoprodil causes relief of chronic pain outlasting the treatment period with no side effects makes it an attractive alternative to ketamine in the treatment of chronic neuropathic pain.

Topics: Acute Disease; Analgesics; Animals; Chronic Disease; Cold Temperature; Data Interpretation, Statistical; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Female; Foot Injuries; Hyperalgesia; Infrared Rays; Ketamine; Motor Activity; Neuralgia; Pain; Pain Measurement; Physical Stimulation; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Stereotyped Behavior

The c-AMP-responsive element binding protein (CREB) and its phosphorylated product (P-CREB) are nuclear proteins expressed after stimulation of pain-producing areas of the spinal cord. There is evidence indicating that central sensitization within dorsal horn neurons is dependent on P-CREB transcriptional regulation. The objectives of the study were to investigate the expression of P-CREB in cells in rat trigeminal nucleus caudalis after noxious stimulation and to determine whether pre-treatment with specific anti-migraine agents modulate this expression. CREB and P-CREB labelling was investigated within the trigeminal caudalis by immunohistochemistry after capsaicin stimulation. Subsequently, the effect of i.v. pre-treatment with either sumatriptan (n = 5), or naratriptan (n = 7) on P-CREB expression was studied. Five animals pre-treated with i.v. normal saline were served as controls. CREB and P-CREB labelling was robust in all animal groups within Sp5C. Both naratriptan and sumatriptan decreased P-CREB expression (p = 0.0003 and 0.0013) within the Sp5C. Triptans attenuate activation of CREB within the central parts of the trigeminal system, thereby leading to potential inhibition of central sensitization. P-CREB may serve as a new marker for post-synaptic neuronal activation within Sp5C in animal models relevant to migraine.

Topics: Animals; Capsaicin; Cyclic AMP Response Element-Binding Protein; Hyperalgesia; Immunohistochemistry; Male; Pain; Phosphorylation; Piperidines; Rats; Rats, Sprague-Dawley; Sensory System Agents; Sumatriptan; Trigeminal Caudal Nucleus; Tryptamines

Spinal blockade of 5-HT7 receptors has been reported to inhibit the antinociceptive effect of opioids. In this study, we found that subcutaneous administration of the selective 5-HT7 receptor agonist E-55888 (10 mg/kg) or the antagonist SB-258719 (5 mg/kg) exerted no effect on the tail-flick test in mice. However, E-55888, but not SB-258719, increased (2.6-fold) the analgesic potency of oral morphine. The potentiating effect exerted by E-55888 was prevented by SB-258719. A pharmacokinetic interaction was discarded as morphine plasma and brain concentrations were not significantly modified when co-administered with E-55888. These results reinforce the involvement of 5-HT7 receptors in opioid analgesia and point to a potential use of 5-HT7 receptor agonists as adjuvants of opioid analgesia.

Topics: Analgesia; Analgesics, Opioid; Animals; Drug Synergism; Male; Mice; Morphine; Pain; Pain Measurement; Piperidines; Pyrazoles; Receptors, Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Sulfonamides

Nucleus cuneiformis (NCF) along with periaqueductal gray (PAG) and rostral ventromedial medulla (RVM) is a part of descending system for pain modulation. Cannabinoids have analgesic effects on the PAG and RVM. This study investigates the possible role of cannabinoids in pain modulation in the NCF. Cannabinoid agonist, WIN55,212-2 (5, 10 and 20μg/0.3μl DMSO per side), and selective cannabinoid CB1 receptor antagonist, AM251(1, 5 and 10μg/0.3μl DMSO per side), were microinjected alone or in succession. As models of acute and inflammatory pain, tail-flick and formalin test were utilized to examine the effects of these drugs on pain modulation in 5min time blocks for 60min. Results of tail-flick and formalin tests demonstrated a dose-dependent analgesic effects for WIN55,212-2, with the most significant response at the dose of 20μg/side. The analgesic responses were more effective during the first 45-min period of the tail-flick test (P<0.001) and during the late phase (P<0.001) of formalin test, compared to the early phase (P<0.05). These analgesic effects were blocked in the presence of AM251 (1μg/0.3μl DMSO per side) in both tests. Administration of AM251 alone did not have any effect on nociceptive responses in either test. The cannabinoid-mediated analgesia demonstrated in this study suggests the presence of a cannabinoid-sensitive nociceptive modulatory system in the NCF.

Topics: Analgesics; Analysis of Variance; Animals; Area Under Curve; Benzoxazines; Cannabinoid Receptor Agonists; Cannabinoid Receptor Antagonists; Disease Models, Animal; Dose-Response Relationship, Drug; Formaldehyde; Hot Temperature; Inflammation; Male; Medulla Oblongata; Microinjections; Morpholines; Motor Activity; Naphthalenes; Pain; Pain Measurement; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptors, Cannabinoid; Time Factors

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

Orexin A and B are hypothalamic peptides known to modulate arousal, feeding, and reward via OX1 and OX2 receptors. Orexins are also antinociceptive in the brain, but their mechanism(s) of action remain unclear. Here, we investigated the antinociceptive mechanism of orexin A in the rat ventrolateral periaqueductal gray (vlPAG), a midbrain region crucial for initiating descending pain inhibition. In vlPAG slices, orexin A (30-300 nm) depressed GABAergic evoked IPSCs. This effect was blocked by an OX1 [1-(2-methylbenzoxazol-6-yl)-3-[1,5]naphthyridin-4-yl urea (SB 334867)], but not OX2 [N-acyl 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (compound 29)], antagonist. Orexin A increased the paired-pulse ratio of paired IPSCs and decreased the frequency, but not amplitude, of miniature IPSCs. Orexin A-induced IPSC depression was mimicked by (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-napthalenylmethanone (WIN 55,212-2), a cannabinoid 1 (CB1) receptor agonist. 1-(2,4-Dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-(1-piperidyl)pyrazole-3-carboxamide (AM 251), a CB1 antagonist, reversed depressant effects by both agonists. Orexin A-induced IPSC depression was prevented by 1-[6-[[(17β)-3-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1H-pyrrole-2,5-dione (U73122) and tetrahydrolipstatin, inhibitors of phospholipase C (PLC) and diacylglycerol lipase (DAGL), respectively, and enhanced by cyclohexyl[1,1'-biphenyl]-3-ylcarbamate (URB602), which inhibits enzymatic degradation of 2-arachidonoylglycerol (2-AG). Moderate DAGLα, but not DAGLβ, immunoreactivity was observed in the vlPAG. Orexin A produced an overall excitatory effect on evoked postsynaptic potentials and hence increased vlPAG neuronal activity. Intra-vlPAG microinjection of orexin A reduced hot-plate nociceptive responses in rats in a manner blocked by SB 334867 and AM 251. Therefore, orexin A may produce antinociception by activating postsynaptic OX1 receptors, stimulating synthesis of 2-AG, an endocannabinoid, through a Gq-protein-mediated PLC-DAGLα enzymatic cascade culminating in retrograde inhibition of GABA release (disinhibition) in the vlPAG.

Topics: Analysis of Variance; Animals; Animals, Newborn; Arachidonic Acids; Benzoxazines; Benzoxazoles; Biphenyl Compounds; Calcium Channel Blockers; Cannabinoid Receptor Modulators; Disease Models, Animal; Electric Stimulation; Endocannabinoids; Enzyme Inhibitors; Estrenes; gamma-Aminobutyric Acid; Glycerides; In Vitro Techniques; Inhibitory Postsynaptic Potentials; Intracellular Signaling Peptides and Proteins; Lactones; Male; Morpholines; Naphthalenes; Naphthyridines; Neural Inhibition; Neural Pathways; Neuropeptides; Orexin Receptors; Orexins; Orlistat; Pain; Pain Measurement; Patch-Clamp Techniques; Periaqueductal Gray; Piperidines; Pyrazoles; Pyrrolidinones; Rats; Rats, Wistar; Receptors, G-Protein-Coupled; Receptors, Neuropeptide; Urea

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

Orofacial pain disorders are frequent in the general population and their pharmacological treatment is not always adequately resolved. Cannabinoids have demonstrated their analgesic effect in several pain conditions, both in animal models and in clinical situations. The aim of the present study was to evaluate the cannabinoid-mediated antinociception in two inflammatory models of orofacial pain (orofacial and temporomandibular joint (TMJ) formalin test) and to compare it with a spinal inflammatory model (paw formalin test). WIN 55,212-2 (0.5, 1mg/kg), a synthetic cannabinoid agonist, was intraperitoneally (i.p.) administered prior to formalin and significantly reduced the nociceptive behavioural responses in these inflammatory tests. To elucidate which subtype of receptor could be involved in such effect, two selective cannabinoid antagonists were administered prior to WIN. SR141716A (1mg/kg i.p.), the CB1 receptor-selective antagonist, was able to prevent the cannabinoid-induced analgesia in all three models, whereas SR144528 (1mg/kg i.p.), the CB2 receptor-selective antagonist, only prevented it in the paw formalin test. A comparison with the antinociceptive effects of morphine (2.5, 5, 10mg/kg, i.p.), indomethacin (2.5, 5mg/kg, i.p.) and ketamine (25, 50mg/kg, i.p.) was also performed. Morphine displayed a dose-dependent reduction of acute and inflammatory pain in all three models, whereas indomethacin and ketamine only attenuated inflammatory pain at the highest tested doses. These results indicate that the cannabinoid-induced antinociception in the orofacial region is mediated by activation of CB1 cannabinoid receptor. Moreover WIN was as effective as morphine and more effective than indomethacin and ketamine, in oral inflammatory pain.

Topics: Analgesics; Analgesics, Opioid; Anesthetics, Dissociative; Animals; Anti-Inflammatory Agents, Non-Steroidal; Behavior, Animal; Benzoxazines; Camphanes; Facial Pain; Formaldehyde; Indomethacin; Inflammation; Ketamine; Male; Morphine; Morpholines; Motor Activity; Naphthalenes; Pain; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Rimonabant; Temporomandibular Joint Disorders

The basolateral amygdala (BLA) contains a high density of cannabinoid CB1 receptors and is critically involved in pain and fear-related behaviour. We investigated the effects of bilateral intra-BLA administration of the CB1 receptor antagonist/inverse agonist, rimonabant, on formalin-evoked nociceptive behaviour, fear-conditioned behaviour including analgesia, and associated brain regional alterations in Fos expression in rats. Intra-BLA administration of rimonabant significantly reduced formalin-evoked nociceptive behaviour in the absence, but not presence, of conditioned fear. Rimonabant attenuated a formalin-evoked reduction in freezing while emitting 22 kHz ultrasonic vocalisation in the early part of the fear expression trial. Formalin-evoked nociceptive behaviour was associated with increased Fos immunoreactivity (FI) in the CA2/3 region of the hippocampus and rostral ventromedial medulla, effects attenuated by intra-BLA rimonabant. Formalin also decreased FI in the cingulate cortex, an effect which was not observed in fear-conditioned rats. Contextually-induced fear was associated with increased FI in the dorsal caudal periaqueductal grey in the absence, but not presence, of formalin-evoked nociceptive tone. In conclusion, bilateral intra-BLA administration of rimonabant reduces nociceptive behaviour in a model of tonic, persistent inflammatory pain, an effect associated with reduced activation of neurons in the CA2/3 hippocampus and rostral ventromedial medulla. The data also provide evidence for differential pain- and fear-related brain regional activity in the presence or absence of contextually-induced aversion and nociceptive tone.

Topics: Amygdala; Analysis of Variance; Animals; Behavior, Animal; Cannabinoid Receptor Antagonists; Catheters, Indwelling; Cell Count; Conditioning, Psychological; Fear; Formaldehyde; Hippocampus; Immunohistochemistry; Male; Medulla Oblongata; Neurons; Pain; Pain Measurement; Pain Threshold; Periaqueductal Gray; Piperidines; Proto-Oncogene Proteins c-fos; Pyrazoles; Rats; Receptors, Cannabinoid; Rimonabant

Cancer pain is one kind of the most common and severe kinds of chronic pain. No breakthrough regarding the mechanisms and therapeutics of cancer pains has yet been achieved. Based on the well established involvement of the NMDA (N-methyl-D-aspartate) receptor containing NR2B in inflammatory pain and neuropathic pain and the effective pain relief obtained with ketamine in cancer patients with intractable pain, we supposed that NR2B in the spinal cord was an important factor for cancer pain. In this study, we investigated the possible role of NR2B in the spinal cord using a murine model of bone cancer pain. C3H/HeJ mice were inoculated into the intramedullary space of the right femur with Osteosarcoma NCTC 2472 cells to induce ongoing bone cancer-related pain behaviors. At day 14 after operation, the expression of NR2B mRNA and NR2B protein in the spinal cord were higher in tumor-bearing mice compared to the sham mice. Intrathecal administration of 5 and 10 microg of NR2B subunit-specific NMDA receptor antagonist ifenprodil attenuated cancer-evoked spontaneous pain, thermal hyperalgesia and mechanical allodynia. These results suggest that NR2B in the spinal cord may participate in bone cancer pain in mice, and ifenprodil may be a useful alternative or adjunct therapy for bone cancer pain. The findings may lead to novel strategies for the treatment of bone cancer pain.

Topics: Analysis of Variance; Animals; Behavior, Animal; Bone Neoplasms; Cell Line, Tumor; Cells, Cultured; Hyperalgesia; Immunohistochemistry; Mice; Pain; Pain Measurement; Pain Threshold; Piperidines; Random Allocation; Receptors, N-Methyl-D-Aspartate; Reverse Transcriptase Polymerase Chain Reaction; Spinal Cord; Time Factors

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

We have previously demonstrated that parathyroid hormone 2 (PTH2) receptors are expressed in dorsal root ganglion (DRG) neurons and that its endogenous agonist tuberoinfundibular peptide of 39 residues (TIP39) causes nociceptive paw flexor responses after intraplantar administration. Here we found that the PTH2 receptor is selectively localized on myelinated A-, but not unmyelinated C-fibers using immunohistochemical labeling, based on PTH2 receptor expression on antibody N52-positive medium/large-sized DRG neurons, but not on TRPV1, substance P, P2X(3) receptor or isolectin B4-binding protein-positive small-sized DRG neurons. Pharmacological studies showed that TIP39-induced nociceptive responses were mediated by activation of G(s) and cAMP-dependent protein kinase. We also found that nociceptive responses induced by TIP39- or the cAMP analog 8-bromo-cAMP were significantly greater following partial sciatic nerve injury induced neuropathic pain, without changes in PTH2 receptor expression. Together these data suggest that activation of PTH2 receptors stimulates nociceptive A-fiber through G(s)-cAMP-dependent protein kinase signaling, and this pathway has elevated sensitization following nerve injury.

Topics: 8-Bromo Cyclic Adenosine Monophosphate; Animals; Behavior, Animal; Capsaicin; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Ganglia, Spinal; Gene Expression Regulation; Glutamic Acid; Male; Mice; Mice, Inbred C57BL; Nerve Fibers, Myelinated; Neurons; Neuropeptides; Pain; Pain Measurement; Piperidines; Receptor, Parathyroid Hormone, Type 2; Reflex; Sciatica; Signal Transduction; Time Factors; TRPV Cation Channels

The rostral ventromedial medulla (RVM), a central relay in the bulbospinal pathways that modulate nociception, contains high concentrations of substance P (Sub P) and neurokinin-1 (NK1) receptors. However, the function of Sub P in the RVM is poorly understood. This study characterized the actions of Sub P in the RVM in the absence of injury and then used two NK1 receptor antagonists, L-733,060 and L-703, 606, to probe the role of endogenously released Sub P in the development and maintenance of persistent inflammatory nociception of immune or neurogenic origin. In uninjured rats, microinjection of Sub P in the RVM produced a transient thermal antinociception that was attenuated by pretreatment with L-733,060 or L-703,606. It did not alter threshold to withdrawal from tactile stimulation with von Frey filaments. Microinjection of the antagonists alone did not alter paw withdrawal latency (PWL) or threshold suggesting that Sub P is not tonically released in the RVM in the absence of injury. However, microinjection of either antagonist in the RVM was sufficient to reverse heat hyperalgesia 4 h, 4 days or 2 weeks after intraplantar (ipl) injection of complete Freund's adjuvant (CFA). Antagonism of NK1 receptors in the RVM did not prevent or reverse tactile hypersensitivity induced by CFA, but did attenuate that produced by capsaicin. NK1 receptor antagonism did not prevent the development of thermal hyperalgesia, tactile hypersensitivity or spontaneous pain behaviors induced by mustard oil (MO). The results suggest that Sub P has bimodal actions in the RVM and that following inflammatory injury, it can play a critical role as a pronociceptive agent in the development and maintenance of hyperalgesia and tactile hypersensitivity. However, its actions are highly dependent on the stimulus modality and the type of injury, and this may be an additional basis for the poor efficacy of NK1 receptor antagonists in clinical trials.

Topics: Animals; Capsaicin; Central Nervous System Agents; Freund's Adjuvant; Hot Temperature; Male; Medulla Oblongata; Mustard Plant; Neurokinin-1 Receptor Antagonists; Pain; Pain Measurement; Pain Threshold; Physical Stimulation; Piperidines; Plant Oils; Quinuclidines; Rats; Rats, Sprague-Dawley; Receptors, Neurokinin-1; Substance P; Time Factors

The ventrolateral periaqueductal gray (vlPAG) is a major site of opioid analgesic action and a key locus for the development of morphine tolerance. Previous experimental evidence supports the hypothesis that the brain synthesizes and secretes neuropeptides, which act as a part of the homeostatic system to attenuate the effects of morphine and endogenous opioid peptides. Among the known antiopioid peptides, nociceptin/orphanin FQ (N/OFQ) has been shown to inhibit various opioid effects, especially analgesia. The present study investigated the effect of NOP receptor blockade on the tolerance to morphine antinociception in the vlPAG. Systemic morphine (10mg/kg s.c. twice per day) induced an antinociceptive effect that diminished significantly on the third day when tolerance developed, as quantified by the tail flick and the hot plate tests. Intra vlPAG (i.vlPAG) administration of the NOP receptor antagonist (+/-)-J 113397 restored the opioid's analgesic effect. When (+/-)-J 113397 was administered beginning the first day preceding each morphine administration, tolerance did not develop, but it appeared if the NOP antagonist had been suspended. These data suggest that the N/OFQ in the vlPAG may play a key role in opioid-induced antinociceptive tolerance.

Topics: Analgesics, Opioid; Animals; Benzimidazoles; Drug Tolerance; Male; Morphine; Narcotic Antagonists; Nociceptin; Nociceptin Receptor; Opioid Peptides; Pain; Pain Measurement; Periaqueductal Gray; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Opioid

The contribution of CB1 receptors in the spinal cord to cannabinoid analgesia is still unclear. The objective of this study was to investigate the effect of CB1 receptors on substance P release from primary afferent terminals in the spinal cord. Substance P release was measured as neurokinin 1 (NK1) receptor internalization in lamina I neurons. It was induced in spinal cord slices by dorsal root stimulation and in live rats by a noxious stimulus. In spinal cord slices, the CB1 receptor antagonists AM251, AM281 and rimonabant partially but potently inhibited NK1 receptor internalization induced by electrical stimulation of the dorsal root. This was due to an inhibition of substance P release and not of NK1 receptor internalization itself, because AM251 and AM281 did not inhibit NK1 receptor internalization induced by exogenous substance P. The CB1 receptor agonist ACEA increased NK1 receptor internalization evoked by dorsal root stimulation. The effects of AM251 and ACEA cancelled each other. In vivo, AM251 injected intrathecally decreased NK1 receptor internalization in spinal segments L5 and L6 induced by noxious hind paw clamp. Intrathecal AM251 also produced analgesia to radiant heat stimulation of the paw. The inhibition by AM251 of NK1 receptor internalization was reversed by antagonists of mu-opioid and GABA(B) receptors. This indicates that CB1 receptors facilitate substance P release by inhibiting the release of GABA and opioids next to primary afferent terminals, producing disinhibition. This results in a pronociceptive effect of CB1 receptors in the spinal cord.

Topics: Animals; Capsaicin; Electric Stimulation; GABA-B Receptor Antagonists; Injections, Spinal; Male; Morpholines; Neurons; Pain; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Receptors, G-Protein-Coupled; Receptors, Neurokinin-1; Receptors, Opioid, mu; Sensory System Agents; Spinal Cord; Spinal Nerve Roots; Substance P; TRPV Cation Channels

Various strategies have been studied to reduce the discomfort of rocuronium injection. This study was designed to determine the effect-site target concentration (Ce) of remifentanil at which there was a 50% probability of preventing movement from pain in response to the injection of rocuronium (EC(50)).. Anesthesia was induced with a propofol target-controlled infusion (TCI, Marsh model) and remifentanil TCI (Minto model). Effect-site target concentration of propofol was 3 microg/ml. Ce of remifentanil for the first patient started at 2.0 ng/ml. Ce of remifentanil for each subsequent patient was determined by the response of the previous patient by the Dixon up-and-down method with an interval of 0.5 ng/ml. After both drugs reached target concentration, rocuronium 0.8 mg/kg was administered, and the pain response was observed.. The EC(50) of remifentanil was 1.5 +/- 0.45 ng/ml by Dixon's up-and-down method. From probit analysis, the EC(50) of remifentanil was 1.37 ng/ml (95% confidence limits, 0.69-2.15 ng/ml), and the EC(95) was 3.19 ng/ml (95% confidence limits, 2.31-11.24 ng/ml).. The EC(50) of remifentanil to blunt the withdrawal responses to rocuronium injection was 1.37-1.5 ng/ml during 3 microg/ml propofol TCI anesthesia.

Topics: Adolescent; Adult; Aged; Androstanols; Dose-Response Relationship, Drug; Female; Humans; Hypnotics and Sedatives; Male; Middle Aged; Movement; Neuromuscular Nondepolarizing Agents; Pain; Piperidines; Reflex; Remifentanil; Rocuronium; Young Adult

The aim of this study was to evaluate the effect of diphenidol on blocking Na(+) currents and spinal anesthesia. We used the patch-clamp method to examine if diphenidol blocked Na(+) currents. Lidocaine, a common used local anesthesia, was used as control. We also evaluated the potencies and durations of diphenidol and lidocaine on spinal blockades of motor function, proprioception, and nociception in rats. Lidocaine exhibited a concentration- and state-dependent effect on tonic blockade of voltage-gated Na(+) currents in mouse neuroblastoma N2A cells (IC(50) of 8.1 and 138.9 microM at holding potentials of -70 and -100 mV, respectively). Diphenidol was more potent (IC(50) of 0.77 and 62.6 microM at holding potentials of -70 and -100 mV, respectively). However, unlike lidocaine, block of Na(+) currents by diphenidol lacked use-dependence. We also found that diphenidol acted like lidocaine and produced dose-related spinal blockades of motor function, proprioception and nociception. Although diphenidol had similar potencies of spinal anesthesia compared with lidocaine it produced a much longer duration of spinal blockades than lidocaine. Our results demonstrated that intrathecal diphenidol produced a long duration and similar potency on spinal anesthesia compared with lidocaine in rats. The anesthetic effect of diphenidol could be in part due to its blockade of Na(+) currents.

Topics: Anesthetics, Local; Animals; Cell Line, Tumor; Dose-Response Relationship, Drug; Lidocaine; Male; Membrane Potentials; Mice; Motor Activity; Neurons; Pain; Piperidines; Proprioception; Rats; Rats, Sprague-Dawley; Sodium; Spinal Cord; Time Factors

Endothelin-1 (ET-1) produced by various cancers is known to be responsible for inducing pain. While ET-1 binding to ETAR on peripheral nerves clearly mediates nociception, effects from binding to ETBR are less clear. The present study assessed the effects of ETBR activation and the role of endogenous opioid analgesia in carcinoma pain using an orthotopic cancer pain mouse model. mRNA expression analysis showed that ET-1 was nearly doubled while ETBR was significantly down-regulated in a human oral SCC cell line compared to normal oral keratinocytes (NOK). Squamous cell carcinoma (SCC) cell culture treated with an ETBR agonist (10(-4)M, 10(-5)M, and 10(-6) M BQ-3020) significantly increased the production of beta-endorphin without any effects on leu-enkephalin or dynorphin. Cancer inoculated in the hind paw of athymic mice with SCC induced significant pain, as indicated by reduction of paw withdrawal thresholds in response to mechanical stimulation, compared to sham-injected and NOK-injected groups. Intratumor administration of 3mg/kg BQ-3020 attenuated cancer pain by approximately 50% up to 3h post-injection compared to PBS-vehicle and contralateral injection, while intratumor ETBR antagonist BQ-788 treatment (100 and 300microg/kg and 3mg/kg) had no effects. Local naloxone methiodide (500microg/kg) or selective mu-opioid receptor antagonist (CTOP, 500microg/kg) injection reversed ETBR agonist-induced antinociception in cancer animals. We propose that these results demonstrate that peripheral ETBR agonism attenuates carcinoma pain by modulating beta-endorphins released from the SCC to act on peripheral opioid receptors found in the cancer microenvironment.

Topics: Animals; beta-Endorphin; Cell Line, Tumor; Disease Models, Animal; Down-Regulation; Endothelin-1; Endothelins; Humans; Mice; Mice, Nude; Narcotic Antagonists; Neoplasm Transplantation; Neoplasms; Nociceptors; Oligopeptides; Opioid Peptides; Pain; Peptide Fragments; Piperidines; Receptor, Endothelin B; Receptors, Opioid; Sensory Receptor Cells; Up-Regulation

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

The kappa opioid receptor (KOR) antagonist, JDTic, was reported to prevent stress-induced reinstatement of cocaine-maintained responding and to have antidepressant-like effects.. Our objectives were to determine whether analogs of JDTic retained KOR antagonist activity and whether an orally effective analog prevented footshock-induced cocaine reinstatement.. RTI-194 (i.g. 1-30 mg/kg, s.c. 0.3-10 mg/kg, and i.p. 30 mg/kg), RTI-212 (s.c. 0.3-10 mg/kg and i.p. 30 mg/kg), and RTI-230 (i.g. 3-30 mg/kg and i.p. 1-30 mg/kg) were evaluated for their ability to block diuresis induced by 10-mg/kg U50,488 in rats. RTI-194 was additionally evaluated i.g. (3-100 mg/kg) for its ability to prevent footshock-induced reinstatement of responding previously reinforced with 0.5-mg/kg/inf cocaine.. RTI-194 significantly (p < 0.05) attenuated U50,488-induced diuresis when given i.g., s.c., and i.p. RTI-194s effectiveness increased 1 week following administration. RTI-212 was ineffective. RTI-230 was ineffective when given i.g., but blocked diuresis at 24 h and 8 days (1, 10, and 30 mg/kg), 15 days (10 and 30 mg/kg), 22 and 29 days (30 mg/kg) following i.p. administration. Footshock reinstated responding in vehicle-but not RTI-194 (30 and 100 mg/kg)-treated rats.. RTI-194 and RTI-230 are effective KOR antagonists, and RTI-194 is now included with JDTic as the only reported compounds capable of antagonizing the KOR following oral administration. The failure of stress to reinstate cocaine seeking in rats treated with RTI-194 is consistent with results reported with JDTic, although it had less efficacy in lowering response levels than JDTic, suggesting a diminished overall effectiveness relative to it.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Cocaine-Related Disorders; Diuresis; Dose-Response Relationship, Drug; Male; Naltrexone; Pain; Piperidines; Rats; Rats, Long-Evans; Receptors, Opioid, kappa; Self Administration; Tetrahydroisoquinolines

The present studies examined the effect of chronic neuropathic pain on cannabinoid receptor density and receptor-mediated G-protein activity within supraspinal brain areas involved in pain processing and modulation in mice. Chronic constriction injury (CCI) produced a significant decrease in WIN 55,212-2-stimulated [(35)S]GTPgammaS binding in membranes prepared from the rostral anterior cingulate cortex (rACC) of CCI mice when compared to sham-operated controls. Saturation binding with [(3)H]SR 141716A in membranes of the rACC showed no significant differences in binding between CCI and sham mice. Analysis of levels of the endocannabinoids anandamide (AEA) or 2-arachidonoylglycerol (2-AG) in the rACC following CCI showed no significant differences between CCI and sham mice. These data suggest that CCI produced desensitization of the cannabinoid 1 receptor in the rACC in the absence of an overall decrease in cannabinoid 1 receptor density or change in levels of AEA or 2-AG. These data are the first to show alterations in cannabinoid receptor function in the rostral anterior cingulate cortex in response to a model of neuropathic pain.

Topics: Analgesics; Animals; Arachidonic Acids; Benzoxazines; Cannabinoid Receptor Modulators; Cell Membrane; Constriction; Disease Models, Animal; Endocannabinoids; Glycerides; Guanosine 5'-O-(3-Thiotriphosphate); Male; Mice; Mice, Inbred Strains; Models, Neurological; Morpholines; Naphthalenes; Pain; Piperidines; Polyunsaturated Alkamides; Prefrontal Cortex; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Sulfur Radioisotopes; Tritium

Diabetes is one of the leading causes of painful neuropathy and to date, besides a tight glycemic control, a viable treatment for this complication is not available. Rimonabant is a selective cannabinoid CB(1) receptor antagonist that produces a significant increase in insulin sensitivity and a reduction of HbA(1c) in diabetic patients. This study aimed to investigate the therapeutic potential of rimonabant in relieving diabetes-induced neuropathic pain. The repeated treatment with rimonabant evoked a significant attenuation of mechanical allodynia in diabetic mice that was dose- and time-dependent. This effect occurred without alteration of hyperglycemia, but it was associated with significant effects on many key players in the pathogenesis of diabetic neuropathy. Metabolic changes induced by hyperglycemia lead to oxidative stress, deregulation of cytokine control and reduced production and transport of nerve growth factor (NGF), and all these factors contribute to neuropathic pain. Rimonabant treatment reduced oxidative stress in peripheral nerve, as revealed by the ability of the compound to counteract the reduced glutathione (GSH) depletion. The same repeated treatment inhibited tumor necrosis factor (TNFalpha) overproduction in the spinal cord and increased the NGF support. This rimonabant-induced improvement might favour the nerve regeneration; accordingly, the histological analysis of sciatic nerves showed a marked degeneration of myelinated fibers in diabetic mice, that was substantially reduced after rimonabant administration. These findings support the hypothesis that CB(1) antagonists would represent a new opportunity for diabetic patients, since currently there are no treatments for painful diabetic neuropathy other than treating the diabetic condition per se.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Dose-Response Relationship, Drug; Hindlimb; Male; Mice; Mice, Inbred C57BL; Nerve Growth Factors; Oxidative Stress; Pain; Pain Measurement; Physical Stimulation; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Sciatic Nerve; Time Factors

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

Hemokinin-1 is a novel mammalian tachykinin cloned from mouse bone marrow. At present, pharmacological profile and physiological role of hemokinin-1 are still unclear. In the present study, we found that intrathecal (i.t.) administration of hemokinin-1 (0.00625-1.6 nmol) induced nociceptive responses consisting of scratching, biting and licking, which resemble substance P-induced behavioral responses in mice. The behaviors evoked by low-dose of hemokinin-1 (0.0125 nmol) were dose-dependently inhibited by i.t. co-administration of CP-99,994, a non-peptidic tachykinin NK(1) receptor antagonist, whereas high-dose of hemokinin-1 (0.1 nmol)-induced behaviors were not affected. Moreover, sendide, a peptidic tachykinin NK(1) receptor antagonist, failed to reduce the behavioral responses of both low- and high-dose of hemokinin-1. In contrast, substance P-induced behaviors were completely suppressed by both CP-99,994 and sendide. These results suggest that hemokinin-1 plays an important role in pain transmission at spinal cord. Moreover, the mechanism of hemokinin-1-induced nociceptive behaviors may be dose-dependent, and distinct from substance P-induced nociceptive behaviors.

Topics: Analgesics; Animals; Behavior, Animal; Dose-Response Relationship, Drug; Injections, Spinal; Lumbar Vertebrae; Male; Mice; Neurokinin-1 Receptor Antagonists; Neurotransmitter Agents; Pain; Pain Measurement; Peptide Fragments; Piperidines; Pyrrolidonecarboxylic Acid; Receptors, Neurokinin-1; Spinal Nerves; Substance P; Synaptic Transmission; Tachykinins; Time Factors

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

TRPV1 (transient receptor potential vanilloid 1) is a ligand-gated ion channel expressed predominantly in nociceptive primary afferents that plays a key role in pain processing. In vivo activation of TRPV1 receptors by natural agonists like capsaicin is associated with a sharp and burning pain, frequently described as pungency. To elucidate the mechanisms underlying pungency we investigated a series of TRPV1 agonists that included both pungent and non-pungent compounds covering a large range of potencies. Pungency of capsaicin, piperine, arvanil, olvanil, RTX (resiniferatoxin) and SDZ-249665 was evaluated in vivo, by determining the increase in the number of eye wipes caused by direct instillation of agonist solutions into the eye. Agonist-induced calcium fluxes were recorded using the FLIPR technique in a recombinant, TRPV1-expressing cell line. Current-clamp recordings were performed in rat DRG (dorsal root ganglia) neurons in order to assess the consequences of TRPV1 activation on neuronal excitability. Using the eye wipe assay the following rank of pungency was obtained: capsaicin>piperine>RTX>arvanil>olvanil>SDZ-249665. We found a strong correlation between kinetics of calcium flux, pungency and lipophilicity of TRPV1 agonists. Current-clamp recordings confirmed that the rate of receptor activation translates in the ability of agonists to generate action potentials in sensory neurons. We have demonstrated that the lipophilicity of the compounds is directly related to the kinetics of TRPV1 activation and that the latter influences their ability to trigger action potentials in sensory neurons and, ultimately, pungency.

Topics: Action Potentials; Alkaloids; Animals; Benzodioxoles; Capsaicin; Diterpenes; Ganglia, Spinal; Kinetics; Lipid Metabolism; Male; Neurons, Afferent; Pain; Patch-Clamp Techniques; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Sensory Receptor Cells; Solubility; TRPV Cation Channels; Urea

A series of spiro-azetidines and azetidinones has been evaluated as novel blockers of the T-type calcium channel (Ca(V)3.2) which is a new therapeutic target for the potential treatment of both inflammatory and neuropathic pain. Confirmation and optimization of the potency, selectivity and DMPK properties of leads will be described.

Topics: Animals; Azetidines; Calcium Channel Blockers; Calcium Channels, T-Type; Drug Design; Humans; Pain; Piperidines; Protein Binding; Rats; Spiro Compounds; Structure-Activity Relationship

It is still controversial which drugs, proton pump inhibitors (PPI) or histamine-2 receptor antagonists (H2RA), are more effective for dyspepsia in the Japanese population.. Patients with uninvestigated dyspepsia (n = 104; male/female 41/63) were treated with either rabeprazole 10 mg o.d. (n = 62) or lafutidine 10 mg b.i.d. (n = 42) for 4 weeks. Questionnaires (modified Frequency Scale for the Symptoms of Gastroesophageal Reflux Disease [mFSSG] and quality of life [QOL], SF-8) were administered before and after therapy. The mFSSG was classified into a total score (Q-T), reflux score (Q-R), dyspepsia score (Q-D) and pain score (Q-P). The SF-8 had a physical component summary (PCS) and mental component summary (MCS). The predominant type of symptom was reflux (R-S), pain (P-S) or dysmotility (D-S).. R-S was 19.2%, P-S 48.1%, D-S 24.0% and overlap 8.7%. In the R-S, Q-T and Q-R significantly improved with rabeprazole, but neither scale improved with lafutidine. MCS significantly improved with rabeprazole. In P-S, Q-T, Q-R, Q-D and Q-P significantly improved with both drugs. PCS significantly improved with both, whereas the MCS significant improved with rabeprazole. In D-S, Q-R and Q-D significant improved with rabeprazole, but neither improved with lafutidine. QOL did not improve with either. With overlap, neither scale nor the QOL reached a significant difference.. Both PPI and H2RA have a positive effect on P-S, but H(2)RA therapy is limited for R-S and D-S, whereas PPI therapy is generally effective. Therefore, careful prescription based on symptoms is important.

Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; Acetamides; Adult; Dyspepsia; Esophageal Motility Disorders; Female; Gastroesophageal Reflux; Histamine H2 Antagonists; Humans; Japan; Male; Middle Aged; Pain; Pain Measurement; Piperidines; Proton Pump Inhibitors; Pyridines; Rabeprazole; Retrospective Studies; Severity of Illness Index; Surveys and Questionnaires; Treatment Outcome

Recent studies suggest that the effects of cyclooxygenase-2 (COX-2) inhibition are mediated by cannabinoid receptor activation. However, some non-steroidal anti-inflammatory drugs inhibit the enzyme fatty acid amide hydrolase, which regulates levels of some endocannabinoids. Whether COX-2 directly regulates levels of endocannabinoids in vivo is unclear. Here, the effect of the COX-2 inhibitor nimesulide, which does not inhibit fatty acid amide hydrolase, on spinal nociceptive processing was determined. Effects of nimesulide on tissue levels of endocannabinoids and related compounds were measured and the role of cannabinoid 1 (CB(1)) receptors was determined.. Effects of spinal and peripheral administration of nimesulide (1-100 microg per 50 microL) on mechanically evoked responses of rat dorsal horn neurones were measured, and the contribution of the CB(1) receptor was determined with the antagonist AM251 (N-(piperidin-1-yl)-5-(-4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide), in anaesthetized rats. Effects of nimesulide on spinal levels of endocannabinoids and related compounds were quantified using liquid chromatography-tandem mass spectrometry.. Spinal, but not peripheral, injection of nimesulide (1-100 microg per 50 microL) significantly reduced mechanically evoked responses of dorsal horn neurones. Inhibitory effects of spinal nimesulide were blocked by the CB(1) receptor antagonist AM251 (1 microg per 50 microL), but spinal levels of endocannabinoids were not elevated. Indeed, both anandamide and N-oleoylethanolamide (OEA) were significantly decreased by nimesulide.. Although the inhibitory effects of COX-2 blockade on spinal neuronal responses by nimesulide were dependent on CB(1) receptors, we did not detect a concomitant elevation in anandamide or 2-AG. Further understanding of the complexities of endocannabinoid catabolism by multiple enzymes is essential to understand their contribution to COX-2-mediated analgesia.

Topics: Animals; Cannabinoid Receptor Modulators; Cyclooxygenase 2; Cyclooxygenase Inhibitors; Dose-Response Relationship, Drug; Drug Administration Routes; Endocannabinoids; Evoked Potentials; Male; Pain; Piperidines; Posterior Horn Cells; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Spinal Cord; Sulfonamides

Nociceptin/Orphanin FQ (N/OFQ) counteracts supraspinal opioid effects and plays a role in antinociceptive morphine tolerance. Therefore, in the present study, the selective mu-opioid agonist [D-Ala(2)-NMe-Phe(4)-Gly-ol(5)]-enkephalin (DAMGO) was used. Repeated injection of DAMGO (1 microg/ 1 microl) into the ventrolateral periaqueductal gray (vlPAG), a key site for the development of opioid tolerance, induced analgesia that lasted up to 3 days. In DAMGO-tolerant rats, injection of the N/OFQ antagonist (+/-)-J 113397 (4 microg/1 microl), into the same site, restored the antinociceptive effect of DAMGO. If (+/-)-J 113397 treatment preceded each DAMGO injection, tolerance did not develop. Inhibition of N/OFQ signaling can reverse and prevent the development of DAMGO tolerance in the vlPAG. The results confirm that N/OFQ acts as a functional opioid antagonist.

Topics: Analgesia; Analgesics, Opioid; Animals; Benzimidazoles; Drug Tolerance; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Male; Morphine; Narcotic Antagonists; Nociceptin; Nociceptin Receptor; Opioid Peptides; Pain; Periaqueductal Gray; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Opioid; Vasodilator Agents

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

Prolonged exposure to drugs of abuse, such as cannabinoids and opioids, leads to pharmacological tolerance and receptor desensitization in the nervous system. We found that a similar form of functional antagonism was produced by sustained inactivation of monoacylglycerol lipase (MAGL), the principal degradative enzyme for the endocannabinoid 2-arachidonoylglycerol. After repeated administration, the MAGL inhibitor JZL184 lost its analgesic activity and produced cross-tolerance to cannabinoid receptor (CB1) agonists in mice, effects that were phenocopied by genetic disruption of Mgll (encoding MAGL). Chronic MAGL blockade also caused physical dependence, impaired endocannabinoid-dependent synaptic plasticity and desensitized brain CB1 receptors. These data contrast with blockade of fatty acid amide hydrolase, an enzyme that degrades the other major endocannabinoid anandamide, which produced sustained analgesia without impairing CB1 receptors. Thus, individual endocannabinoids generate distinct analgesic profiles that are either sustained or transitory and associated with agonism and functional antagonism of the brain cannabinoid system, respectively.

Topics: Amidohydrolases; Analgesics; Animals; Benzodioxoles; Brain; Cannabinoid Receptor Modulators; Endocannabinoids; Enzyme Inhibitors; Female; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Models, Animal; Monoacylglycerol Lipases; Neuronal Plasticity; Pain; Piperidines; Receptor, Cannabinoid, CB1; Synapses

1,3-Disubstituted ureas possessing a piperidyl moiety have been synthesized to investigate their structure-activity relationships as inhibitors of the human and murine soluble epoxide hydrolase (sEH). Oral administration of 13 1-aryl-3-(1-acylpiperidin-4-yl)urea inhibitors in mice revealed substantial improvements in pharmacokinetic parameters over previously reported 1-adamantylurea based inhibitors. For example, 1-(1-(cyclopropanecarbonyl)piperidin-4-yl)-3-(4-(trifluoromethoxy)phenyl)urea (52) showed a 7-fold increase in potency, a 65-fold increase in C(max), and a 3300-fold increase in AUC over its adamantane analogue 1-(1-adamantyl)-3-(1-propionylpiperidin-4-yl)urea (2). This novel sEH inhibitor showed a 1000-fold increase in potency when compared to morphine by reducing hyperalgesia as measured by mechanical withdrawal threshold using the in vivo carrageenan induced inflammatory pain model.

Topics: Adamantane; Analgesics, Opioid; Animals; Anti-Inflammatory Agents, Non-Steroidal; Carrageenan; Epoxide Hydrolases; Humans; Male; Mice; Morphine; Pain; Piperidines; Rats; Rats, Sprague-Dawley; Solubility; Structure-Activity Relationship; Urea

Peripheral cannabinoid receptors exert a powerful inhibitory control over pain initiation, but the endocannabinoid signal that normally engages this intrinsic analgesic mechanism is unknown. To address this question, we developed a peripherally restricted inhibitor (URB937) of fatty acid amide hydrolase (FAAH), the enzyme responsible for the degradation of the endocannabinoid anandamide. URB937 suppressed FAAH activity and increased anandamide levels outside the rodent CNS. Despite its inability to access brain and spinal cord, URB937 attenuated behavioral responses indicative of persistent pain in rodent models of peripheral nerve injury and inflammation and prevented noxious stimulus-evoked neuronal activation in spinal cord regions implicated in nociceptive processing. CB₁ cannabinoid receptor blockade prevented these effects. These results suggest that anandamide-mediated signaling at peripheral CB₁ receptors controls the access of pain-related inputs to the CNS. Brain-impenetrant FAAH inhibitors, which strengthen this gating mechanism, might offer a new approach to pain therapy.

Topics: Amidohydrolases; Animals; Arachidonic Acids; Cannabinoid Receptor Modulators; Cannabinoids; Carrageenan; Chromatography, Liquid; Disease Models, Animal; Drug Administration Routes; Drug Administration Schedule; Endocannabinoids; Enzyme Inhibitors; Escape Reaction; Ethylene Glycols; Feeding Behavior; Formaldehyde; Gene Expression Regulation; Hyperalgesia; Indoles; Male; Mass Spectrometry; Mice; Mice, Inbred C57BL; Mice, Knockout; Monoacylglycerol Lipases; Motor Activity; Oncogene Proteins v-fos; Pain; Pain Measurement; Pain Threshold; Peripheral Nervous System Diseases; Piperidines; Polyunsaturated Alkamides; PPAR alpha; Pyrazoles; Rats; Rats, Sprague-Dawley; Rimonabant; Sciatica; Spinal Cord; Statistics, Nonparametric; Time Factors; Tissue Distribution; Tritium

δ-Opioid receptors are G-protein-coupled receptors that regulate nociceptive and emotional responses. It has been well established that distinct agonists acting at the same G-protein-coupled receptor can engage different signaling or regulatory responses. This concept, known as biased agonism, has important biological and therapeutic implications. Ligand-biased responses are well described in cellular models, however, demonstrating the physiological relevance of biased agonism in vivo remains a major challenge. The aim of this study was to investigate the long-term consequences of ligand-biased trafficking of the δ-opioid receptor, at both the cellular and behavioral level. We used δ agonists with similar binding and analgesic properties, but high [SNC80 ((+)-4-[(αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide)]- or low [ARM390 (N,N-diethyl-4-(phenyl-piperidin-4-ylidenemethyl)-benzamide)]-internalization potencies. As we found previously, a single SNC80-but not ARM390-administration triggered acute desensitization of the analgesic response in mice. However, daily injections of either compound over 5 d produced full analgesic tolerance. SNC80-tolerant animals showed widespread receptor downregulation, and tolerance to analgesic, locomotor and anxiolytic effects of the agonist. Hence, internalization-dependent tolerance developed, as a result of generalized receptor degradation. In contrast, ARM390-tolerant mice showed intact receptor expression, but δ-opioid receptor coupling to Ca²+ channels was abolished in dorsal root ganglia. Concomitantly, tolerance developed for agonist-induced analgesia, but not locomotor or anxiolytic responses. Therefore, internalization-independent tolerance was produced by anatomically restricted adaptations leading to pain-specific tolerance. Hence, ligand-directed receptor trafficking of the δ-opioid receptor engages distinct adaptive responses, and this study reveals a novel aspect of biased agonism in vivo.

Topics: Analgesics; Animals; Benzamides; Brain; Calcium; Cell Membrane; Disease Models, Animal; Drug Interactions; Drug Tolerance; Female; Freund's Adjuvant; Ganglia, Spinal; Green Fluorescent Proteins; Guanosine 5'-O-(3-Thiotriphosphate); Hyperalgesia; Inflammation; Ligands; Locomotion; Male; Maze Learning; Membrane Potentials; Mice; Mice, Inbred C57BL; Mice, Transgenic; Pain; Pain Threshold; Patch-Clamp Techniques; Piperazines; Piperidines; Protein Binding; Protein Transport; Receptors, Opioid, delta; Sensory Receptor Cells; Spinal Cord; Statistics, Nonparametric; Sulfur Isotopes; Time Factors

Temporomandibular disorders represent one of the major challenges in dentistry therapeutics. This study was undertaken to evaluate the time course of carrageenan-induced inflammation in the rat temporomandibular joint (TMJ) and to investigate the role of tachykinin NK(1) receptors. Inflammation was induced by a single intra-articular (i.art.) injection of carrageenan into the left TMJ (control group received sterile saline). Inflammatory parameters such as plasma extravasation, leukocyte influx and mechanical allodynia (measured as the head-withdrawal force threshold) and TNFalpha and IL-1beta concentrations were measured in the TMJ lavages at selected time-points. The carrageenan-induced responses were also evaluated after treatment with the NK(1) receptor antagonist SR140333. The i.art. injection of carrageenan into the TMJ caused a time-dependent plasma extravasation associated with mechanical allodynia, and a marked neutrophil accumulation between 4 and 24h. Treatment with SR140333 substantially inhibited the increase in plasma extravasation and leukocyte influx at 4 and 24h, as well as the production of TNFalpha and IL-1beta into the joint cavity, but failed to affect changes in head-withdrawal threshold. The results obtained from the present TMJ-arthritis model provide, for the first time, information regarding the time course of this experimental inflammatory process. In addition, our data show that peripheral NK(1) receptors mediate the production of both TNFalpha and IL-1beta in the TMJ as well as some of the inflammatory signs, such as plasma extravasation and leukocyte influx, but not the nociceptive component.

Topics: Animals; Carrageenan; Data Interpretation, Statistical; Extravasation of Diagnostic and Therapeutic Materials; Inflammation; Interleukin-1beta; Leukocyte Count; Male; Neurokinin-1 Receptor Antagonists; Pain; Peroxidase; Piperidines; Quinuclidines; Radiopharmaceuticals; Rats; Rats, Wistar; Receptors, Neurokinin-1; Serum Albumin, Radio-Iodinated; Substance P; Temporomandibular Joint Disorders; Tumor Necrosis Factor-alpha

Improgan, a cimetidine derivative which lacks activity at known histamine, opioid or cannabinoid receptors, acts by an unknown mechanism in the periaqueductal gray (PAG) and raphe magnus (RM) to stimulate descending, analgesic circuits. These circuits may utilize cannabinoid mechanisms. To characterize further the nature of these circuits, the effects of intracerebral (i.c.) microinjections of rimonabant (a CB(1) receptor inverse agonist) were studied on antinociceptive responses following i.c. microinjections of improgan and the cannabinoid agonist WIN 55,212 (WIN) in rats. Separate intra-RM injections of improgan (30 microg) and WIN (8 microg) produced near-maximal antinociception on both the hot plate (HP) and tail flick (TF) nociceptive tests. Pretreatment with intra-RM rimonabant (20 microg) antagonized the antinociception produced by both intra-RM improgan and intra-RM WIN, but had no effects when given alone. Similar studies with improgan demonstrated rimonabant-sensitive sites within the dorsal and ventrolateral PAG. However, intra-RM pretreatment with rimonabant had no effect on antinociceptive responses following intra-PAG improgan. These studies show that improgan activates pain-relieving mechanisms in the PAG and the RM, both of which may utilize local cannabinoid mechanisms.

Topics: Analgesics; Animals; Benzoxazines; Brain Stem; Cannabinoid Receptor Modulators; Cimetidine; Male; Microinjections; Morpholines; Naphthalenes; Neural Pathways; Nociceptors; Pain; Pain Measurement; Pain Threshold; Periaqueductal Gray; Piperidines; Pyrazoles; Raphe Nuclei; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Rhombencephalon; Rimonabant

Behavioral effects of a nonpeptidic NOP (nociceptin/orphanin FQ Peptide) receptor agonist, Ro 64-6198, have not been studied in primate species. The aim of the study was to verify the receptor mechanism underlying the behavioral effects of Ro 64-6198 and to systematically compare behavioral effects of Ro 64-6198 with those of a mu-opioid receptor agonist, alfentanil, in monkeys. Both Ro 64-6198 (0.001-0.06 mg/kg, s.c.) and alfentanil (0.001-0.06 mg/kg, s.c.) produced antinociception against an acute noxious stimulus (50 degrees C water) and capsaicin-induced allodynia. An NOP receptor antagonist, J-113397 (0.01-0.1 mg/kg, s.c.), dose-dependently produced rightward shifts of the dose-response curve of Ro 64-6198-induced antinociception. The apparent pA(2) value of J-113397 was 8.0. Antagonist studies using J-113397 and naltrexone revealed that Ro 64-6198 produced NOP receptor-mediated antinociception independent of mu-opioid receptors. In addition, alfentanil dose-dependently produced respiratory depression and itch/scratching responses, but antinociceptive doses of Ro 64-6198 did not produce such effects. More important, Ro 64-6198 did not produce reinforcing effects comparable with those of alfentanil, cocaine, or methohexital under self-administration procedures in monkeys. These results provide the first functional evidence that the activation of NOP receptors produces antinociception without reinforcing effects in primates. Non-peptidic NOP receptor agonists may have therapeutic value as novel analgesics without abuse liability in humans.

Topics: Alfentanil; Analgesics, Opioid; Animals; Behavior, Animal; Benzimidazoles; Capsaicin; Central Nervous System Agents; Dose-Response Relationship, Drug; Female; Hot Temperature; Imidazoles; Macaca mulatta; Male; Naltrexone; Narcotic Antagonists; Nociceptin Receptor; Pain; Piperidines; Pruritus; Receptors, Opioid; Receptors, Opioid, mu; Reinforcement, Psychology; Respiratory Insufficiency; Spiro Compounds

Neurotensin modulates pain via its actions within descending analgesic pathways which include brain regions such as the midbrain periaqueductal grey (PAG). The aim of this study was to examine the cellular actions of neurotensin on PAG neurons. Whole cell patch clamp recordings were made from rat midbrain PAG slices in vitro to examine the postsynaptic effects of neurotensin and its effects on GABA(A) mediated inhibitory postsynaptic currents (IPSCs). Neurotensin (100-300 nM) produced an inward current in subpopulations of opioid sensitive and insensitive PAG neurons which did not reverse over membrane potentials between -50 and -130 mV. The neurotensin induced current was abolished by the NTS1 and NTS1/2 antagonists SR48692 (300 nM) and SR142948A (300 nM). Neurotensin also produced a reduction in the amplitude of evoked IPSCs, but had no effect on the rate and amplitude of TTX-resistant miniature IPSCs. The neurotensin induced inhibition of evoked IPSCs was reduced by the mGluR5 antagonist MPEP (5microM) and abolished by the cannabinoid CB(1) receptor antagonist AM251 (3 microM). These results suggest that neurotensin produces direct neuronal depolarisation via NTS1 receptors and inhibits GABAergic synaptic transmission within the PAG. The inhibition of synaptic transmission is mediated by neuronal excitation and action potential dependent release of glutamate, leading to mGluR5 mediated production of endocannabinoids which activate presynaptic CB(1) receptors. Thus, neurotensin has cellular actions within the PAG which are consistent with both algesic and analgesic activity, some of which are mediated via the endocannabinoid system.

Topics: Adamantane; Animals; Cannabinoid Receptor Modulators; Endocannabinoids; Excitatory Amino Acid Antagonists; Female; gamma-Aminobutyric Acid; Imidazoles; In Vitro Techniques; Inhibitory Postsynaptic Potentials; Male; Miniature Postsynaptic Potentials; Neural Inhibition; Neurons; Neurotensin; Pain; Periaqueductal Gray; Piperidines; Presynaptic Terminals; Pyrazoles; Pyridines; Quinolines; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate; Receptors, Neurotensin; Synaptic Transmission; Tetrodotoxin; Time Factors

Endocannabinoids are lipid signaling molecules that regulate a wide range of mammalian behaviors, including pain, inflammation, and cognitive/emotional state. The endocannabinoid anandamide is principally degraded by the integral membrane enzyme fatty acid amide hydrolase (FAAH), and there is currently much interest in developing FAAH inhibitors to augment endocannabinoid signaling in vivo. Here, we report the discovery and detailed characterization of a highly efficacious and selective FAAH inhibitor, PF-3845. Mechanistic and structural studies confirm that PF-3845 is a covalent inhibitor that carbamylates FAAH's serine nucleophile. PF-3845 selectively inhibits FAAH in vivo, as determined by activity-based protein profiling; raises brain anandamide levels for up to 24 hr; and produces significant cannabinoid receptor-dependent reductions in inflammatory pain. These data thus designate PF-3845 as a valuable pharmacological tool for in vivo characterization of the endocannabinoid system.

Topics: Amidohydrolases; Animals; Arachidonic Acids; Brain; Crystallography, X-Ray; Endocannabinoids; Enzyme Inhibitors; Humans; Male; Pain; Piperazine; Piperazines; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Sprague-Dawley; Receptors, Cannabinoid; Structure-Activity Relationship; Urea

The pharmacology and metabolism of the potent sigma1 receptor ligand 1'-benzyl-3-methoxy-3H-spiro[[2]benzofuran-1,4'-piperidine] were evaluated.. The compound was tested against a wide range of receptors, ion channels and neurotransmitter transporters in radioligand binding assays. Analgesic activity was evaluated using the capsaicin pain model. Metabolism by rat and human liver microsomes was investigated, and the metabolites were identified by a variety of analytical techniques.. 1'-benzyl-3-methoxy-3H-spiro[[2]benzofuran-1,4'-piperidine] (compound 1) is a potent sigma1 receptor ligand (Ki 1.14 nM) with extraordinarily high sigma1/sigma2 selectivity (>1100). It was selective for the sigma1 receptor over more than 60 other receptors, ion channels and neurotransmitter transporters, and did not interact with the human ether-a-go-go-related gene (hERG) cardiac potassium channel. Compound 1 displayed analgesic activity against neuropathic pain in the capsaicin pain model (53% analgesia at 16 mg/kg), indicating that it is a sigma1 receptor antagonist. It was rapidly metabolised by rat liver microsomes. Seven metabolites were unequivocally identified; an N-debenzylated metabolite and a hydroxylated metabolite were the major products. Pooled human liver microsomes formed the same metabolites. Studies with seven recombinant cytochrome P450 isoenzymes revealed that CYP3A4 produced all the metabolites identified. The isoenzyme CYP2D6 was inhibited by 1 (IC50 88 nM) but did not produce any metabolites.. 1'-benzyl-3-methoxy-3H-spiro[[2]benzofuran-1,4'-piperidine] is a potent and selective sigma1 receptor antagonist, which is rapidly metabolised. Metabolically more stable sigma1 ligands could be achieved by stabilising the N-benzyl substructure.

Topics: Analgesics; Animals; Capsaicin; Chromatography, High Pressure Liquid; Humans; Ligands; Mice; Microsomes, Liver; Pain; Piperidines; Radioligand Assay; Rats; Receptors, sigma; Sigma-1 Receptor

Acupuncture is widely used clinically to treat acute and chronic pain conditions, but the mechanisms underlying its effect are not fully understood. Although endocannabinoids are involved in modulation of nociception in animal models and in humans, their role in acupuncture analgesia has not been assessed. In this report, we determined the effect of electroacupuncture (EA) on the level of anandamide in the skin tissue and the role of cannabinoid CB1 and CB2 receptors in the analgesic effect of EA in an animal model of inflammatory pain. Inflammatory pain was induced by local injection of complete Freund's adjuvant (CFA) into the hind paw of rats. Thermal hyperalgesia was tested with a radiant heat stimulus, and mechanical allodynia was quantified with von Frey filaments. The anandamide concentration in the skin tissue was measured by using high-performance liquid chromatography. EA, applied to GB30 and GB34, at 2 and 100Hz significantly reduced thermal hyperalgesia and mechanical allodynia induced by CFA injection. Compared with the sham group, EA significantly increased the anandamide level in the inflamed skin tissue. Local pretreatment with a specific CB2 receptor antagonist, AM630, significantly attenuated the antinociceptive effect of EA. However, the effect of EA was not significantly altered by AM251, a selective CB1 receptor antagonist. These findings suggest that EA potentiates the local release of endogenous anandamide from inflamed tissues. Activation of peripheral CB2 receptors contributes to the analgesic effect of EA on inflammatory pain.. This study shows that electroacupuncture increases the anandamide level in inflammatory skin tissues, and CB2 receptors contribute to the analgesic effect of electroacupuncture in a rat model of inflammatory pain. This information improves our understanding of the mechanisms involved in the analgesic effect of acupuncture.

Topics: Animals; Arachidonic Acids; Chromatography, High Pressure Liquid; Electroacupuncture; Endocannabinoids; Freund's Adjuvant; Hindlimb; Hot Temperature; Hyperalgesia; Indoles; Male; Pain; Pain Management; Physical Stimulation; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Skin

GPCRs regulate a remarkable diversity of biological functions, and are thus often targeted for drug therapies. Stimulation of a GPCR by an extracellular ligand triggers receptor signaling via G proteins, and this process is highly regulated. Receptor activation is typically accompanied by desensitization of receptor signaling, a complex feedback regulatory process of which receptor internalization is postulated as a key event. The in vivo significance of GPCR internalization is poorly understood. In fact, the majority of studies have been performed in transfected cell systems, which do not adequately model physiological environments and the complexity of integrated responses observed in the whole animal.. In this study, we used knock-in mice expressing functional fluorescent delta opioid receptors (DOR-eGFP) in place of the native receptor to correlate receptor localization in neurons with behavioral responses. We analyzed the pain-relieving effects of two delta receptor agonists with similar signaling potencies and efficacies, but distinct internalizing properties. An initial treatment with the high (SNC80) or low (AR-M100390) internalizing agonist equally reduced CFA-induced inflammatory pain. However, subsequent drug treatment produced highly distinct responses. Animals initially treated with SNC80 showed no analgesic response to a second dose of either delta receptor agonist. Concomitant receptor internalization and G-protein uncoupling were observed throughout the nervous system. This loss of function was temporary, since full DOR-eGFP receptor responses were restored 24 hours after SNC80 administration. In contrast, treatment with AR-M100390 resulted in retained analgesic response to a subsequent agonist injection, and ex vivo analysis showed that DOR-eGFP receptor remained G protein-coupled on the cell surface. Finally SNC80 but not AR-M100390 produced DOR-eGFP phosphorylation, suggesting that the two agonists produce distinct active receptor conformations in vivo which likely lead to differential receptor trafficking.. Together our data show that delta agonists retain full analgesic efficacy when receptors remain on the cell surface. In contrast, delta agonist-induced analgesia is abolished following receptor internalization, and complete behavioral desensitization is observed. Overall these results establish that, in the context of pain control, receptor localization fully controls receptor function in vivo. This finding has both fundamental and therapeutic implications for slow-recycling GPCRs.

Topics: Animals; Behavior, Animal; Benzamides; Biological Transport, Active; Cell Membrane; Cells, Cultured; Green Fluorescent Proteins; In Vitro Techniques; Ligands; Mice; Mice, Transgenic; Neurons; Pain; Phosphorylation; Piperazines; Piperidines; Protein Conformation; Receptors, Opioid, delta; Recombinant Fusion Proteins

Direct-acting cannabinoid receptor agonists are well known to reduce hyperalgesic responses and allodynia after nerve injury, although their psychoactive side effects have damped enthusiasm for their therapeutic development. Alternatively, inhibiting fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), the principal enzymes responsible for the degradation of the respective endogenous cannabinoids, anandamide (AEA) and 2-arachydonylglycerol (2-AG), reduce nociception in a variety of nociceptive assays, with no or minimal behavioral effects. In the present study we tested whether inhibition of these enzymes attenuates mechanical allodynia, and acetone-induced cold allodynia in mice subjected to chronic constriction injury of the sciatic nerve. Acute administration of the irreversible FAAH inhibitor, cyclohexylcarbamic acid 3'-carbamoylbiphenyl-3-yl ester (URB597), or the reversible FAAH inhibitor, 1-oxo-1-[5-(2-pyridyl)-2-yl]-7-phenylheptane (OL-135), decreased allodynia in both tests. This attenuation was completely blocked by pretreatment with either CB(1) or CB(2) receptor antagonists, but not by the TRPV1 receptor antagonist, capsazepine, or the opioid receptor antagonist, naltrexone. The novel MAGL inhibitor, 4-nitrophenyl 4-(dibenzo[d][1,3]dioxol-5-yl(hydroxy)methyl)piperidine-1-carboxylate (JZL184) also attenuated mechanical and cold allodynia via a CB(1), but not a CB(2), receptor mechanism of action. Whereas URB597 did not elicit antiallodynic effects in FAAH(-/-) mice, the effects of JZL184 were FAAH-independent. Finally, URB597 increased brain and spinal cord AEA levels, whereas JZL184 increased 2-AG levels in these tissues, but no differences in either endo-cannabinoid were found between nerve-injured and control mice. These data indicate that inhibition of FAAH and MAGL reduces neuropathic pain through distinct receptor mechanisms of action and present viable targets for the development of analgesic therapeutics.

Topics: Amidohydrolases; Analgesics, Non-Narcotic; Animals; Arachidonic Acids; Benzamides; Benzodioxoles; Cannabinoid Receptor Modulators; Carbamates; Cold Temperature; Endocannabinoids; Enzyme Inhibitors; Glycerides; Hyperalgesia; Male; Mice; Mice, Inbred C57BL; Monoacylglycerol Lipases; Narcotic Antagonists; Pain; Pain Measurement; Peripheral Nervous System Diseases; Piperidines; Polyunsaturated Alkamides; Pyridines; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; TRPV Cation Channels

There is evidence from animal studies that serotonin (5-HT) can influence the antinociceptive effects of opioids at the spinal cord level. Therefore, there could be an influence of genetic polymorphisms in the serotonin system on individual variability in response to opioid treatment of pain. The serotonin transporter (5-HTT) is a key regulator of serotonin metabolism and availability and its gene harbors several known polymorphisms that are known to affect 5-HTT expression (e.g. 5-HTTLPR, rs25531). The aim of this study was to investigate if the triallelic 5-HTTLPR influences pain sensitivity or the analgesic effect of opioids in humans. 43 healthy volunteers (12 men, 31 women, mean age 26 years) underwent heat pain stimulations before and after intravenous injection of Remifentanil; a rapid and potent opioid drug acting on micro-type receptors. Subjects rated their perceived pain on a visual analogue scale (VAS). All participants were genotyped for the 5-HTTLPR and the rs25531 polymorphism. We recruited by advertising, with no history of drug abuse, chronic pain or psychiatric disorders.. At baseline, there was no difference in pain ratings for the different triallelic 5-HTTLPR genotype groups. However, the opiod drug had a differential analgesic effect depending on the triallelic 5-HTTLPR genotype. Remifentanil had a significantly better analgesic effect in individuals with a genotype coding for low 5-HTT expression (SA/SA and SA/LG) as compared to those with high expression(LA/LA), p < 0.02. The analgesic effect for the three different genotype groups was linear to degree of 5-HTT expression.. This is the first report showing an influence of the triallelic 5-HTTLPR on pain sensitivity or the analgesic effect of opioids in humans. Previously the 5-HTTLPR s-allele has been associated with higher risk of developing chronic pain conditions but in this study we show that the genotype coding for low 5-HTT expression is associated with a better analgesic effect of an opioid. The s-allele has been associated with downregulation of 5-HT1 receptors and we suggest that individuals with a desensitization of 5-HT1 receptors have an increased analgesic response to opioids during acute pain stimuli, but may still be at increased risk of developing chronic pain conditions.

Topics: Adult; Analgesics, Opioid; Female; Genotype; Humans; Male; Pain; Pain Measurement; Pharmacogenetics; Piperidines; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Remifentanil; Serotonin Plasma Membrane Transport Proteins

Central neurotensin (NT) administration results in a naloxone-insensitive antinociceptive response in animal models of acute and persistent pain. Both NTS1 and NTS2 receptors were shown to be required for different aspects of NT-induced analgesia. We recently demonstrated that NTS2 receptors were extensively associated with ascending nociceptive pathways, both at the level of the dorsal root ganglia and of the spinal dorsal horn. Then, we found that spinally administered NTS2-selective agonists induced dose-dependent antinociceptive responses in the acute tail-flick test. In the present study, we therefore investigated whether activation of spinal NTS2 receptors suppressed the persistent inflammatory pain symptoms observed after intraplantar injection of formalin.. We first demonstrated that spinally administered NT and NT69L agonists, which bind to both NTS1 and NTS2 receptors, significantly reduced pain-evoked responses during the inflammatory phase of the formalin test. Accordingly, pretreatment with the NTS2-selective analogs JMV-431 and levocabastine was effective in inhibiting the aversive behaviors induced by formalin. With resolution at the single-cell level, we also found that activation of spinal NTS2 receptors reduced formalin-induced c-fos expression in dorsal horn neurons. However, our results also suggest that NTS2-selective agonists and NTS1/NTS2 mixed compounds differently modulated the early (21-39 min) and late (40-60 min) tonic phase 2 and recruited endogenous pain inhibitory mechanisms integrated at different levels of the central nervous system. Indeed, while non-selective drugs suppressed pain-related behaviors activity in both part of phase 2, intrathecal injection of NTS2-selective agonists was only efficient in reducing pain during the late phase 2. Furthermore, assessment of the stereotypic pain behaviors of lifting, shaking, licking and biting to formalin also revealed that unlike non-discriminative NTS1/NTS2 analogs reversing all nociceptive endpoint behaviors, pure NTS2 agonists specifically inhibited paw lifting, supporting a role of NTS2 in spinal modulation of persistent nociception.. The present study provides the first demonstration that activation of NTS2 receptors produces analgesia in the persistent inflammatory pain model of formalin. The dichotomy between these two classes of compounds also indicates that both NTS1 and NTS2 receptors are involved in tonic pain inhibition and implies that these two NT receptors modulate the pain-induced behavioral responses by acting on distinct spinal and/or supraspinal neural circuits. In conclusion, development of NT agonists targeting both NTS1 and NTS2 receptors could be useful for chronic pain management.

Topics: Animals; Formaldehyde; Histamine H1 Antagonists, Non-Sedating; Inflammation; Male; Neurotensin; Pain; Peptide Fragments; Piperidines; Posterior Horn Cells; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Receptors, Neurotensin; Spinal Nerves; Time Factors

Hemlock was used as an analgesic in certain ethnopharmacological traditions and there has been no record about the antinociceptive effect of coniine which is the major alkaloid compound of Hemlock.. The present study was undertaken to evaluate the possible antinociceptive activity of coniine.. Antinociceptive activity of coniine was tested dose in Hotplate test (thermal pain model) and in Writhing test (chemical pain model) in different nociception models.. Coniine caused a prolongation in reaction time in Hotplate test at 20mg/kg dose. In addition, it was observed that coniine decreased the number of writhes in Writhing test. Both data indicated an antinociceptive effect of coniine. A rotarod test was also conducted in order to clarify, whether this activity was related with a loss of locomotion or with an analgesic activity. None of the chemical agents at those doses used in experiments caused a loss of locomotor activity. It was also shown that antinociceptive effect of morphine was potentialized by coniine which was inhibited by nicotinic receptor blocker mecamylamine (1mg/kg).. Coniine has antinociceptive effect via the nicotinic receptors. A pharmacological assessment about the painless death of Socrates due to Hemlock (coniine) toxicity has also been presented by using this data.

Topics: Acetic Acid; Alkaloids; Analgesics; Animals; Conium; Drug Synergism; Male; Mecamylamine; Mice; Morphine; Nicotinic Antagonists; Pain; Piperidines; Plant Extracts

Intrathecal (i.t.) injection of morphine-3-glucuronide (M3G), a major metabolite of morphine without analgesic actions, produces a severe hindlimb scratching followed by biting and licking in mice. The pain-related behavior evoked by M3G was inhibited dose-dependently by i.t. co-administration of tachykinin NK(1) receptor antagonists, sendide, [D-Phe(7), D-His(9)] substance P(6-11), CP-99994 or RP-67580 and i.t. pretreatment with antiserum against substance P. The competitive NMDA receptor antagonists, D-APV and CPP, the NMDA ion-channel blocker, MK-801 or the competitive antagonist of the polyamine recognition site of NMDA receptor ion-channel complex, ifenprodil, produced inhibitory effects on i.t. M3G-evoked nociceptive response. The NO-cGMP-PKG pathway, which involves the extracellular signal-regulated kinase (ERK), has been implicated as mediators of plasticity in several pain models. Here, we investigated whether M3G could influence the ERK activation in the NO-cGMP-PKG pathway. The i.t. injection of M3G evoked a definite activation of ERK in the lumbar dorsal spinal cord, which was prevented dose-dependently by U0126, a MAP kinase-ERK inhibitor. The selective nNOS inhibitor N(omega)-propyl-l-arginine, the selective iNOS inhibitor W1400, the soluble guanylate cyclase inhibitor ODQ and the PKG inhibitor KT-5823 inhibited dose-dependently the nociceptive response to i.t. M3G. In western blotting analysis, inhibiting M3G-induced nociceptive response using these inhibitors resulted in a significant blockade of ERK activation induced by M3G in the spinal cord. Taken together, these results suggest that activation of the spinal ERK signaling in the NO-cGMP-PKG pathway contributes to i.t. M3G-evoked nociceptive response.

Topics: Analgesics; Animals; Behavior, Animal; Butadienes; Central Nervous System Stimulants; Cyclic GMP; Dose-Response Relationship, Drug; Enzyme Activation; Enzyme Inhibitors; Extracellular Signal-Regulated MAP Kinases; Injections, Spinal; Isoindoles; Male; Mice; Mice, Inbred Strains; Morphine Derivatives; Nitric Oxide; Nitriles; Nociceptors; Pain; Peptide Fragments; Piperidines; Pyrrolidonecarboxylic Acid; Receptors, Tachykinin; Specific Pathogen-Free Organisms; Spinal Cord; Stereoisomerism; Substance P

Previous studies have implicated a potential role for histamine H3 receptor in pain processing. There have been conflicting data, however, on the roles of H3 receptors in pain perception, and little information is available about the role of spinal histamine H3 receptors in morphine-induced antinociception. In the present study we examined the role of histamine H3 receptor in morphine-induced antinociception using histamine H3 receptor knockout mice and a histamine H3 receptor antagonist. Anitinociception was evaluated by assays for four nociceptive stimuli: hot-plate, tail-flick, paw-withdrawal, and formalin tests. Antinociception induced by morphine (0.125 nmol/5 microl, i.t.) was significantly augmented in histamine H3 receptor knockout (-/-) mice compared to the wild-type (+/+) mice in all four assays of pain. Furthermore, the effect of intrathecally administered morphine with thioperamide, a histamine H3 antagonist, was examined in C57BL/6J mice. A low dose of i.t. administered thioperamide (0.125 nmol/5 microl) alone had no significant effect on the nociceptive response. In contrast, the combination of morphine (0.125 nmol/5 microl, i.t.) with the same dose of thioperamide resulted in a significant reduction in the pain-related behaviors in all four nociceptive tests. These results suggest that histamine exerts inhibitory effects on morphine-induced antinociception through H3 receptors at the spinal level.

Topics: Analgesics, Opioid; Animals; Histamine Antagonists; Injections, Spinal; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Morphine; Pain; Pain Measurement; Pain Threshold; Piperidines; Receptors, Histamine H3; Time Factors

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

Neurotensin (NT) is a neuropeptide with antinociceptive effects that are mediated through NT receptors, of which there are three known subtypes (NTS1, NTS2, and NTS3). Morphine is a mu-opioid receptor agonist commonly used for pain treatment but is associated with side effects that can be serious. We hypothesize that selective NT receptor agonists may represent a novel class of analgesics and their use in conjunction with morphine will have synergistic properties which may reduce the dose of morphine administered and its side effects.. The antinociceptive activity of an NT agonist (NT69L) and morphine was studied in rats using the hot plate test to determine if there is synergism between the two drugs in reducing pain. The NTS2 receptor antagonist, levocabastine, was used to determine the receptor subtype involved in the analgesic effect of NT69L and morphine.. The administration of both NT69L and morphine resulted in a dose-dependent analgesic effect. The isobolographic analysis demonstrated that the combination of sub-analgesic doses of NT69L and morphine was synergistic in the hot plate test. Pretreatment with the NTS2 receptor antagonist, levocabastine attenuated the antinociceptive effect of NT69L and the combined effect of NT69L and morphine in the hot plate test.. The results support the hypothesis that the synergistic combination of NT69L and morphine would improve the pharmacological treatment of pain while minimizing specific adverse effects of each of the drugs at a higher dose. NTS2 is important for the antinociceptive effect of NT69L and morphine.

Topics: Analgesics; Analgesics, Opioid; Animals; Dose-Response Relationship, Drug; Drug Synergism; Hot Temperature; Male; Morphine; Neurotensin; Pain; Pain Measurement; Peptide Fragments; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Neurotensin; Time Factors

Diminished synaptic inhibition in the spinal dorsal horn is a major contributor to chronic pain. Pathways that reduce synaptic inhibition in inflammatory and neuropathic pain states have been identified, but central hyperalgesia and diminished dorsal horn synaptic inhibition also occur in the absence of inflammation or neuropathy, solely triggered by intense nociceptive (C-fiber) input to the spinal dorsal horn. We found that endocannabinoids, produced upon strong nociceptive stimulation, activated type 1 cannabinoid (CB1) receptors on inhibitory dorsal horn neurons to reduce the synaptic release of gamma-aminobutyric acid and glycine and thus rendered nociceptive neurons excitable by nonpainful stimuli. Our results suggest that spinal endocannabinoids and CB1 receptors on inhibitory dorsal horn interneurons act as mediators of heterosynaptic pain sensitization and play an unexpected role in dorsal horn pain-controlling circuits.

Topics: Adult; Animals; Cannabinoid Receptor Modulators; Electric Stimulation; Endocannabinoids; Excitatory Postsynaptic Potentials; Female; Humans; Hyperalgesia; Inhibitory Postsynaptic Potentials; Interneurons; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Nerve Fibers, Unmyelinated; Neural Inhibition; Pain; Piperidines; Posterior Horn Cells; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Rimonabant; Spinal Cord; Synaptic Transmission; Young Adult

Considerable preclinical research has demonstrated the efficacy of Delta(9)-tetrahydrocannabinol (Delta(9)-THC), the primary psychoactive constituent of Cannabis sativa, in a wide variety of animal models of pain, but few studies have examined other phytocannabinoids. Indeed, other plant-derived cannabinoids, including cannabidiol (CBD), cannabinol (CBN), and cannabichromene (CBC) elicit antinociceptive effects in some assays. In contrast, tetrahydrocannabivarin (THCV), another component of cannabis, antagonizes the pharmacological effects of Delta(9)-THC. These results suggest that various constituents of this plant may interact in a complex manner to modulate pain. The primary purpose of the present study was to assess the antinociceptive effects of these other prevalent phytocannabinoids in the acetic acid stretching test, a rodent visceral pain model. Of the cannabinoid compounds tested, Delta(9)-THC and CBN bound to the CB(1) receptor and produced antinociceptive effects. The CB(1) receptor antagonist, rimonabant, but not the CB(2) receptor antagonist, SR144528, blocked the antinociceptive effects of both compounds. Although THCV bound to the CB(1) receptor with similar affinity as Delta(9)-THC, it had no effects when administered alone, but antagonized the antinociceptive effects of Delta(9)-THC when both drugs were given in combination. Importantly, the antinociceptive effects of Delta(9)-THC and CBN occurred at lower doses than those necessary to produce locomotor suppression, suggesting motor dysfunction did not account for the decreases in acetic acid-induced abdominal stretching. These data raise the intriguing possibility that other constituents of cannabis can be used to modify the pharmacological effects of Delta(9)-THC by either eliciting antinociceptive effects (i.e., CBN) or antagonizing (i.e., THCV) the actions of Delta(9)-THC.

Topics: Acetic Acid; Analgesics; Animals; Anti-Obesity Agents; Camphanes; Cannabinoids; Cyclohexanols; Dose-Response Relationship, Drug; Dronabinol; Male; Mice; Mice, Inbred ICR; Motor Activity; Pain; Pain Measurement; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Rimonabant; RNA, Messenger

Activation of brain nociceptin/orphanin FQ (NOP) receptors leads to attenuation of mu-opioid receptor (MOP receptor)-mediated antinociception. Buprenorphine, a high-affinity partial MOP receptor agonist also binds to NOP receptors with 80 nM affinity. The buprenorphine-induced inverted U-shaped dose-response curve for antinociception may be due to NOP receptor activation, given that, in the presence of the NOP receptor antagonist, 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one (J113397), or in NOP receptor knockout mice, buprenorphine has a steeper dose-response curve and acts as a full agonist. To further explore the involvement of the direct activation of NOP receptors by buprenorphine and other compounds that activate both NOP and MOP receptors, the antinociceptive effects of 1-(1-(2,3,3alpha,4,5,6-hexahydro-1H-phenalen-1-yl)piperidin-4-yl)-indolin-2-one. (SR16435), 3-ethyl-1-(1-(4-isopropylcyclohexyl)piperidin-4-yl)-indolin-2-one (SR16507), buprenorphine, pentazocine, and morphine, compounds with varying levels of MOP and NOP receptor affinity and efficacy, were assessed in mice using the tail-flick assay. The ability of the selective NOP receptor antagonist (-)-cis-1-methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol (SB-612111) to potentiate antinociception induced by the above compounds was examined to investigate whether activation of NOP receptors leads to attenuation of MOP receptor-mediated antinociception. SB-612111 potentiated antinociception induced by buprenorphine and the other mixed NOP/MOP receptor agonists SR16435 and SR16507. However, SB-612111 had no effect on pentazocine or morphine antinociception, two compounds with no NOP receptor-binding affinity. These results further support the hypothesis that activation of NOP receptors can lead to attenuation of MOP receptor-mediated antinociception elicited by mixed NOP/MOP receptor compounds such as buprenorphine, SR16435, and SR16507 and that, although buprenorphine has low efficacy in vitro, it has significant NOP receptor agonist activity in vivo.

Topics: Analgesics, Opioid; Animals; Benzimidazoles; Buprenorphine; CHO Cells; Cricetinae; Cricetulus; Cycloheptanes; Dose-Response Relationship, Drug; Humans; Ligands; Male; Mice; Mice, Inbred ICR; Narcotic Antagonists; Nociceptin Receptor; Pain; Pain Measurement; Pain Threshold; Piperidines; Protein Binding; Receptors, Opioid; Receptors, Opioid, mu; Transfection

Previous studies of peripheral immune cells have documented that activation of adenosine 2A receptors (A(2A)Rs) decrease proinflammatory cytokine release and increase release of the potent anti-inflammatory cytokine, interleukin-10 (IL-10). Given the growing literature supporting that glial proinflammatory cytokines importantly contribute to neuropathic pain and that IL-10 can suppress such pain, we evaluated the effects of intrathecally administered A(2A)R agonists on neuropathic pain using the chronic constriction injury (CCI) model. A single intrathecal injection of the A(2A)R agonists 4-(3-(6-amino-9-(5-cyclopropylcarbamoyl-3,4-dihydroxytetrahydrofuran-2-yl)-9H-purin-2-yl)prop-2-ynyl)piperidine-1-carboxylic acid methyl ester (ATL313) or 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamido adenosine HCl (CGS21680), 10-14 d after CCI versus sham surgery, produced a long-duration reversal of mechanical allodynia and thermal hyperalgesia for at least 4 weeks. Neither drug altered the nociceptive responses of sham-operated controls. An A(2A)R antagonist [ZM241385 (4-(2-[7-amino-2-(2-furyl)(1,2,4)triazolo(2,3-a)(1,3,5)triazin-5-ylamino]ethyl)phenol)] coadministered intrathecally with ATL313 abolished the action of ATL313 in rats with neuropathy-induced allodynia but had no effect on allodynia in the absence of the A(2A)R agonist. ATL313 attenuated CCI-induced upregulation of spinal cord activation markers for microglia and astrocytes in the L4-L6 spinal cord segments both 1 and 4 weeks after a single intrathecal ATL313 administration. Neutralizing IL-10 antibodies administered intrathecally transiently abolished the effect of ATL313 on neuropathic pain. In addition, IL-10 mRNA was significantly elevated in the CSF cells collected from the lumbar region. Activation of A(2A)Rs after intrathecal administration may be a novel, therapeutic approach for the treatment of neuropathic pain by increasing IL-10 in the immunocompetent cells of the CNS.

Topics: Adenosine A2 Receptor Agonists; Animals; Injections, Spinal; Male; Neuralgia; Pain; Pain Measurement; Piperidines; Rats; Rats, Sprague-Dawley; Receptor, Adenosine A2A

A series of N-(N-methylpiperazinoacetyl)-2,6-diarylpiperidin-4-ones (13c-21c) were synthesized by the base catalyzed nucleophilic substitution of N-chloroacetyl-2,6-diarylpiperidin-4-ones obtained from their corresponding 2,6-diarylpiperidin-4-ones with N-methylpiperazine. These newly synthesized compounds were characterized by one- and two-dimensional NMR spectral studies. In all the cases, the piperazine ring adopted normal chair conformation with equatorial orientation of methyl group irrespective of the non-chair conformations of the piperidin-4-one moiety. All the compounds were screened for their possible antibacterial and antifungal activities against a spectrum of microbial agents besides analgesic and antipyretic activities. These biological studies proved that compounds 17c/18c against bacterial and 18c/20c against fungal strains exhibited promising antimicrobial activities whereas 17c/19c and 18c/19c showed beneficial analgesic and antipyretic profiles, respectively, at a concentration of 60mg/kg and were also found to be more potent than the reference drug.

Topics: Analgesics; Analgesics, Non-Narcotic; Animals; Anti-Infective Agents; Bacteria; Drug Evaluation, Preclinical; Fungi; Mice; Microbial Sensitivity Tests; Molecular Structure; Pain; Piperidines; Spectrum Analysis; Structure-Activity Relationship

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

We have previously demonstrated antinociceptive effects of fatty acid amide hydrolase (FAAH) inhibition that were accompanied by increases in the levels of endocannabinoids (ECs) in the hind paw. Here, the effects of the FAAH inhibitor URB597 (3'-carbamoyl-biphenyl-3-yl-cyclohexylcarbamate) on responses of spinal neurons were studied.. Extracellular single-unit recordings of dorsal horn neurons were made in anaesthetized rats with hind paw inflammation induced by lambda-carrageenan. Effects of intraplantar pre-administration of URB597, or vehicle, on carrageenan-evoked expansion of peripheral receptive fields of spinal neurons and mechanically evoked responses of neurons were studied. The cannabinoid receptor type 1 (CB(1)) antagonist AM251 (N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide) and the peroxisome proliferator-activated receptor (PPAR)-alpha antagonist GW6471 ([(2S)-2-[[(1Z)-1-methyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl]amino]-3-[4-[2-(5-methyl-2-phenyl-4-oxa zolyl)ethoxy]phenyl]propyl]-carbamic acid ethyl ester) were used to investigate the roles of these receptors in mediating the effects of URB597.. URB597 (25 microg in 50 microL) pretreatment significantly inhibited carrageenan-evoked receptive field expansion and this was significantly reversed by co-administration of the PPAR-alpha antagonist but not the CB(1) antagonist. Pretreatment with the PPAR-alpha receptor agonist WY14643 ([[4-chloro-6-[(2,3-dimethylphenyl)amino]-2-pyrimidinyl]thio]acetic acid) also significantly inhibited receptive field expansion. URB597 (25 or 100 microg in 50 microL) had no significant effect on mechanically evoked responses of spinal neurons.. URB597 inhibited receptive field expansions but not mechanically evoked responses of spinal neurons in rats with hind paw inflammation. These effects were blocked by PPAR-alpha receptor antagonism. These data support the contention that URB597 exerts its antinociceptive effects by indirect inhibition of sensitization of neuronal responses at least partly through PPAR-alpha activation due to enhanced EC levels.

Topics: Amidohydrolases; Analgesia; Animals; Benzamides; Carbamates; Carrageenan; Disease Models, Animal; Inflammation; Oxazoles; Pain; Piperidines; PPAR gamma; Pyrazoles; Rats; Receptor, Cannabinoid, CB1; Tyrosine

Herein, the synthesis and pharmacological evaluation of thiophene bioisosteres of the highly potent spirocyclic benzopyran 1 are detailed. The synthesis of 1-benzyl-6'-methoxy-6',7'-dihydrospiro[piperidine-4,4'-thieno[3.2- c]pyran] (2a) was performed starting with 3-bromothiophene (3). After introduction of the acetaldehyde substructure (7), halogen metal exchange, addition of 1-benzylpiperidin-4-one, and cyclization led to the spirocyclic thienopyran 2a. The removal of the benzyl group afforded the secondary amine 2f, which was substituted with various residues. With respect to sigma 1 affinity the N-benzyl derivative 2a, the N-cyclohexylmethyl derivative 2d, and the N-p-fluorobenzyl derivative 2i represent the most potent compounds of this series binding with K i values of 0.32, 0.29, and 0.62 nM, respectively. Electronic properties of the substituents have only little impact on sigma 1 affinity. The most potent sigma 1 ligands display high selectivity against sigma 2, 5-HT 1A, 5-HT 6, 5-HT 7, alpha 1A, alpha 2, and NMDA receptors. The activity of 2a in the mouse capsaicin assay seems to indicate sigma 1 antagonistic activity.

Topics: Alkylation; Animals; Cyclization; Ligands; Mice; Models, Molecular; Molecular Structure; Oxidation-Reduction; Pain; Piperidines; Protein Binding; Pyrans; Rats; Receptors, sigma; Spiro Compounds; Structure-Activity Relationship; Thiophenes

We previously reported that gabapentin activates the bulbospinal-spinal noradrenergic-cholinergic pathway to produce analgesia in rats after nerve injury. Also, gabapentin interacts synergistically with a cholinesterase inhibitor donepezil to produce analgesia. Duloxetine, a serotonin/noradrenaline re-uptake inhibitor, has been used for the treatment of neuropathic pain and should amplify the noradrenergic mechanisms recruited by gabapentin. In the present study, we determined the interaction between duloxetine and gabapentin with and without donepezil when administered by the clinically preferred oral route in rats after spinal nerve ligation. The ED(50) value of gabapentin, donepezil, and duloxetine to reduce mechanical hypersensitivity after nerve injury was 45, 3.7, and 32 mg/kg, respectively. In the examination of two drug combinations, oral duloxetine with either gabapentin or donepezil were additive to reduce hypersensitivity. The combination of all three drugs yielded a synergistic interaction with an observed ED(50) at 1/4th the predicted dose of additivity, likely due to the gabapentin-donepezil interaction. This three drug combination did not affect motor coordination or show signs of sedation in the rotarod test. Analgesia by the combination of these three drugs was reversed by intrathecal injection either of the alpha(2)-adrenoceptor antagonist idazoxan or by the muscarinic receptor antagonist atropine. These results suggest that the combination of these drugs, which stimulate and augment the bulbospinal-spinal noradrenergic-cholinergic pathway, lowers the dose requirement for each drug to reduce hypersensitivity after nerve injury without sedative effects. The current study provides the rationale for clinical study of the combination of gabapentin, donepezil and duloxetine to treat neuropathic pain.

Topics: Amines; Analgesics; Animals; Cyclohexanecarboxylic Acids; Donepezil; Dose-Response Relationship, Drug; Drug Interactions; Duloxetine Hydrochloride; Gabapentin; gamma-Aminobutyric Acid; Indans; Injections, Spinal; Ligation; Male; Neurotransmitter Uptake Inhibitors; Nootropic Agents; Pain; Pain Measurement; Peripheral Nervous System Diseases; Physical Stimulation; Piperidines; Postural Balance; Psychomotor Performance; Rats; Rats, Sprague-Dawley; Spinal Nerves; Thiophenes

The potential modulation of TRPV1 nociceptive activity by the CB(1) receptor was investigated here using CB(1) wild-type (WT) and knock-out (KO) mice as well as selective CB(1) inverse agonists. No significant differences were detected in baseline thermal thresholds of ICR, CB(1)WT or CB(1)KO mice. Intraplantar capsaicin produced dose- and time-related paw flinch responses in ICR and CB(1)WT mice and induced plasma extravasation yet minimal responses were seen in CB(1)KO animals with no apparent differences in TRPV1 channel expression. Capsaicin-evoked CGRP release from spinal cord tissue and capsaicin-evoked action potentials on isolated skin-nerve preparation were significantly decreased in CB(1)KO mice. Pretreatment with intraplantar galanin and bradykinin, compounds known to sensitize TRPV1 receptors, restored capsaicin-induced flinching in CB(1)KO mice. The possibility that constitutive activity at the CB(1) receptor is required to maintain the TRPV1 receptor in a "sensitized" state was tested using CB(1) inverse agonists. The CB(1) inverse agonists elicited concentration-related inhibition of capsaicin-induced calcium influx in F-11 cells and produced dose-related inhibition of capsaicin-induced flinching in ICR mice. These data suggest that constitutive activity at the CB(1) receptor maintains the TRPV1 channel in a sensitized state responsive to noxious chemical stimuli. Treatment with CB(1) inverse agonists may promote desensitization of the channel resulting in antinociceptive actions against chemical stimulus modalities. These studies propose possible therapeutic exploitation of a novel mechanism providing pain relief by CB(1) inverse agonists.

Topics: Analysis of Variance; Animals; Behavior, Animal; Bradykinin; Calcitonin Gene-Related Peptide; Calcium; Capsaicin; Cell Line, Tumor; Dose-Response Relationship, Drug; Galanin; Gene Expression Regulation; Male; Mice; Mice, Inbred ICR; Mice, Knockout; Morphine; Narcotics; Nerve Fibers, Unmyelinated; Neuroblastoma; Pain; Pain Measurement; Pain Threshold; Piperidines; Pyrazoles; Rats; Reaction Time; Receptor, Cannabinoid, CB1; Rimonabant; Stimulation, Chemical; Sulfonamides; TRPV Cation Channels

Advances in minimally invasive procedures have resulted in an increased demand for procedural sedation. Patient-controlled sedation (PCS) has been in clinical use for almost 20 years, but has not been reviewed in over 10 years.. Advances in microprocessor technology, increased demand for procedural sedation in a cost-conscious environment, and the availability of readily titratable pharmacologic agents together stimulated the development of alternative sedation practices. Continued research into the neurobiology of pain perception and the placebo effect has also played a role. PCS and patient-maintained sedation, primarily with propofol, have emerged as intriguing clinical alternatives to traditional sedation based in part on extensions of traditional PCA models.. PCS has been applied to a wide variety of procedures, but systems that can be applied 'off-the-shelf' are not easy to tune. New approaches to PCS may address these limitations. Better understanding of the psychology of sedation may lead to better patient acceptance of PCS.

Topics: Analgesia, Patient-Controlled; Conscious Sedation; Equipment Design; Humans; Hypnotics and Sedatives; Infusion Pumps; Pain; Piperidines; Propofol; Remifentanil

Windup is a progressive, frequency-dependent increase in the excitability of trigeminal and spinal dorsal horn wide dynamic range (WDR) nociceptive neurons to repetitive stimulation of primary afferent nociceptive C-fibers. Superficial dorsal horn neurokinin 1 receptor (NK1R)-expressing neurons were recently shown to regulate sensitization of WDR nociceptive neurons through activation of a defined spino-bulbo-spinal loop. However, the windup of WDR nociceptive neurons was not regulated through this loop. In the present study, we sought to identify the alternative circuit activated by dorsal horn NK1Rs that mediates WDR neuron windup. As a model we used the rat spinal trigeminal nucleus, in which the subnucleus oralis (Sp5O) contains a pool of WDR neurons that receive their nociceptive C-input indirectly via interneurons located in the medullary dorsal horn (MDH). First, we found that intravenous injection of NK1R antagonists (SR140333 and RP67580) produced a reversible inhibition of Sp5O WDR neuron windup. Second, we anatomically identified in the MDH lamina III a subpopulation of NK1R-expressing local interneurons that relay nociceptive information from the MDH to downstream Sp5O neurons. Third, using microinjections of NK1R antagonists during in vivo electrophysiological recordings from Sp5O WDR neurons, we showed that WDR neuron windup depends on activation of NK1Rs located in the MDH laminae I-III. We conclude that, in contrast to central sensitization that is controlled by a spino-bulbo-spinal loop, Sp5O WDR neuron windup is regulated through a local circuit activated by MDH lamina III NK1Rs.

Topics: Afferent Pathways; Animals; Male; Nerve Fibers, Unmyelinated; Neural Pathways; Neurokinin-1 Receptor Antagonists; Neurons, Afferent; Nociceptors; Pain; Piperidines; Posterior Horn Cells; Presynaptic Terminals; Quinuclidines; Rats; Rats, Sprague-Dawley; Receptors, Neurokinin-1; Substance P; Synaptic Transmission; Trigeminal Caudal Nucleus; Trigeminal Nerve; Trigeminal Nuclei

To determine whether local administration of the cannabinoid 1 (CB(1)) receptor agonist arachidonyl-2-chloroethylamide (ACEA) can modulate joint nociception in control rat knee joints and in experimental osteoarthritis (OA).. OA was induced in male Wistar rats by intraarticular injection of 3 mg of sodium mono-iodoacetate, with a recovery period of 14 days. Electrophysiologic recordings were made of knee joint primary afferent nerve fibers in response to normal rotation and noxious hyperrotation of the joint both before and after close intraarterial injection of different doses of ACEA.. Local application of the CB(1) agonist significantly reduced the firing rate of afferent nerve fibers by up to 50% in control knee joints (n=19) and up to 62% in OA knee joints (n=29; P<0.01). Coadministration of the CB(1) receptor antagonist AM251 or the transient receptor potential vanilloid 1 (TRPV-1) ion channel antagonist SB366791 significantly reduced the desensitizing effect of ACEA. The CB(1) receptor antagonist AM251 by itself had no effect in the control joint but significantly increased the firing rate of afferent nerve fibers in the OA joint.. These findings indicate that activation of peripheral CB(1) receptors reduces the mechanosensitivity of afferent nerve fibers in control and OA knee joints. Blockade of either the CB(1) receptor or the TRPV-1 channel significantly reduced the efficacy of ACEA, which suggests that both receptors are involved in cannabinoid-mediated antinociception. The increased nerve activity observed following CB(1) receptor antagonism suggests a tonic release of endocannabinoids during OA. As such, peripheral CB(1) receptors may be important targets in controlling OA pain.

Topics: Afferent Pathways; Anilides; Animals; Arachidonic Acids; Cinnamates; Knee Joint; Male; Nociceptors; Osteoarthritis, Knee; Pain; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; TRPV Cation Channels

The pharmacology of tachykinin NK receptors varies greatly among species. The aim of the present study was to assess the role of NK(1) and NK(2) receptors in mediating colorectal distension-evoked nociception and psychological stress-induced defecation in gerbils, a species with human-like NK receptor pharmacology. The effects of the selective NK(1) and NK(2) receptor antagonists, aprepitant and saredutant, on acute (1 h) restraint stress-evoked defecation and plasma adenocorticotropin (ACTH) levels in gerbils were assessed. The effects of antagonists alone or in combination on colorectal distension-evoked visceral pain in conscious gerbils were evaluated using the visceromotor response as a surrogate marker of pain. Restraint stress increased fecal pellet output 2-3-fold and plasma ACTH levels 9-fold. Aprepitant inhibited the defecatory and endocrine responses to stress by 50%, while saredutant completely normalized the same parameters. Visceral pain responses during colorectal distension were attenuated by both compounds, but aprepitant (19+/-6% inhibition, P<0.01) was slightly more effective than saredutant (10+/-9% inhibition, P<0.05). A combination of both compounds resulted in an additive effect (30+/-10% inhibition, P<0.01). The results demonstrate that NK(1) and NK(2) receptors are involved in stress-related colonic motor alterations and visceral pain responses in gerbils and that combined antagonism provides enhanced inhibition of visceral pain responses. This suggests that for therapeutic use in for instance functional gastrointestinal disorders, dual NK(1)/NK(2) receptor antagonists may provide better clinical outcome than selective compounds.

Topics: Adrenocorticotropic Hormone; Animals; Aprepitant; Benzamides; Colon; Defecation; Dose-Response Relationship, Drug; Gastrointestinal Motility; Gerbillinae; Male; Morpholines; Neurokinin-1 Receptor Antagonists; Pain; Piperidines; Receptors, Neurokinin-1; Receptors, Neurokinin-2; Stress, Psychological

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

We investigated whether endothelin (ET) would be involved in skin cancer pain in mice. Orthotopic inoculation of B16-BL6 melanoma cells into the plantar region of the hind paw produced marked mechanical allodynia in C57BL/6 mice. Intraplantar injections of the ET(A)-receptor antagonist BQ-123 (0.3 - 3 nmol/site), but not the ET(B)-receptor antagonist BQ-788 (1 and 3 nmol/site), inhibited mechanical allodynia in mice with grown melanoma. In naive mice, an intraplantar injection of tumor extract (1 and 3 mg/site), which was prepared from the grown melanoma in the paw, produced mechanical allodynia, which was inhibited by BQ-123 and BQ-788 at doses of 3 and 10 nmol/site. An intraplantar injection of ET-1 (1 and 10 pmol/site) elicited licking behavior, which was increased in the melanoma-bearing hind paw. BQ-123 (3 and 10 nmol/site) inhibited licking induced by ET-1 (10 pmol/site). The level of mRNA of ET(A), but not ET(B), receptor, was significantly increased in the dorsal root ganglia on the inoculated side. Cultured B16-BL6 cells contained ET, and the melanoma mass increased the concentration of ET as it grew bigger. These results suggest that ET-1 and ET(A) receptor are at least partly involved in the induction of pain induced by melanoma cell inoculation.

Topics: Animals; Behavior, Animal; Cell Line, Tumor; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Ganglia, Spinal; Male; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Neoplasm Transplantation; Oligopeptides; Pain; Peptides, Cyclic; Piperidines; Receptor, Endothelin A; Receptor, Endothelin B; RNA, Messenger

Growing evidence supports the idea that in addition to their well established role in the immune system, chemokines might play a role in both normal and pathological brain function, and the chemokine network could interact with other neuromodulators. The chemokine stromal cell-derived growth factor (SDF)-1alpha/CXCL12, a member of the CXC chemokine family, was tested for its possible effect on the analgesic responses of the cannabinoid receptor agonist aminoalkylindole 4,5-dihydro-2-methyl-4-(4-morpholinylmethyl)-1-(1-naphthalenyl-carbonyl)-6H-pyrrolo-[3,2,1ij]quinolin-6-one [(+)-WIN 55,212-2, hereafter WIN 55,212-2] at the level of the periaqueductal gray (PAG), a brain region critical to the processing of pain signals, and a primary site of action of many analgesic compounds. The administration of WIN 55,212-2 (0.1-0.4 microg/microl) into the PAG resulted in antinociception in a dose-dependent manner. The selective cannabinoid (CB)1 antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride (SR 141716A; 1-10 microg) given into the PAG blocked the WIN 55,212-2-induced antinociception. In contrast, the selective CB2 antagonist N-[(1S)-endo-1,3,3-trimethyl bicyclo heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide (SR144528; 10 microg) did not alter the WIN 55,212-2-induced antinociception. Pretreatment with SDF-1alpha/CXCL12 (100 ng) caused a reduction in antinociceptive responses of WIN 55,212-2. The inhibitory effect of SDF-1alpha/CXCL12 on WIN 55,212-2-induced antinociception was reversed by octahydrochloride [corrected] hydrate (AMD 3100) (10-50 ng), an antagonist of the SDF-1alpha/CXCL12, acting at its receptor, CXCR4. This study reports the first in vivo evidence of a functional interaction between chemokine and cannabinoid systems in the brain, showing that the activation of SDF-1alpha/CXCL12 receptors (CXCR4) in the PAG interferes with the analgesic effects of WIN 55212-2.

Topics: Analgesics; Animals; Benzoxazines; Camphanes; Chemokine CXCL12; Male; Morpholines; Naphthalenes; Pain; Periaqueductal Gray; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Receptors, CXCR4; Rimonabant

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

A prescription is a health-care program implemented by a physician or other qualified practitioner in the form of instructions that govern the plan of care for an individual patient. Although the algorithmic nature of prescriptions is axiomatic, this insight has not been applied systematically to medication safety. We used software design principles and debugging methods to create a "Patient-oriented Prescription for Analgesia" (POPA), assessed the rate and extent of adoption of POPA by physicians, and conducted a statistical process control clinical trial and a subsidiary cohort analysis to evaluate whether POPA would reduce the rate of severe and fatal opioid-associated adverse drug events (ADEs). We conducted the study in a population of 153,260 hospitalized adults, 50,576 (33%) of whom received parenteral opioids. Hospitalwide, the use of POPA increased to 62% of opioid prescriptions (diffusion half-life = 98 days), while opioid-associated severe/fatal ADEs fell from an initial peak of seven per month to zero per month during the final 6 months (P < 0.0016) of the study. In the nested orthopedics subcohort, the use of POPA increased the practice of recording pain scores (94% vs. 72%, P < 0.00001) and the use of adjuvant analgesics (95% vs. 40%, P < 0.00001) and resulted in fewer opioid-associated severe ADEs than routine patient-controlled analgesia (PCA) (0% vs. 2.7%, number needed to treat (NNT) = 35, P < 0.015). The widespread diffusion of POPA was associated with a substantial hospitalwide decline in opioid-associated severe/fatal ADEs.

Topics: Adult; Aged; Analgesia, Patient-Controlled; Analgesics, Opioid; Blood Glucose; Carbamates; Clinical Trials as Topic; Drug Interactions; Female; Gemfibrozil; Hospital Mortality; Humans; Hypoglycemic Agents; Hypolipidemic Agents; Male; Medication Errors; Middle Aged; Multicenter Studies as Topic; Pain; Patient-Centered Care; Piperidines; Software

Although participation of opioids in antinociception induced by cannabinoids has been documented, there is little information regarding the participation of cannabinoids in the antinociceptive mechanisms of opioids. The aim of the present study was to determine whether endocannabinoids could be involved in peripheral antinociception induced by activation of mu-, delta- and kappa-opioid receptors.. Nociceptive thresholds to mechanical stimulation of rat paws treated with intraplantar prostaglandin E2 (PGE2, 2 microg) to induce hyperalgesia were measured 3 h after injection using an algesimetric apparatus. Opioid agonists morphine (200 microg), (+)-4-[(alphaR)-alpha-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC80) (80 microg), bremazocine (50 microg); cannabinoid receptor antagonists N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251) (20-80 microg), 6-iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indol-3-yl(4-methoxyphenyl) methanone (AM630) (12.5-100 microg); and an inhibitor of methyl arachidonyl fluorophosphonate (MAFP) (1-4 microg) were also injected in the paw.. The CB1-selective cannabinoid receptor antagonist AM251 completely reversed the peripheral antinociception induced by morphine in a dose-dependent manner. In contrast, the CB2-selective cannabinoid receptor antagonist AM630 elicited partial antagonism of this effect. In addition, the administration of the fatty acid amide hydrolase inhibitor, MAFP, enhanced the antinociception induced by morphine. The cannabinoid receptor antagonists AM251 and AM630 did not modify the antinociceptive effect of SNC80 or bremazocine. The antagonists alone did not cause any hyperalgesic or antinociceptive effect.. Our results provide evidence for the involvement of endocannabinoids, in the peripheral antinociception induced by the mu-opioid receptor agonist morphine. The release of cannabinoids appears not to be involved in the peripheral antinociceptive effect induced by kappa- and delta-opioid receptor agonists.

Topics: Amidohydrolases; Analgesics, Opioid; Animals; Arachidonic Acids; Benzamides; Benzomorphans; Cannabinoid Receptor Modulators; Dinoprostone; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Inhibitors; Hyperalgesia; Indoles; Male; Morphine; Organophosphonates; Pain; Pain Measurement; Piperazines; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu

Acetaminophen is the most used analgesic/antipyretic drug. Its unclear mechanism of action could rely on cyclooxygenase inhibition, NO synthesis blockade or reinforcement of the serotonergic system. Here we show that in thermal, mechanical and chemical pain tests, AM-251, a specific CB(1) receptor antagonist, abolished the analgesic action of acetaminophen, which was also lost in CB(1) receptor knockout mice. Moreover, acetaminophen was shown unable to bind to CB(1) receptors demonstrating an indirect involvement of these receptors in the analgesic effect of this compound. Accordingly with these results, we also demonstrated that the inhibition of FAAH, an enzyme involved in the cerebral metabolism of acetaminophen into AM404, known to reinforce the activity of the endocannabinoid system, suppressed the antinociceptive effect of acetaminophen. In addition, similarly to the interaction of acetaminophen with bulbospinal serotonergic pathways and spinal serotonin receptors, we observed that the antinociceptive activity of ACEA, a CB(1) receptor agonist, was inhibited by lesion of bulbospinal serotonergic pathways and antagonists of spinal 5-HT receptors. We therefore propose that acetaminophen-induced analgesia could involve the following sequence: (1) FAAH-dependent metabolism of acetaminophen into AM404; (2) indirect involvement of CB(1) receptors by this metabolite; (3) endocannabinoid-dependent reinforcement of the serotonergic bulbospinal pathways, and (4) involvement of spinal pain-suppressing serotonergic receptors.

Topics: Acetaminophen; Analgesia; Animals; Cannabinoid Receptor Modulators; Dose-Response Relationship, Drug; Endocannabinoids; Male; Mice; Mice, Knockout; Pain; Pain Measurement; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Receptors, Serotonin; Serotonin

Topics: Adult; Airway Obstruction; Analgesia, Obstetrical; Anesthesia, Epidural; Anesthesia, Intravenous; Anesthesia, Obstetrical; Anesthetics, Intravenous; Delivery, Obstetric; Female; Fetal Diseases; Fetoscopy; Fetus; Gestational Age; Humans; Hysterotomy; Pain; Perception; Piperidines; Postoperative Complications; Pregnancy; Remifentanil

The excellent pharmacological profile displayed by the selective nociceptin/orphanin FQ (N/OFQ) peptide (NOP) receptor antagonist SB-612111 [(-)-cis-1-methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol] in vitro prompted us to investigate the actions of this compound in vivo. In the mouse tail withdrawal assay, SB-612111 given i.p. up to 3 mg/kg did not modify per se tail withdrawal latencies but was able to prevent the pronociceptive and the antinociceptive action of 1 nmol of N/OFQ given i.c.v. and i.t., respectively. In food intake studies performed in sated mice, SB-612111 (1 mg/kg i.p.) had no effect on food consumption but fully prevented the orexigenic effect of 1 nmol of N/OFQ i.c.v. In 17-h food-deprived mice, the opioid receptor antagonist naltrexone (1 mg/kg s.c.), but not SB-612111 (1 and 10 mg/kg i.p.), produced a statistically significant reduction of food intake. In the mouse forced swimming and tail suspension tests, SB-612111 (1-10 mg/kg) reduced immobility time. The antidepressant-like effect elicited by SB-612111 in the forced swimming test was reversed by the i.c.v. injection of 1 nmol of N/OFQ and no longer evident in mice knockout for the NOP receptor gene. In conclusion, the present findings demonstrate that SB-612111 behaves in vivo as a potent and selective NOP antagonist and suggest that the N/OFQ-NOP receptor endogenous system plays an important role in regulating mood-related behaviors. The use of SB-612111 in future pathophysiological studies will certainly contribute to define the therapeutic potential of selective NOP receptor antagonists in different disease areas.

Topics: Animals; Antidepressive Agents; Cycloheptanes; Eating; Hindlimb Suspension; Locomotion; Male; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Mice, Knockout; Narcotic Antagonists; Nociceptin Receptor; Pain; Pain Measurement; Piperidines; Receptors, Opioid; Swimming

Intrathecal (i.t.) administration of D-cycloserine (100 and 300 fmol), a partial agonist of the glycine recognition site on the N-methyl-D-aspartate (NMDA) receptor ion-channel complex, produced a behavioral response mainly consisting of biting and/or licking of the hindpaw and the tail along with slight hindlimb scratching directed toward the flank in mice, which peaked at 5 - 10 min and almost disappeared at 15 min after the injection. The behavior induced by D-cycloserine (300 fmol) was dose-dependently inhibited by an intraperitoneal injection of morphine (0.5-2 mg/kg), suggesting that the behavioral response is related to nociception. The nociceptive behavior was also dose-dependently inhibited by i.t. co-administration of 7-chlorokynurenic acid (0.25-4 nmol), a competitive antagonist of the glycine recognition site on the NMDA receptor ion-channel complex; D-(-)-2-amino-5-phosphonovaleric acid (62.5-500 pmol), a competitive NMDA receptor antagonist; MK-801 (62.5-500 pmol), an NMDA ion-channel blocker; ifenprodil (0.5-8 nmol); arcaine (31-125 pmol); and agmatine (0.1-10 pmol), all being antagonists of the polyamine recognition site on the NMDA receptor ion-channel complex. However, [D-Phe7,D-His9]-substance P(6-11), a specific antagonist for substance P (NK1) receptors, and MEN-10,376, a tachykinin NK2-receptor antagonist, had no effect on D-cycloserine-induced nociceptive behavior. These results in the mouse spinal cord suggest that D-cycloserine-induced nociceptive behavior is mediated through the activation of the NMDA receptor ion-channel complex by acting on the glycine recognition site and that it does not involve the tachykinin receptor mechanism.

Topics: 2-Amino-5-phosphonovalerate; Agmatine; Animals; Cycloserine; Dizocilpine Maleate; Dose-Response Relationship, Drug; Injections, Spinal; Ion Channels; Kynurenic Acid; Mice; Morphine; Neurokinin A; Nociceptors; Pain; Peptide Fragments; Piperidines; Receptors, Glycine; Receptors, N-Methyl-D-Aspartate; Receptors, Tachykinin; Substance P

Cholinesterase inhibitors which reach the central nervous system produce pain relief but are poorly tolerated because of gastrointestinal side effects. Here, the authors tested whether donepezil, a central nervous system penetrant cholinesterase inhibitor with a low incidence of gastrointestinal side effects, would relieve hypersensitivity in an animal model of neuropathic pain.. Male rats were anesthetized, and the L5 and L6 spinal nerves were ligated unilaterally. Hypersensitivity was measured by withdrawal threshold to von Frey filament application to the hind paw after oral donepezil, and antagonists administered centrally and peripherally. Efficacy of chronic oral donepezil to relieve hypersensitivity was tested, and activation of G proteins by M(2) muscarinic receptors was determined by carbachol-stimulated [(35)S]guanosine triphosphate (gamma)S autoradiography in brain and spinal cord.. Spinal nerve ligation resulted in hypersensitivity that was more severe ipsilateral than contralateral to surgery. Oral donepezil reduced hypersensitivity bilaterally in a dose-dependent manner for 2 h, and this effect was blocked by spinal but not supraspinal or peripheral muscarinic receptor antagonism. Oral donepezil maintained efficacy over 2 weeks of twice daily administration, and this treatment did not lead to desensitization of muscarinic receptor-coupled G proteins in brain or spinal cord.. Donepezil, a well-tolerated cholinesterase inhibitor used in the treatment of Alzheimer dementia, reduces hypersensitivity in this rat model of neuropathic pain by actions on muscarinic receptors in the spinal cord. Lack of tolerance to this effect, in contrast to rapid tolerance to direct receptor agonists, suggests that cholinesterase inhibition may be useful in the treatment of neuropathic pain.

Topics: Administration, Oral; Animals; Cholinesterase Inhibitors; Donepezil; Dose-Response Relationship, Drug; Drug Tolerance; Guanosine 5'-O-(3-Thiotriphosphate); Indans; Male; Pain; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Muscarinic; Spinal Cord

Cannabinoids, such as anandamide, are involved in pain transmission. We evaluated the effects of AM404 (N-(4-hydroxyphenyl)-5Z,8Z,11Z,14Z-eicosatetraenamide), an anandamide reuptake inhibitor, monitoring the expression of c-fos, a marker of activated neurons and the pain-related behaviours using formalin test. The study was carried out in an experimental model of inflammatory pain made by a single injection of formalin in rat hind paws. Formalin test showed that the antinociceptive effect of AM404 was evident in phase I. We found that Fos-positive neurons in dorsal superficial and deep laminae of the lumbar spinal cord increased in formalin-injected animals and that AM404 significantly reduced Fos induction. Co-administration of cannabinoid CB(1) receptor antagonist (AM251), cannabinoid CB(2) receptor antagonist (AM630) and transient receptor potential vanilloid type 1 (TRPV-1) antagonist (capsazepine), attenuate the inhibitory effect of AM404 and this effect was higher using cannabinoid CB(2) and vanilloid TRPV-1 receptor antagonists. These results suggest that AM404 could be a useful drug to reduce inflammatory pain in our experimental model and that cannabinoid CB(2) receptor and vanilloid TRPV-1 receptor, and to a lesser extent, the cannabinoid CB(1) receptor are involved.

Topics: Animals; Arachidonic Acids; Capsaicin; Endocannabinoids; Immunohistochemistry; Indoles; Inflammation; Male; Pain; Pain Measurement; Piperidines; Polyunsaturated Alkamides; Proto-Oncogene Proteins c-fos; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Spinal Cord; TRPV Cation Channels

High-efficacy activation of central 5-HT(1A) receptors by means of the recently discovered, selective 5-HT(1A) receptor ligand, F 13640 [(3-chloro-4-fluoro-phenyl)-[4-fluoro-4-{[(5-methyl-pyridin-2-ylmethyl)-amino]methyl}piperidin-1-yl]methanone, fumaric acid salt] causes an unprecedented, broad-spectrum analgesia in rat models of acute and chronic pain of nociceptive and neuropathic origin; it also is effective in conditions where opioids either are ineffective, induce analgesic tolerance, or elicit persistent hyperalgesia/allodynia. Inversely mirroring morphine's actions, F 13640's ("curative-like") analgesic effects persist after the discontinuation of treatment. Here, we examined the relationships, if any, between the dose and the duration of F 13640 treatment on the one hand, and the duration of persistent analgesia on the other. Rats received unilateral infraorbital nerve injury and developed allodynia - as assessed by an increased response to von Frey filament stimulation - within 24 days; thereafter, using osmotic pumps, rats were subcutaneously infused with F 13640 in two experiments. In one, a one-week infusion was instituted at 0.04-10-mg/day doses; in a second experiment, a 0.63-mg/day dose was implemented for a duration ranging from 1 to 56 days. These 250- and 56-fold variations of the dose and duration of treatment caused post-treatment, persistent analgesia for about 10 and 40 days, respectively. At least as much as dose, the duration of F 13640 treatment determines F 13640-induced persistent analgesia. Neuroadaptive modulations at pre- and postsynaptic, brain and spinal cord 5-HT(1A) receptors may be involved in the dynamical, dose- and time-dependent, pre-treatment rise and post-treatment decay of the analgesia induced by high-efficacy 5-HT(1A) receptor activation.

Topics: Analgesia; Analgesics; Animals; Cranial Nerve Injuries; Disease Models, Animal; Dose-Response Relationship, Drug; Male; Orbit; Pain; Piperidines; Pyridines; Rats; Rats, Sprague-Dawley; Serotonin 5-HT1 Receptor Agonists; Serotonin Receptor Agonists

Gabapentin administration into the brain of mice reduces nerve injury-induced hypersensitivity and is blocked by intrathecal atropine and enhanced by intrathecal neostigmine. The authors tested the relevance of these findings to oral therapy by examining the efficacy of oral gabapentin to reduce hypersensitivity after nerve injury in rats and its interaction with the clinically used cholinesterase inhibitor, donepezil.. Male rats with hypersensitivity after spinal nerve ligation received gabapentin orally, intrathecally, and intracerebroventricularly with or without intrathecal atropine, and withdrawal threshold to paw pressure was determined. The effects of oral gabapentin and donepezil alone and in combination on withdrawal threshold were determined in an isobolographic design.. Gabapentin reduced hypersensitivity to paw pressure by all routes of administration, and was more potent and with a quicker onset after intracerebroventricular than intrathecal injection. Intrathecal atropine reversed the effect of intracerebroventricular and oral gabapentin. Oral gabapentin and donepezil interacted in a strongly synergistic manner, with an observed efficacy at one tenth the predicted dose of an additive interaction. The gabapentin-donepezil combination was reversed by intrathecal atropine.. Although gabapentin may relieve neuropathic pain by actions at many sites, these results suggest that its actions in the brain to cause spinal cholinergic activation predominate after oral administration. Side effects, particularly nausea, cannot be accurately determined on rats. Nevertheless, oral donepezil is well tolerated by patients in the treatment of Alzheimer dementia, and the current study provides the rationale for clinical study of combination of gabapentin and donepezil to treat neuropathic pain.

Topics: Administration, Oral; Amines; Analgesics; Animals; Cholinesterase Inhibitors; Cyclohexanecarboxylic Acids; Donepezil; Drug Synergism; Gabapentin; gamma-Aminobutyric Acid; Hyperalgesia; Indans; Injections, Spinal; Male; Pain; Peripheral Nerve Injuries; Piperidines; Rats; Rats, Sprague-Dawley; Spinal Cord

The antinociceptive effects of WIN55,212-2, a synthetic cannabinoid, were evaluated in the model of partial sciatic nerve ligation after daily subcutaneous administration of 0.1 mg/kg a week before and two weeks after surgery. Mechanical allodynia and thermal hyperalgesia were evaluated in 46 rats allocated to receive: (1) Vehicle (before surgery)-Vehicle (after surgery); (2) Vehicle-WIN55,212-2; (3) WIN55,212-2-Vehicle; (4) WIN55,212-2-WIN55,212-2; (5) AM251+vehicle; (6) AM251+WIN55,212-2; (7) AM630+vehicle; (8) AM630+WIN55,212-2; (9) Sham receiving vehicle; and (10) Sham receiving WIN55,212-2. The decreased in mechanical allodynia and thermal hyperalgesia by WIN55,212-2 was significantly greater when it was administered during one week before surgery. In conclusion, pre-emptive use of cannabinoids produced greater antinociceptive effects in a model of neuropathic pain and this effect is mediated by cannabinoid CB(1) and CB(2) receptors.

Topics: Analgesics; Animals; Benzoxazines; Cannabinoids; Hyperalgesia; Indoles; Male; Morpholines; Naphthalenes; Pain; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Sciatic Nerve; Sciatic Neuropathy

Cannabinoids are associated with analgesia in acute and chronic pain states. A spectrum of central cannabinoid (CB(1)) receptor-mediated motor and psychotropic side effects limit their therapeutic potential. Here, we investigate the analgesic effect of the palmitoylethanolamide (PEA) analogue, palmitoylallylamide (L-29), which via inhibition of fatty acid amide hydrolase (FAAH) may potentiate endocannabinoids thereby avoiding psychotropic side effects.. The in vivo analysis of the effect of L-29 on measures of pain behaviour in three rat models of neuropathic pain.. Systemically administered L-29 (10 mg kg(-1)) reduced hypersensitivity to mechanical and thermal stimuli in the partial sciatic nerve injury (PSNI) model of neuropathic pain; and mechanical hypersensitivity in a model of antiretroviral (ddC)-associated hypersensitivity and a model of varicella zoster virus (VZV)-associated hypersensitivity. The effects of L-29 were comparable to those of gabapentin (50 mg kg(-1)). The CB(1) receptor antagonist SR141716a (1 mg kg(-1)) and the CB(2) receptor antagonist SR144528 (1 mg kg(-1)) reduced the effect of L-29 on hypersensitivity in the PSNI and ddC models, but not in the VZV model. The peroxisome proliferator-activated receptor-alpha antagonist, MK-886 (1 mg kg(-1)), partially attenuated the effect of L-29 on hypersensitivity in the PSNI model. L-29 (10 mg kg(-1)) significantly attenuated thigmotactic behaviour in the open field arena without effect on locomotor activity.. L-29 produces analgesia in a range of neuropathic pain models. This presents L-29 as a novel analgesic compound that may target the endogenous cannabinoid system while avoiding undesirable side effects associated with direct cannabinoid receptor activation.

Topics: Amides; Amines; Animals; Behavior, Animal; Camphanes; Cyclohexanecarboxylic Acids; Dose-Response Relationship, Drug; Endocannabinoids; Ethanolamines; Gabapentin; gamma-Aminobutyric Acid; Hindlimb; Indoles; Injections, Intraperitoneal; Male; Pain; Pain Measurement; Pain Threshold; Palmitic Acids; Physical Stimulation; Piperidines; PPAR alpha; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Rimonabant; Sciatic Neuropathy; Temperature; Zalcitabine

Cannabinoid CB(2) receptors have been implicated in antinociception in animal models of both acute and chronic pain. We evaluated the role both cannabinoid CB(1) and CB(2) receptors in mechanonociception in non-arthritic and arthritic rats. The antinociceptive effect of Delta(9)-tetrahydrocannabinol (Delta(9)THC) was determined in rats following administration of the cannabinoid CB(1) receptor-selective antagonist, SR141716A, the cannabinoid CB(2) receptor-selective antagonist, SR144528, or vehicle. Male Sprague-Dawley rats were rendered arthritic using Freund's complete adjuvant and tested for mechanical hyperalgesia in the paw-pressure test. Arthritic rats had a baseline paw-pressure of 83 +/- 3.6 g versus a paw-pressure of 177 +/- 6.42 g in non-arthritic rats. SR144528 or SR141716A (various doses mg/kg; i.p.) or 1:1:18 (ethanol:emulphor:saline) vehicle were injected 1 h prior to Delta(9)THC (4 mg/kg; i.p) or 1:1:18 vehicle and antinociception determined 30min post Delta(9)THC. AD(50)'s for both antagonists were calculated with 95% confidence limits. In addition, midbrain and spinal cord were removed for determination of cannabinoid CB(1) and CB(2) receptor protein density in the rats. SR144528 significantly attenuated the antinociceptive effect of Delta(9)THC in the arthritic rats [AD(50) = 3.3 (2.7-4) mg/kg], but not in the non-arthritic rats at a dose of 10/mg/kg. SR141716A significantly attenuated Delta(9)THC-induced antinociception in both the non-arthritic [AD(50) = 1.4 (0.8-2) mg/kg] and arthritic rat [AD(50) = 2.6 (1.8-3.1) mg/kg]. SR141716A or SR144528 alone did not result in a hyperalgesic effect as compared to vehicle. Our results indicate that the cannabinoid CB(2) receptor plays a critical role in cannabinoid-mediated antinociception, particularly in models of chronic inflammatory pain.

Topics: Analgesics; Animals; Arthritis, Experimental; Camphanes; Dronabinol; Male; Mesencephalon; Pain; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Rimonabant; Spinal Cord

Topically applied morphine is routinely used to alleviate pain in cutaneous wounds such as burns and pressure sores. Evidence suggests the topical administration of exogenous opioid drugs may impair wound closure. This study examined the effects of topical morphine on a standardized model of cutaneous wound healing in the rat. Full-thickness 4mm diameter circular skin flaps were excised from the intrascapular region of male Sprague-Dawley rats. IntraSite Gel infused with either morphine-sulfate, neurokinin-1 (NK-1) or neurokinin-2 (NK-2) receptor antagonists, substance P (SP), neurokinin A (NKA), SP+morphine-sulfate, or NKA+morphine-sulfate was applied to the wound twice daily. Results demonstrated a significant overall delay in the time course of wound contraction in morphine-treated animals when compared with gel-only treated controls. The delay in wound contraction seen in morphine-treated animals increased in a concentration-dependent manner. Topical application of NK-1 or NK-2 receptor antagonists mimicked the effects of morphine in delaying wound closure, suggesting topical opioids impair wound closure via the inhibition of SP and NKA release peripherally into the healing wound. Additionally, no significant delays in closure were seen in rats receiving morphine combined with SP or NKA, demonstrating the ability of each neuropeptide to attenuate the effects of morphine in delaying wound closure and restore normal wound closure rates. The combination of SP or NKA and morphine-sulfate for wound therapy may provide local analgesia while maintaining normal closure rates.

Topics: Analgesics, Opioid; Animals; Dose-Response Relationship, Drug; Indoles; Male; Morphine; Pain; Piperidines; Rats; Rats, Sprague-Dawley; Tachykinins; Wound Healing

Improgan is a congener of the H(2) antagonist cimetidine, which produces potent antinociception. Because a) the mechanism of action of improgan remains unknown and b) this drug may indirectly activate cannabinoid CB(1) receptors, the effects of the CB(1) antagonist/inverse agonist rimonabant (SR141716A) and 3 congeners with varying CB(1) potencies were studied on improgan antinociception after intracerebroventricular (icv) dosing in rats. Consistent with blockade of brain CB(1) receptors, rimonabant (K(d) = 0.23 nM), and O-1691 (K(d) = 0.22 nM) inhibited improgan antinociception by 48% and 70% after icv doses of 43 nmol and 25 nmol, respectively. However, 2 other derivatives with much lower CB(1) affinity (O-1876, K(d) = 139 nM and O-848, K(d) = 352 nM) unexpectedly blocked improgan antinociception by 65% and 50% after icv doses of 300 nmol and 30 nmol, respectively. These derivatives have 600-fold to 1500-fold lower CB(1) potencies than that of rimonabant, yet they retained improgan antagonist activity in vivo. In vitro dose-response curves with (35)S-GTPgammaS on CB(1) receptor-containing membranes confirmed the approximate relative potency of the derivatives at the CB(1) receptor. Although antagonism of improgan antinociception by rimonabant has previously implicated a mechanistic role for the CB(1) receptor, current findings with rimonabant congeners suggest that receptors other than, or in addition to CB(1) may participate in the pain-relieving mechanisms activated by this drug. The use of congeners such as O-848, which lack relevant CB(1)-blocking properties, will help to identify these cannabinoid-like, non-CB(1) mechanisms.. This article describes new pharmacological characteristics of improgan, a pain-relieving drug that acts by an unknown mechanism. Improgan may use a marijuana-like (cannabinoid) pain-relieving mechanism, but it is shown presently that the principal cannabinoid receptor in the brain (CB(1)) is not solely responsible for improgan analgesia.

Topics: Analgesics; Analysis of Variance; Animals; Cimetidine; Disease Models, Animal; Dose-Response Relationship, Drug; Guanosine 5'-O-(3-Thiotriphosphate); Injections, Intraventricular; Male; Pain; Pain Measurement; Pain Threshold; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Reaction Time; Receptor, Cannabinoid, CB1; Rimonabant; Time Factors

Antiepileptic and network inhibitory actions of Q5 (2-methyl-4-oxo-3H-quinazoline-3-acetyl piperidine) have recently been described in hippocampal slices. Here we present evidence on the in vivo antiabsence effect of Q5. All doses of Q5 tested (0.3 mg/kg, 0.9 mg/kg, 2.8 mg/kg) decreased the number, but not the duration and the frequency of absence spike-wave discharges (SWDs) in freely moving WAG/Rij rats. In vivo network inhibitory action of Q5 was monitored by following c-fos expression in different brain areas of Wistar rats. Significant depletion of c-fos expression was observed after single or repeated injections of Q5 (2.8 mg/kg and 2x2.8 mg/kg) in various brain areas, including hypothalamic paraventricular nucleus, medial amygdaloid nucleus, piriform cortex, somatosensory cortex, periventricular thalamic nucleus and periaqueductal central gray. Thus, our in vivo results demonstrate that in addition to the prevention of absence seizures, Q5 effectively suppresses neuronal activation in various stress- and pain-sensitive brain areas.

Topics: Animals; Anticonvulsants; Brain Chemistry; Dose-Response Relationship, Drug; Electroencephalography; Epilepsy, Absence; Gene Expression; Genes, fos; Immunohistochemistry; Nerve Net; Pain; Piperidines; Quinazolines; Rats; Rats, Inbred Strains; Stress, Psychological

2-arachidonoylglycerol (2-AG) is an endocannabinoid whose hydrolysis is predominantly catalysed by the enzyme monoacylglycerol lipase (MAGL). The development of MAGL inhibitors could offer an opportunity to investigate the anti-inflammatory and anti-nociceptive role of 2-AG, which have not yet been elucidated. On these bases, URB602, a MAGL inhibitor, was tested in a murine model of inflammation/inflammatory pain.. Acute inflammation was induced by intraplantar injection of lambda-carrageenan into mice. The highest dose to be employed has been selected performing the tetrad assays for cannabimimetic activity in mice. URB602 anti-inflammatory and anti-nociceptive efficacy (assessed by plethysmometer and plantar test, respectively) was evaluated both in a preventive regimen (drug administered 30 min before carrageenan) and in a therapeutic regimen (URB602 administered 30 min after carrageenan). To elucidate the cannabinoid receptor involvement, rimonabant and SR144528, CB1 and CB2 selective antagonists, respectively, were given 15 min before URB602.. Systemic administration of URB602 elicited a dose-dependent anti-oedemigen and anti-nociceptive effect that was reversed exclusively by the CB2 receptor antagonist. The efficacy of URB602 persisted also when the compound was administered in a therapeutic regimen, suggesting the ability of URB602 to improve established disease.. The present report highlighted the ability of the selective MAGL inhibitor, URB602, to prevent and treat an acute inflammatory disease without producing adverse psychoactive effects. The data presented herein also contributed to clarify the physiological role of 2-AG in respect to inflammatory reactions, suggesting its protective role in the body.

Topics: Acute Disease; Animals; Biphenyl Compounds; Body Temperature; Camphanes; Carrageenan; Disease Models, Animal; Dose-Response Relationship, Drug; Edema; Hindlimb; Hyperalgesia; Inflammation; Injections, Intraperitoneal; Male; Mice; Mice, Inbred C57BL; Monoacylglycerol Lipases; Pain; Pain Measurement; Pain Threshold; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Rimonabant

(-)-6-[2-[4-(3-Fluorophenyl)-4-hydroxy-1-piperidinyl]-1-hydroxyethyl]-3,4-dihydro-2(1H)-quinolinone was identified as an orally active NR2B-subunit selective N-methyl-d-aspartate (NMDA) receptor antagonist. It has very high selectivity for NR2B subunits containing NMDA receptors versus the HERG-channel inhibition (therapeutic index=4200 vs NR2B binding IC(50)). This compound has improved pharmacokinetic properties compared to the prototype CP-101,606.

Topics: Animals; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP2D6 Inhibitors; Enzyme Inhibitors; Ether-A-Go-Go Potassium Channels; Inhibitory Concentration 50; Molecular Structure; N-Methylaspartate; Pain; Piperidines; Quinolones; Rats; Receptors, N-Methyl-D-Aspartate; Structure-Activity Relationship

1. Although cannabinoid receptor agonists have analgesic activity in chronic pain states, they produce a spectrum of central cannabinoid CB(1) receptor-mediated motor and psychotropic side-effects. The actions of endocannabinoids, such as anandamide, are terminated by uptake and subsequent intracellular enzymatic degradation. In the present study, we examined the effect of acute administration of the anandamide transport inhibitor AM404 in rat models of chronic neuropathic and inflammatory pain. 2. Systemic administration of AM404 (10 mg/kg) reduced mechanical allodynia in the partial sciatic nerve ligation (PNL) model of neuropathic pain, but not in the complete Freund's adjuvant (CFA) model of inflammatory pain. 3. The effect of AM404 in the PNL model was abolished by coapplication with the selective cannabinoid CB(1) receptor antagonist AM251 (1 mg/kg). AM404 did not produce a reduction in motor performance in either the PNL or CFA models. 4. These findings suggest that acute administration of AM404 reduces allodynia in a neuropathic pain model via cannabinoid CB(1) receptor activation, without causing the undesirable motor disruption associated with cannabinoid receptor agonists.

Topics: Analgesics; Animals; Arachidonic Acids; Cannabinoid Receptor Modulators; Carrier Proteins; Disease Models, Animal; Endocannabinoids; Freund's Adjuvant; Inflammation; Ligation; Male; Motor Activity; Pain; Pain Measurement; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Sciatic Nerve; Sciatic Neuropathy; Time Factors

The endocannabinoid system mediates analgesia expressed following exposure to conditioned or unconditioned aversive stimuli, and controls the extinction of conditioned aversive behaviour. The present study investigated the effects of administration of the cannabinoid(1) (CB(1)) receptor antagonist SR141716A into the right basolateral amygdala (BLA) on expression of conditioned fear, formalin-evoked nociceptive behaviour, fear-conditioned analgesia and associated alterations in monoamine levels in discrete rat brain areas. Re-exposure to a context previously paired with footshock significantly reduced formalin-evoked nociceptive behaviour. Intra-BLA administration of SR141716A did not attenuate fear-conditioned analgesia, but reduced formalin-evoked nociceptive behaviour and attenuated the formalin-induced decrease in freezing and 22-kHz ultrasonic vocalizations in the early part of the trial. Furthermore, intra-BLA SR141716A significantly prolonged the duration of these fear-related behaviours in fear-conditioned rats not receiving formalin. Fear-conditioned analgesia was accompanied by increased homovanillic acid (HVA) : dopamine (DA) ratio and reduced serotonin (5-HT) in the cerebellum, an effect not altered by SR141716A. SR141716A-induced analgesia was accompanied by reduced DA, increased HVA : DA ratio and reduced 5-HT levels in the cerebellum, increased hippocampal HVA levels and increased 5-hydroxyindole-3-acetic acid (5-HIAA) in the amygdaloid cortex. The SR141716A-induced prolongation of contextually induced aversive behaviour was accompanied by reduced DA and 3,4-dihydroxyphenylacetic acid (DOPAC), levels in the hippocampus, and increased DA and 5-HIAA in the periaqueductal grey. These data suggest an important role for CB(1) receptors in the right BLA in mediating short-term extinction of conditioned aversive behaviour but not fear-conditioned analgesia. The results also enhance our understanding of endocannabinoid-monoamine interactions of relevance to conditioned fear and associated analgesia.

Topics: Amygdala; Analgesia; Analgesics; Animals; Cannabinoid Receptor Modulators; Cerebellum; Conditioning, Psychological; Dopamine; Electric Stimulation; Fear; Functional Laterality; Male; Pain; Pain Measurement; Periaqueductal Gray; Piperidines; Pyrazoles; Rats; Receptor, Cannabinoid, CB1; Rimonabant; Serotonin; Synaptic Transmission; Vocalization, Animal

Clinically, inflammatory pain is far more persistent than that typically modelled pre-clinically, with the majority of animal models focussing on short-term effects of the inflammatory pain response. The large attrition rate of compounds in the clinic which show pre-clinical efficacy suggests the need for novel models of, or approaches to, chronic inflammatory pain if novel mechanisms are to make it to the market. A model in which a more chronic inflammatory hypersensitivity phenotype is profiled may allow for a more clinically predictive tool. The aims of these studies were to characterise and validate a chronic model of inflammatory pain. We have shown that injection of a large volume of adjuvant to the intra-articular space of the rat knee results in a prolonged inflammatory pain response, compared to the response in an acute adjuvant model. Additionally, this model also results in a hypersensitive state in the presence and absence of inflammation. A range of clinically effective analgesics demonstrate activity in this chronic model, including morphine (3mg/kg, t.i.d.), dexamethasone (1mg/kg, b.i.d.), ibuprofen (30mg/kg, t.i.d.), etoricoxib (5mg/kg, b.i.d.) and rofecoxib (0.3-10mg/kg, b.i.d.). A further aim was to exemplify the utility of this chronic model over the more acute intra-plantar adjuvant model using two novel therapeutic approaches; NR2B selective NMDA receptor antagonism and iNOS inhibition. Our data shows that different effects were observed with these therapies when comparing the acute model with the model of chronic inflammatory joint pain. These data suggest that the chronic model may be more relevant to identifying mechanisms for the treatment of chronic inflammatory pain states in the clinic.

Topics: Animals; Arthritis; Chronic Disease; Cyclooxygenase 2 Inhibitors; Disease Models, Animal; Freund's Adjuvant; Lactones; Male; Nitric Oxide Synthase Type II; Pain; Phenols; Piperidines; Rats; Receptors, N-Methyl-D-Aspartate; Stifle; Sulfides; Sulfones; Time Factors; Weight-Bearing

Pain may become intractable as tolerance develops to opioids and the opioids, paradoxically, induce pain. We examined the hypothesis that the analgesia produced by the novel analgesic and high-efficacy 5-hydroxytryptamine (5-HT)(1A) receptor agonist (3-chloro-4-fluoro-phenyl)-[4-fluoro-4-[[(5-methyl-pyridin-2-ylmethyl)-amino]methyl]piperidin-1-yl]methanone, fumaric acid salt (F 13640) may counteract opioid-induced pain. In studies of the somatosensory quality of pain in infraorbital nerve-injured rats, morphine infusion (5 mg/day) by means of osmotic pumps initially caused analgesia (i.e., decreased the behavioral response to von Frey filament stimulation), followed by hyperallodynia and analgesic tolerance. Infusion of F 13640 (0.63 mg/day) prevented the development of opioid hyperallodynia and reversed opioid hyperallodynia once established. In studies of the affective/motivational quality of pain, F 13640 both prevented and reversed the conditioned place aversion induced by naloxone (0.04 mg/kg i.p.) in morphine-infused rats; F 13640 also prevented and reversed the conditioned place preference induced by morphine injections (7.5 mg/kg i.p.). The data confirm that opioids produce bidirectional hypo- and proalgesic actions, and offer initial evidence that high-efficacy 5-HT(1A) receptor activation counteracts both the sensory and the affective/motivational qualities of opioid-induced pain. The data also indicate that F 13640 may be effective with opioid-resistant pain. It further is suggested that opioid addiction may represent self-therapy of opioid-induced pathological pain.

Topics: Analgesics, Opioid; Animals; Behavior, Animal; Cranial Nerve Injuries; Dose-Response Relationship, Drug; Drug Tolerance; Hyperalgesia; Male; Orbit; Pain; Pain Measurement; Piperidines; Pyridines; Rats; Rats, Sprague-Dawley; Serotonin 5-HT1 Receptor Agonists; Serotonin Receptor Agonists

Recent work in our laboratories has demonstrated that an opioid-independent form of stress-induced analgesia (SIA) is mediated by endogenous ligands for cannabinoid receptors-anandamide and 2-arachidonoylglycerol (2-AG) [A.G. Hohmann, R.L. Suplita, N.M. Bolton, M.H. Neely, D. Fegley, R. Mangieri, J.F. Krey, J.M. Walker, P.V. Holmes, J.D. Crystal, A. Duranti, A. Tontini, M. Mor, G. Tarzia, D. Piomelli, An endocannabinoid mechanism for stress-induced analgesia, Nature 435 (2005) 1108-1112]. The present study was conducted to examine the contribution of cannabinoid CB1 receptors in the basolateral nucleus of the amygdala (BLA) and central nucleus of the amygdala (CeA) to nonopioid SIA. SIA was induced by continuous footshock (3 min 0.9 mA) and quantified behaviorally using the tail-flick test. Microinjection of the CB1 antagonist/inverse agonist rimonabant (SR141716A) into the BLA, a limbic forebrain region with high densities of CB1 receptors, suppressed SIA relative to control conditions. By contrast, the same dose administered into the CeA, where CB1 immunoreactivity is largely absent, or outside the amygdala did not alter SIA. To examine the contribution of endocannabinoids in the BLA to SIA, we used selective pharmacological inhibitors of the anandamide-degrading enzyme fatty-acid amide hydrolase (FAAH) and the 2-arachidonoylglycerol-degrading enzyme monoacylglycerol lipase (MGL). The FAAH inhibitor URB597 and MGL inhibitor URB602, at doses that enhanced SIA following microinjection in the midbrain periaqueductal gray, did not alter SIA relative to control conditions. Our findings suggest that CB1 receptors in the BLA but not the CeA contribute to SIA, but pharmacological inhibition of endocannabinoid degradation at these sites does not affect the expression of stress antinociception.

Topics: Amidohydrolases; Amygdala; Animals; Benzamides; Biphenyl Compounds; Cannabinoid Receptor Modulators; Carbamates; Endocannabinoids; Male; Microinjections; Monoacylglycerol Lipases; Pain; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Rimonabant; Stress, Psychological

Topics: Animals; Anti-Obesity Agents; Anxiety; Arachidonic Acids; Blood Pressure; Brain; Cannabinoid Receptor Antagonists; Cannabinoid Receptor Modulators; Controlled Clinical Trials as Topic; Drug Evaluation, Preclinical; Endocannabinoids; Humans; Inflammation; Neurons; Obesity; Osteoporosis; Pain; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Receptors, Cannabinoid; Rimonabant; Smoking Cessation

Anandamide, an endocannabinoid, is degraded by the enzyme fatty acid amide hydrolase which can be inhibited by nonsteroidal anti-inflammatory drugs (NSAIDs). The present work was designed to study the peripheral interactions between anandamide and ibuprofen (a non-specific cyclooxygenase inhibitor) in the rat formalin test. We first determined the ED50 for anandamide (0.018 microg +/- 0.009), ibuprofen (0.18 microg +/- 0.09), and their combination (0.006 microg +/- 0.002). Drugs were given 15 min before a 2.5% formalin injection into the dorsal surface of the right hind paw. Results were analyzed using isobolographic analysis. The antinociceptive interaction between anandamide and ibuprofen was synergistic. To further investigate the mechanisms by which the combination of anandamide with ibuprofen produced their antinociceptive effects, we used specific antagonists for the cannabinoid CB1 (AM251; 80 microg) and CB2 (AM630; 25 microg) receptors. We demonstrated that the antinociceptive effects of ibuprofen were not antagonized by either AM251 or AM630 and that those of anandamide were antagonized by AM251 but not by AM630. The synergistic antinociceptive effects of the combination of anandamide with ibuprofen were completely antagonized by AM251 but only partially inhibited by AM630. In conclusion, locally (hind paw) injected anandamide, ibuprofen or combination thereof decreased pain behavior in the formalin test. The combination of anandamide with ibuprofen produced synergistic antinociceptive effects involving both cannabinoid CB1 and CB2 receptors. Comprehension of the mechanisms involved needs further investigation.

Topics: Acute Disease; Analysis of Variance; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arachidonic Acids; Area Under Curve; Cannabinoid Receptor Modulators; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Combinations; Drug Interactions; Endocannabinoids; Ibuprofen; Indoles; Inflammation; Male; Pain; Pain Measurement; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Random Allocation; Rats

Remifentanil is a relatively new opioid analgesic related to the fentanyl family of mu opioid receptor agonists and is used clinically for its unique property of having an ultra-short duration of action. However, there is little preclinical data on the analgesic (antinociceptive) effects of remifentanil and none obtained in non-mammalian animal models. The antinociceptive effects of remifentanil were assessed by using the acetic acid test in amphibians. Systemic and spinal administration of remifentanil was made by subcutaneous and intraspinal injections in the Northern grass frog, Rana pipiens. After administration, remifentanil produced dose-dependent and long-lasting antinociceptive effects which persisted for five hours after systemic administration but gave a shorter duration of action after spinal delivery. The antinociceptive effects of remifentanil were significantly blocked by pretreatment with systemic naltrexone. Systemic and spinal administration of remifentanil produced log dose-response curves which yielded ED50 values of 7.1 nmol/g and 3.2 nmol/animal respectively. The relative antinociceptive potency of remifentanil compared to other opioids administered to amphibians is similar to that found in mammalian models.

Topics: Acetic Acid; Analgesics, Opioid; Animals; Dose-Response Relationship, Drug; Injections, Spinal; Injections, Subcutaneous; Models, Animal; Naltrexone; Narcotic Antagonists; Pain; Pain Measurement; Piperidines; Rana pipiens; Receptors, Opioid, mu; Remifentanil; Time Factors

M58373, 4-[2-(4-hydroxy-4-{[N-(4-isopropoxyphenyl)-N-methylamino]methyl}piperidin-1-yl)ethyl]benzonitrile monohydrochloride, is a novel compound, which has an inhibitory activity on neurotoxin binding to the site 2 of voltage-gated sodium channels. In this study, we investigated the effects of M58373 on substance P release from sensory neurons in vitro and pain behaviors/responses in rats, compared with mexiletine. M58373 (1-10 microM) inhibited veratridine-induced release of substance P from dorsal root ganglion cells. In the formalin test, oral M58373 (0.3-10 mg/kg) reduced the time spent in nociceptive behaviors only in the late phase. In the neuropathic pain model, oral M58373 (1-10 mg/kg) attenuated mechanical allodynia and heat hyperalgesia in the nerve-injured paw without affecting normal responses in the uninjured paw. In contrast, oral mexiletine (10-100 mg/kg) had a narrow therapeutic dose range in both models because of the adverse effects on the central nervous system. These results suggest that M58373 is a favorable prototype for novel anti-neuropathic pain agents.

Topics: Analgesics; Animals; Cells, Cultured; Dose-Response Relationship, Drug; Formaldehyde; Ganglia, Spinal; Hot Temperature; Hyperalgesia; Male; Mexiletine; Motor Activity; Neuralgia; Nitriles; Pain; Pain Measurement; Piperidines; Rats; Rats, Wistar; Sodium Channel Blockers; Stress, Mechanical; Substance P; Veratridine

Nociceptin/orphanin FQ (N/OFQ) has been demonstrated to modulate nociceptive transmission via selective activation of N/OFQ peptide (NOP) receptors. Despite huge research efforts, the role(s) of the endogenous N/OFQ-NOP receptor system in pain processing remains incompletely understood. In the present study, we investigated the role of endogenous N/OFQ in the processing of tonic nociceptive input. To address this issue the effects of NOP-selective antagonists [Nphe1,Arg14,Lys15]N/OFQ-NH2 (UFP-101) and J-113397 on nociceptive behaviour, and the nociceptive phenotype of NOP receptor-deficient mice were tested in the mouse formalin test. Twenty microliters of 1.5% formalin solution was injected subcutaneously into the right hind paw causing a characteristic pattern of nociceptive behaviours (licking, biting and lifting of the injected paw). In control mice, the injection of formalin resulted in a classical biphasic nociceptive response with the first phase lasting from 0 to 10 min and the second phase from 15 to 45 min. UFP-101 at 10 nmol/mouse (but not at 1 nmol/mouse) produced antinociceptive action when injected intracerebroventricularly and a pronociceptive action when given intrathecally. Systemic administration of J-113397 (10 mg/kg, intravenously) and the genetic ablation of the NOP receptor gene both produced a significant increase of mouse nociceptive behaviour. Collectively, these results demonstrate that endogenous N/OFQ-NOP receptor signalling is activated during the mouse formalin test producing spinal antinociceptive and supraspinal pronociceptive effects. The overall effect of blocking NOP receptor signalling, by either systemic pharmacological antagonism or genetic ablation, indicates that the spinal antinociceptive action prevails over supraspinal pronociceptive effects.

Topics: Analgesics; Analysis of Variance; Animals; Behavior, Animal; Benzimidazoles; Drug Interactions; Formaldehyde; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Narcotic Antagonists; Nociceptin; Nociceptin Receptor; Opioid Peptides; Pain; Pain Measurement; Piperidines; Reaction Time; Receptors, Opioid; Signal Transduction; Spinal Cord; Time Factors

Topics: Alfentanil; Anesthesia, General; Child; Conscious Sedation; Contraindications; Cooperative Behavior; Dose-Response Relationship, Drug; Drug Administration Schedule; Emergency Service, Hospital; Endoscopy; Fentanyl; France; Health Status; Humans; Midazolam; Pain; Patient Acceptance of Health Care; Patient Care Team; Pediatrics; Piperidines; Propofol; Radiology; Referral and Consultation; Remifentanil; Risk Factors

An 85-year-old lady with a 4-year history of Alzheimer's dementia was started on a dose of 5 mg of Donepezil. Improvements were noted in her overall mental state with an associated reduction in the level of carer stress but with mild and transient subjective gastrointestinal complaints. Therefore, the dose was cautiously increased to 10 mg. But within 10 days of the increase, she reported bilateral leg pain severe enough to cause her mental state to deteriorate significantly. Pain induced by Donepezil undermined the efficacy of the drug, resulted in increased carer stress and worsening cognition not reversed by the change of medication to another cholinesterase inhibitor.

Topics: Aged, 80 and over; Alzheimer Disease; Caregivers; Donepezil; Female; Humans; Indans; Nootropic Agents; Pain; Piperidines

Allodynia or hyperalgesia induced by peripheral nerve injury may be involved in changes in the sensitivity of neurotransmitters at the spinal cord level. In order to clarify the functional role of neurotransmitters in peripheral nerve injury, we used rats with nerve injury induced by chronic constriction of the sciatic nerve (CCI rat model) and estimated the effects of the intrathecal injection of drugs known to affect glutamate and tachykinin receptors. In sham-operated rats, the NMDA receptor agonist NMDA and AMPA-kinate receptor agonist RS-(5)-bromowillardin reduced withdrawal latency. The non-competitive NMDA receptor antagonist MK-801, competitive NMDA receptor antagonist AP-5 and AMPA-kinate receptor antagonist NBQX increased withdrawal latency. Substance P (SP) increased the withdrawal latency but only transitorily. The NK1 receptor antagonist RP67580 increased withdrawal latency, but the NK2 receptor antagonist SR48968 did not show an effect. In CCI rats, RS-(5)-bromowillardin reduced withdrawal latency, but NMDA did not show an effect. NBQX increased withdrawal latency, while MK-801 and AP-5 showed little or no effect. SP reduced withdrawal latency, and both RP67580 and SR48968 increased it. These results indicate that the alteration in sensitivity of ionotropic glutamate receptors and tachykinin receptors in the spinal cord contribute to development and maintenance of nerve injury-evoked neuropathic pain.

Topics: Alanine; Analgesics; Animals; Behavior, Animal; Benzamides; Dizocilpine Maleate; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Indoles; Isoindoles; Male; N-Methylaspartate; Pain; Pain Measurement; Piperidines; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Receptors, Kainic Acid; Receptors, Tachykinin; Sciatic Nerve; Spinal Cord; Substance P; Valine

The analgesic and anti-hyperalgesic effects of cannabinoid- and vanilloid-like compounds, plus the fatty acid amide hydrolase (FAAH) inhibitor Cyclohexylcarbamic acid 3'-carbamoyl-biphenyl-3-yl ester (URB597), and acetaminophen, were evaluated in the phenyl-p-quinone (PPQ) pain model, using different routes of administration in combination with opioid and cannabinoid receptor antagonists. All the compounds tested produced analgesic effects. Delta(9)-tetrahydrocannabinol (Delta(9)-THC) and (R)-(+)-arachidonyl-1'-hydroxy-2'-propylamide ((R)-methanandamide) were active by three routes of administration: i.p., s.c. and, p.o. Delta(9)-THC produced ED(50)s of 2.2 mg/kg (0.3-15.6) i.p., 9 mg/kg (4.3-18.9) s.c., and 6.4 mg/kg (5.5-7.6) p.o. Similarly, (R)-methanandamide yielded ED(50)s of 2.9 mg/kg (1-8) i.p., 11 mg/kg (7-17) s.c., and 11 mg/kg (0.9-134) p.o. N-vanillyl-arachidonyl-amide (arvanil) was active by two routes, producing ED(50)s of 4.7 mg/kg (3.0-7.4) s.c. and 0.06 mg/kg (0.02-0.2) i.p. Palmitoylethanolamide, URB597, and acetaminophen were active i.p., resulting in ED(50)s of 3.7 mg/kg (3.2-4.2), 22.9 mg/kg (11.1-47.2), and 160 mg/kg (63-405), respectively. None of the cannabinoid or opioid receptor antagonists tested blocked the compounds evaluated, with two exceptions: the antinociceptive effects of Delta(9)-THC and URB597 were completely blocked by SR141716A, a cannabinoid CB(1) receptor antagonist. Western immunoassays performed using three opioid receptor antibodies, a cannabinoid CB(1) receptor antibody and a transient receptor potential vanilloid type 1(TRPV(1)) receptor antibody, yielded no change in receptor protein levels after short-term arvanil, (R)-methanandamide or Delta(9)-THC administration. These data suggest that all the compounds tested, except Delta(9)-THC and URB597, produced analgesia via a non-cannabinoid CB(1), non-cannabinoid CB(2) pain pathway not yet identified.

Topics: Acetaminophen; Amides; Analgesics; Animals; Arachidonic Acids; Benzamides; Benzoquinones; Camphanes; Capsaicin; Carbamates; Dose-Response Relationship, Drug; Dronabinol; Endocannabinoids; Ethanolamines; Hyperalgesia; Male; Mesencephalon; Mice; Mice, Inbred ICR; Narcotic Antagonists; Pain; Palmitic Acids; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Receptors, Opioid; Rimonabant; Spinal Cord; TRPV Cation Channels

The effects of the synthetic cannabinoid WIN 55,212-2 on heat-evoked firing of spinal wide dynamic range (WDR) neurons were examined in a rodent model of neuropathic pain. Fifty-eight WDR neurons (1 cell/animal) were recorded from the ipsilateral spinal dorsal horns of rats with chronic constriction injury (CCI) and sham-operated controls. Relative to sham-operated controls, neurons recorded in CCI rats showed elevations in spontaneous firing, noxious heat-evoked responses, and afterdischarge firing as well as increases in receptive field size. WIN 55,212-2 (0.0625, 0.125, and 0.25 mg/kg, intravenous) dose-dependently suppressed heat-evoked activity and decreased the receptive field areas of dorsal horn WDR neurons in both nerve injured and control rats with a greater inhibition in CCI rats. At the dose of 0.125 mg/kg iv, WIN 55,212-2 reversed the hyperalgesia produced by nerve injury. The effect of intravenous administration of WIN 55,212-2 appears to be centrally mediated because administration of the drug directly to the ligated nerve did not suppress the heat-evoked neuronal activity in CCI rats. Pretreatment with the cannabinoid CB(1) receptor antagonists SR141716A or AM251, but not the CB(2) antagonist SR144528, blocked the effects. These results provide a neural basis for reports of potent suppression by cannabinoids of the abnormal sensory responses that result from nerve injury.

Topics: Analgesics; Animals; Behavior, Animal; Benzoxazines; Camphanes; Cannabinoid Receptor Agonists; Cannabinoid Receptor Antagonists; Dose-Response Relationship, Drug; Electrophysiology; Hot Temperature; Hyperalgesia; In Vitro Techniques; Morpholines; Naphthalenes; Neurons; Nociceptors; Pain; Peripheral Nervous System Diseases; Piperidines; Posterior Horn Cells; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Rimonabant; Spinal Cord

Activation of cannabinoid CB1 and CB2 receptors is known to attenuate nociception and hyperalgesia in somatic inflammatory conditions. The aim of this study was to determine whether cannabinoids modulate colonic sensitivity in basal and inflammatory conditions. The effects of CB1 and CB2 receptor agonists and antagonists on the abdominal contractile response to colorectal distension (CRD) in basal conditions and after 2,4,6-trinitrobenzenesulphonic acid-induced colitis were investigated. As previously described, colitis triggered a hypersensitivity to CRD. In basal conditions, both CB1 (WIN 55212-2) and CB2 (JWH 015) agonists reduced the abdominal response to CRD at a dose of 1 mg kg(-1), i.p. Both compounds were active at a lower dose (0.1 mg kg(-1)) abolishing the hypersensitivity induced by colitis. Administered alone, CB1 (Rimonabant) and CB2 (SR 144528) receptor antagonists (10 mg kg(-1)) had no effect on basal sensitivity. In contrast, the CB1, but not the CB2, receptor antagonist enhanced colitis-induced hyperalgesia. It is concluded that colonic inflammation enhances the antinociceptive action of CB1 and CB2 receptor agonists, and activates an endogenous, CB1 receptor mediated, antinociceptive pathway.

Topics: Animals; Benzoxazines; Calcium Channel Blockers; Camphanes; Colitis; Colon; Dose-Response Relationship, Drug; Indoles; Inflammation; Male; Manometry; Morpholines; Muscle Contraction; Muscle, Smooth; Naphthalenes; Nociceptors; Pain; Piperidines; Pressure; Pyrazoles; Rats; Rats, Wistar; Receptors, Cannabinoid; Rimonabant; Trinitrobenzenesulfonic Acid

Adenosine and remifentanil are potent IV analgesics with ultrashort half-lives. The antinociceptive effect of IV adenosine has not been clearly characterized. We compared the antinociceptive effects of adenosine and remifentanil in rabbits.. Sixteen rabbits, placed on a sling allowing reasonably free movement, received IV adenosine (400 microg x kg(-1) x min(-1)) or remifentanil (0.4 microg x kg(-1) x min(-1)) over 240 min.. Both drugs produced profound antinociception, as assessed by the number of animals unresponsive to clamping the forepaw and the electrical stimulation threshold of escape movement. With remifentanil, the antinociceptive effect increased rapidly, reaching its peak at 60 min, and then began to decline despite continued infusion. After stopping the infusion, it decreased rapidly and disappeared within 30 min. The vasodilating effect of IV adenosine was immediate in onset and ultrashort in duration. The antinociceptive effect of adenosine increased slowly but progressively during the infusion, reaching its peak only when the infusion ended. Then it decreased slowly over the following 360 min after terminating the infusion.. Remifentanil had a rapid onset and short duration of action, and probably showed signs of tolerance development, whereas the antinocieptive effect of adenosine was slow in onset and long-lasting, despite its ultrashort plasma half-life and the immediate on-off profiles of its vasodilating effect.

Topics: Adenosine; Analgesics; Analgesics, Opioid; Anesthetics, Inhalation; Animals; Blood Pressure; Carbon Dioxide; Disease Models, Animal; Heart Rate; Infusions, Intravenous; Isoflurane; Male; Nociceptors; Pain; Pain Measurement; Piperidines; Rabbits; Remifentanil; Respiration

We investigated the effects of 4-(N-{1-[2-(4-cyanophenyl)ethyl]-4-hydroxypiperidin-4-ylmethyl}-N-methylamino)benzoic acid monohydrochloride (M58996), a novel analgesic, on persistent and neuropathic pain in rats. In the formalin test, oral M58996 (0.3 - 10 mg/kg) reduced nociceptive behaviors only in the late phase. In the neuropathic pain model, oral M58996 (1 - 10 mg/kg) attenuated mechanical allodynia and heat hyperalgesia in the nerve-injured paw without affecting normal responses of the uninjured paw. High doses (10 - 100 mg/kg) of oral M58996 did not influence normal motor function. Thus, M58996 had a wide dose range showing antinociceptive, antiallodynic, and antihyperalgesic effects without motor dysfunction. In addition, we studied the possible mechanisms involved in the M58996-induced antinociception. The antinociceptive effect of M58996 was reversed by intrathecal pertussis toxin, an inhibitor of the inhibitory- and other-GTP-binding protein (G(i/o) protein), but not by subcutaneous naloxone, an opioid-receptor antagonist. This effect was also reversed by intracerebroventricular or intrathecal tropisetron, a 5-hydroxytryptamine(3) (5-HT(3))-receptor antagonist, and intraperitoneal bicuculline, a gamma-aminobutyric acid(A) (GABA(A))-receptor antagonist. These results suggest that M58996 produces its antinociceptive effect by a pertussis toxin-sensitive G protein mechanism. In addition, the GABA released by the activation of supraspinal and/or spinal 5-HT(3) receptors is likely to contribute to the M58996-induced antinociception.

Topics: 4-Aminobenzoic Acid; Administration, Oral; Analgesics; Animals; Behavior, Animal; Biogenic Monoamines; Disease Models, Animal; Dose-Response Relationship, Drug; Male; Motor Activity; Pain; Pain Measurement; para-Aminobenzoates; Piperidines; Rats; Rats, Wistar; Receptors, GABA; Sciatic Neuropathy

Topics: Analgesics, Opioid; Animals; Anti-Inflammatory Agents; Constipation; Humans; Naltrexone; Narcotic Antagonists; Pain; Piperidines; Pyridines; Quaternary Ammonium Compounds; Receptors, Opioid, mu

In order to examine the site of action of an NR2B subtype-selective NMDA antagonist CP-101,606, we investigated its analgesic effect in a rat model of neuropathic pain at various routes of administration. Mechanical allodynia was induced by chronic constriction injury (CCI) of the sciatic nerve in male Sprague-Dawley rats. Subcutaneous treatment of the animals with CP-101,606 at 10 mg/kg significantly inhibited CCI-induced mechanical allodynia. Intracerebroventricular injection of CP-101,606 at 10, 30 and 100 nmol also inhibited the mechanical allodynia in a dose-dependent manner, the statistically significant effect being achieved at the highest dose tested (100 nmol) without producing any behavioral abnormalities. However, intrathecal injection of CP-101,606 at a dose of 300 nmol failed to inhibit CCI-induced allodynia. A receptor binding assay using rat forebrain and spinal cord membrane preparations demonstrated that [3H]CP-101,606 bound to the brain NR2B receptor with a greater extent compared to the spinal cord one. These findings suggest that the anti-allodynia effect of CP-101,606 is ascribable to blockade of NR2B receptors at the brain, but not at the spinal cord. In contrast, intrathecal injection of a non-selective NMDA antagonist, memantine, significantly inhibited CCI-induced mechanical allodynia at a dose of 300 nmol, indicating the difference in the site of action between the non-selective NMDA antagonist and the NR2B-specific NMDA antagonist.

Topics: Analgesics; Animals; Brain Chemistry; Constriction; Excitatory Amino Acid Antagonists; Injections, Intraventricular; Male; Memantine; Membranes; Pain; Peripheral Nervous System Diseases; Piperidines; Prosencephalon; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Spinal Cord

We wanted to ascertain whether the lateral parabrachial nucleus was involved in mediating the heart-rate response evoked during stimulation of somatic nociceptors. Reversible inactivation of the lateral parabrachial nucleus, using a GABA(A) agonist, reduced the reflex tachycardia evoked during noxious (mechanical) stimulation of the forelimb by approximately 50%. The same effect was observed after blockade of neurokinin 1 receptors within the lateral parabrachial nucleus, indicating a possible involvement for substance P as a neurotransmitter. Immunocytochemistry revealed a strong expression of substance P-immunoreactive fibers and boutons in all lateral subnuclei, but they were particularly dense in the lateral crescent subnucleus. Histological verification showed that the most effective injection sites for attenuating the noxious-evoked tachycardia were all placed in or near to the lateral crescent nucleus of the lateral parabrachial complex. Many single units recorded from this region were activated by high-intensity brachial nerve stimulation. The brachial nerve evoked firing responses of some of these neurons was reversibly reduced after local delivery of a neurokinin 1 receptor antagonist. However, only a minority of these neurons followed a paired-pulse stimulation protocol applied to the spinal cord, suggesting a predominance of indirect projections from the spinal cord to the parabrachial nucleus. We conclude that the cardiac component of the response to somatic nociception involves indirect spinal pathways that most likely excite neurons located in the lateral crescent nucleus of the parabrachial complex via activation of neurokinin 1 receptors.

Topics: Afferent Pathways; Animals; Brachial Plexus; Decerebrate State; Efferent Pathways; Female; GABA Agonists; GABA-A Receptor Agonists; Heart Rate; Hypertension; Isonicotinic Acids; Male; Neurokinin-1 Receptor Antagonists; Nociceptors; Pain; Piperidines; Pons; Posterior Horn Cells; Rats; Rats, Sprague-Dawley; Receptors, Neurokinin-1; Reflex; Spinal Cord; Substance P; Sympathetic Nervous System; Tachycardia

Histamine H 3 receptors have been suggested to inhibit the activity of a variety of central and peripheral neurons. Recent studies revealed that activation of spinal histamine H 3 receptors attenuates tail pinch, but not tail flick, nociception. To determine whether H 3 receptor-mediated antinociception is truly modality-specific, the effects of the selective H 3 agonist immepip were evaluated on nociceptive responses in rats induced by a range of thermal and mechanical intensities applied to the hind paw and the tail. In addition, the modulation of chemical nociceptive (ie, formalin) responses by immepip was evaluated. Immepip (5 to 30 mg/kg, subcutaneous) attenuated responses to low-intensity mechanical pinch, but not to high-intensity mechanical pressure applied to either the hind paw or the tail. The same doses of immepip had no effect on thermal nociceptive responses, regardless of the stimulus intensity. These results suggest that immepip-induced antinociception is modality- and intensity-specific. It is likely that immepip inhibits low-intensity mechanical nociception by activation of H 3 receptors located on the spinal terminals of Adelta and possibly C high-threshold mechanoreceptors. In addition, immepip (5 mg/kg, subcutaneous) significantly attenuated formalin-induced flinching, but not formalin-induced licking, during both phase 1 and phase 2, suggesting that H 3 agonists might be effective in treating some forms of clinically relevant pain. Certain classes of pain-transmitting fibers possess histamine H 3 receptors, but the localization and functional significance of these inhibitory receptors was not known. The present study shows that drugs that stimulate H 3 receptors can reduce behavioral responses produced by some, but not all, painful stimuli. Thus, H 3 agonists could be a new type of therapy for certain kinds of pain disorders.

Topics: Animals; Histamine Agonists; Hot Temperature; Imidazoles; Male; Nociceptors; Pain; Pain Measurement; Pain Threshold; Physical Stimulation; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Histamine H3; Stimulation, Chemical

We studied the effects of the high-efficacy 5-hydroxytryptamine1A (5-HT1A) receptor agonist, F 13640 on both formalin-induced spinal cord c-Fos protein expression and pain behaviours in the rat. Replicating earlier data, F 13640 (0.63 mg/kg, i.p.; t(-15 min)) completely inhibited the elevation and licking of the formalin-injected paw. In the same animals, and in spite of the agent as in earlier data increasing the number of c-Fos labelled nuclei when it was administered alone, F 13640 markedly reduced the number of formalin-induced c-Fos labelled nuclei. This was found in both the superficial (I-II) and deep (V-VI) dorsal horn laminae (2 h post-injection: 72+/-2% and 92+/-1% of reduction, respectively; P<0.001 in either case), spinal areas that contain neurons responsive to nociceptive stimulation. Co-operation occurred so that after the co-administration of F 13640 and formalin, c-Fos expression was inferior to that induced when either stimulation was administered alone. The data provide initial evidence for the agent's inhibitory effects on noxiously evoked c-Fos expression. The results indicate that co-operation between 5-HT1A receptor activation and nociceptive stimulation powerfully inhibits responses to severe, tonic nociception.

Topics: Analgesics, Opioid; Animals; Behavior, Animal; Disease Models, Animal; Formaldehyde; Male; Morphine; Pain; Pain Measurement; Piperidines; Proto-Oncogene Proteins c-fos; Pyridines; Rats; Rats, Sprague-Dawley; Serotonin 5-HT1 Receptor Agonists; Serotonin Receptor Agonists; Spinal Cord; Time Factors

Antinociceptive effects of cannabinoids are mediated, in part, at the spinal level. Cannabinoid CB1 receptors are co-localized with dorsal horn interneurons containing gamma-aminobutyric acid (GABA). In this study, we investigated the interaction between intrathecally administered cannabinoid and GABA(B) receptor agonists and antagonists in the modulation of formalin-induced pain at the spinal level. Intrathecal pretreatment of rats with a cannabinoid receptor antagonist [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1-H-pyrazole-3-carboxamide] (SR141716A, 30 microg) decreased the analgesic effect of the intrathecal administration of the GABA(B) receptor agonist, baclofen (0.125 microg and 0.25 microg). Intrathecal administration of the GABA(B) receptor antagonist, saclofen (30 microg), 10 min before administration of the cannabinoid receptor agonist (-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)-phenyl]-trans-4-(3-hydroxy-propyl)-cyclohexano (CP55940), did not affect the analgesia produced by the cannabinoid receptor agonist. Our results confirm that intrathecal administration of cannabinoid and GABA(B) receptor agonists have analgesic effects and that spinal antinociceptive effects of GABA(B) receptor agonists are likely through endocannabinoid modulation.

Topics: Analysis of Variance; Animals; Baclofen; Cyclohexanols; Dose-Response Relationship, Drug; Drug Interactions; Formaldehyde; GABA Agonists; GABA Antagonists; GABA-B Receptor Agonists; GABA-B Receptor Antagonists; Injections, Spinal; Male; Pain; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Receptors, GABA-B; Rimonabant; Signal Transduction; Spinal Cord

Many reports have shown the efficacy of cannabinoid agonists in chronic pain, whereas no report exists concerning the potential effect of cannabinoid antagonists following prolonged treatment. We tested the effects of repeated administration of the selective cannabinoid receptor type 1 (CB1) antagonist, SR141716 (rimonabant), in rats with chronic constriction injury of the sciatic nerve (CCI), an animal model of neuropathic pain. The repeated oral administration of SR141716 (1, 3 and 10 mg/kg, once a day for 1 week, from day 7 after the injury) dose dependently attenuated both thermal and mechanical hyperalgesia. A similar effect was observed in CCI wild-type mice, whereas SR141716 was unable to elicit pain relief in CB1 knockout mice, suggesting CB1 receptors involvement in the SR141716-induced antihyperalgesia. The antihyperalgesic activity of SR141716 was associated with a significant reduction of several pro-inflammatory and pro-nociceptive mediators such as tumor necrosis factor alpha (TNFalpha), prostaglandin-E2 (PGE2), lipoperoxide and nitric oxide (NO) levels. The histological analysis of sciatic nerve sections showed a marked degeneration of myelinated fibers in CCI rats, which was substantially reduced after repeated administration of SR141716. This suggests that the compound may favour myelin repair and consequently promote long-lasting functional recovery. This was confirmed by the maintenance of recovery for at least four weeks after treatment discontinuation. In conclusion, the present findings suggest that SR141716 is effective not only in alleviating neuropathic pain but also in favouring the nerve myelin repair.

Topics: Analysis of Variance; Animals; Blotting, Western; Cannabinoid Receptor Antagonists; Constriction; Demyelinating Diseases; Dinoprostone; Enzyme-Linked Immunosorbent Assay; Lipid Peroxides; Male; Mice; Mice, Knockout; Nerve Tissue Proteins; Nitrates; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type II; Nitrites; Pain; Pain Measurement; Piperidines; Pyrazoles; Rats; Rats, Wistar; Reaction Time; Receptors, Cannabinoid; Rimonabant; Sciatic Nerve; Sciatic Neuropathy; Staining and Labeling; Tumor Necrosis Factor-alpha

The phenolic hydroxy group of opiate-derived ligands is of known importance for biological activity. We have developed a SAR study around LY255582 by comparing the effect of the hydroxy group in the 2- and 4-position of the phenyl ring. Also, we have proved that the 3-position of the phenyl ring is optimal for opioid activity. Furthermore, we have successfully replaced the hydroxy group in LY255582 by carbamate and carboxamide groups. The new analogs have high affinity for the opioid receptors comparable to the corresponding phenol. Carboxamide analog 12 has an improved metabolism profile and proved to be efficacious in in vivo studies.

Topics: Administration, Oral; Animals; Cyclohexanes; Drug Evaluation, Preclinical; Feeding Behavior; Ligands; Liver; Narcotic Antagonists; Pain; Phenols; Piperidines; Radioligand Assay; Rats; Structure-Activity Relationship

Although N-methyl-D-aspartate (NMDA) receptor antagonists clearly attenuate the development of tolerance to the antinociceptive effects of opioids, it is not clear whether they also alter acute opioid-induced antinociception. The present study was designed to assess NMDA/opioid interactions in C57BL/6 mice by examining various NMDA receptor antagonists of different selectivity in combination with the mu opioid receptor agonists morphine and l-methadone. A mouse hot plate procedure was used to assess the effects of morphine (0.1 to 10.0 mg/kg) and l-methadone (0.1 to 5.6 mg/kg) alone and after pretreatment with the competitive NMDA receptor antagonist LY235959 (0.1 to 1.0 mg/kg), the glycine site NMDA receptor antagonist R(+)-HA-966 (10.0 to 56.0 mg/kg), or the polyamine site and NR2B selective NMDA receptor antagonist ifenprodil (3.2 to 10.0 mg/kg). Morphine and l-methadone produced dose- and time-dependent increases in 56 degrees C hot plate latencies. At the doses tested, the NMDA receptor antagonists produced no effect on hot plate latencies. However, when these drugs were combined with morphine, latency to respond to the hot plate was significantly increased from morphine alone. Combinations of the NMDA receptor antagonist LY235959 and l-methadone produced similar increases in hot plate latencies; however, combinations of l-methadone with R(+)-HA-966 or ifenprodil did not increase hot plate latencies compared with l-methadone alone. These results suggest that a range of NMDA receptor antagonists potentiate morphine-induced antinociception, although the potentiation of l-methadone might be specific to the antagonist examined.. The inclusion of low-dose NMDA receptor antagonists to opioids might be beneficial for the treatment of acute pain by enhancing the antinociceptive effects of the opioid.

Topics: Analgesia; Analgesics, Opioid; Animals; Central Nervous System; Dose-Response Relationship, Drug; Drug Synergism; Excitatory Amino Acid Antagonists; Isoquinolines; Male; Methadone; Mice; Mice, Inbred C57BL; Morphine; Nociceptors; Pain; Pain Measurement; Pain Threshold; Piperidines; Pyrrolidinones; Reaction Time; Receptors, Glycine; Receptors, N-Methyl-D-Aspartate

Normoxic and hypoxic ventilation are influenced by chemoreceptor and nonchemoreceptor drives. Although inhalational anesthetics blunt hypoxic ventilation, this effect is reversed by audiovisual stimulation but not by pain. Opioids reduce both normoxic and hypoxic ventilation, but their interaction with pain and audiovisual stimulation has not been fully reported.. Isocapnic, acute hypoxic ventilatory responses (AHRs) were measured in 11 volunteers. AHR and normoxic ventilation were measured under the following conditions: (1) eyes closed, no audio stimulation (low wakefulness); (2) low wakefulness conditions plus painful thermal stimulation; and (3) playing a computer game (high wakefulness), each with and without remifentanil infusion.. The average (+/- sd) remifentanil dose was 0.035 +/- 0.012 microg x kg x min(-1). Both normoxic and hypoxic ventilation were significantly reduced by the remifentanil infusion under all three conditions. The AHR values under low wakefulness conditions were 0.33 +/- 0.19 and 0.89 +/- 0.49 l x min(-1) x sat(-1) with and without remifentanil, respectively (P < 0.05). High wakefulness significantly increased AHR with and without remifentanil, whereas low wakefulness with pain did not. However, high wakefulness with remifentanil did not increase the AHR back to what was observed during low wakefulness without remifentanil.. The computer game was a more potent stimulus than pain in countering the depressant effect of remifentanil on AHR. Although the effect of high wakefulness was more attenuated than was previously observed with respect to inhalational anesthetics, the significance of these findings is underlined by the more clinically relevant scenario of what is experienced in the face of opioid administration.

Topics: Adolescent; Adult; Analgesics, Opioid; Anesthetics, Inhalation; Female; Humans; Hypoxia; Male; Pain; Piperidines; Remifentanil; Respiration; Wakefulness

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

Intrathecal administration of the neuropeptide neurotensin (NT) was shown previously to exert antinociceptive effects in a variety of acute spinal pain paradigms including hotplate, tail-flick, and writhing tests. In the present study, we sought to determine whether some of these antinociceptive effects might be elicited via stimulation of low-affinity NTS2 receptors. We first established, using immunoblotting and immunohistochemical techniques, that NTS2 receptors were extensively associated with putative spinal nociceptive pathways, both at the level of the dorsal root ganglia and of the superficial layers of the dorsal horn of the spinal cord. We then examined the effects of intrathecal administration of NT or selective NTS2 agonists on acute thermal pain. Both NT and NTS2 agonists, levocabastine and Boc-Arg-Arg-Pro-Tyrpsi(CH2NH)Ile-Leu-OH (JMV-431), induced dose-dependent antinociceptive responses in the tail-flick test. The effects of levocabastine and of JMV-431 were unaffected by coadministration of the NTS1-specific antagonist 2-[(1-(7-chloro-4-quinolinyl)-5-(2,6-dimethoxy-phenyl)pyrazol-3-yl)carboxylamino]tricyclo)3.3.1.1.(3.7))-decan-2-carboxylic acid (SR48692), confirming that they were NTS2 mediated. In contrast, the antinociceptive effects of NT were partly abolished by coadministration of SR48692, indicating that NTS1 and NTS2 receptors were both involved. These results suggest that NTS2 receptors play a role in the regulation of spinal nociceptive inputs and that selective NTS2 agonists may offer new avenues for the treatment of acute pain.

Topics: Analgesics; Animals; Ganglia, Spinal; Hot Temperature; In Vitro Techniques; Injections, Spinal; Lumbar Vertebrae; Models, Animal; Neurotensin; Pain; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Neurotensin; Spinal Cord; Tail

Newly developed cannabinoids may hold the promise of the development of useful and safe drugs. This study aimed to investigate the behavioral effects of the novel 1',1'-dithiolane delta8-HC analogue AMG-3, a cannabinomimetic molecule with high affinity for CB1/CB2 receptors. This analog was chosen for its binding affinity to these receptors, which is higher than that reported for delta8-tetrahydrocannabinol (delta8-THC). Behavioral responses were assessed after the administration of AMG-3 (1, 2, 4, 8 mg/kg, i.p.) in the open field, on the bar test, on the hot plate and in the intracranial self-stimulation procedure. AMG-3 increased the reactivity time on the hot plate in a dose- and time-dependent manner, indicating a long-lasting analgesic effect (at least 24 h). The substance was found dose-dependently to decrease spontaneous motor activity and to induce catalepsy, particularly at the highest dose (8 mg/kg). AMG-3 did not affect the rewarding value of intracranial self-stimulation, except to increase the reward threshold at the highest dose (8 mg/kg). The effects of the highest dose of AMG-3 on spontaneous activity and on the self-stimulation paradigm were completely reversed by pre-treatment with the CB1 receptor antagonist AM-251. These findings indicate that the administration of AMG-3 to rats elicits a specific behavioral profile, most probably associated with the activation of CB1 receptors and without effects indicating abuse potential.

Topics: Animals; Behavior, Animal; Binding, Competitive; Cannabinoids; Catalepsy; Cell Membrane; Cerebral Cortex; Cyclohexanols; Dose-Response Relationship, Drug; Male; Molecular Structure; Motor Activity; Pain; Pain Measurement; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Time Factors; Tritium

There are multiple types of nicotine acetylcholine receptors (nAChR) in the brain associated with synaptic function, signal processing, or cell survival. The therapeutic targeting of nicotinic receptors in the brain will benefit from the identification of drugs, which may be selective for their ability to activate or inhibit a limited range of these receptor subtypes. We previously identified a family of bis-tetramethylpiperidine compounds as selective inhibitors of neuronal-type nicotinic receptors. In the present study we describe the in vivo effects and properties of 2,2,6,6-tetramethylpiperidin-4-yl heptanoate (TMPH), a novel inhibitor of neuronal nicotinic receptors. Delivered systemically, this drug can block central nervous system effects of nicotine, indicating that this drug is able to cross the blood-brain barrier and access sites in the brain. Unlike the prototype CNS-active nicotinic inhibitor, mecamylamine, TMPH blocked some but not all of the CNS effects of nicotine, indicating that it has a unique selectivity for specific receptor subtypes in the brain. The nAChR subtypes that mediate the locomotor effects and hypothermic effects of nicotine appear to be less sensitive to TMPH than those which mediate analgetic effects and discriminative stimuli. These results indicate that TMPH may possess unique selectivity for specific nicotinic receptor subtypes.

Topics: Analgesics; Animals; Body Temperature; Central Nervous System; Discrimination, Psychological; Dose-Response Relationship, Drug; Heptanoic Acids; Male; Mice; Mice, Inbred ICR; Motor Activity; Nicotine; Pain; Pain Measurement; Piperidines; Rats; Rats, Long-Evans; Receptors, Nicotinic; Time Factors

Despite abundant evidence implicating the importance of N-methyl-D-aspartate (NMDA) receptors in the spinal cord for pain transmission, the signal transduction coupled to NMDA receptor activation is largely unknown for the neuropathic pain state that lasts over periods of weeks. To address this, we prepared mice with neuropathic pain by transection of spinal nerve L5. Wild-type, NR2A-deficient, and NR2D-deficient mice developed neuropathic pain; in addition, phosphorylation of NR2B subunits of NMDA receptors at Tyr1472 was observed in the superficial dorsal horn of the spinal cord 1 week after nerve injury. Neuropathic pain and NR2B phosphorylation at Tyr1472 were attenuated by the NR2B-selective antagonist CP-101,606 and disappeared in mice lacking Fyn kinase, a Src-family tyrosine kinase. Concomitant with the NR2B phosphorylation, an increase in neuronal nitric oxide synthase activity was visualized in the superficial dorsal horn of neuropathic pain mice by NADPH diaphorase histochemistry. Electron microscopy showed that the phosphorylated NR2B was localized at the postsynaptic density in the spinal cord of mice with neuropathic pain. Indomethacin, an inhibitor of prostaglandin (PG) synthesis, and PGE receptor subtype EP1-selective antagonist reduced the NR2B phosphorylation in these mice. Conversely, EP1-selective agonist stimulated Fyn kinase-dependent nitric oxide formation in the spinal cord. The present study demonstrates that Tyr1472 phosphorylation of NR2B subunits by Fyn kinase may have dual roles in the retention of NMDA receptors in the postsynaptic density and in activation of nitric oxide synthase, and suggests that PGE2 is involved in the maintenance of neuropathic pain via the EP1 subtype.

Topics: Animals; Behavior, Animal; Blotting, Western; Dinoprostone; Dose-Response Relationship, Drug; Histocytochemistry; Mice; Mice, Inbred C57BL; Mice, Inbred CBA; Mice, Knockout; Microscopy, Immunoelectron; Neoplasm Proteins; Nitric Oxide; Pain; Peripheral Nervous System Diseases; Phosphorylation; Piperidines; Protein-Tyrosine Kinases; Receptors, N-Methyl-D-Aspartate; Signal Transduction; src-Family Kinases; Tyrosine

The antinociceptive profile of selected histamine H(2) and histamine H(3) receptor antagonists led to the discovery of improgan, a non-brain-penetrating analgesic agent which does not act on known histamine receptors. Because no chemical congener of improgan has yet been discovered which has both antinociceptive and brain-penetrating properties, the present study investigated the antinociceptive effects of a series of chemical compounds related to zolantidine, a brain-penetrating histamine H(2) receptor antagonist. The drugs studied presently contain the piperidinomethylphenoxy (PMPO) moiety, hypothesized to introduce brain-penetrating characteristics. Following intracerebroventricular (i.c.v.) dosing in rats, six of eight drugs produced dose- and time-related antinociception on both the tail flick and hot plate tests over a nearly eight-fold range of potencies. Ataxia and other motor side effects were observed after high doses of these drugs, but two of the compounds (SKF94674 and loxtidine) produced maximal antinociception at doses which were completely devoid of these motor effects. Consistent with the hypothesis that PMPO-containing drugs are brain-penetrating analgesics, SKF94674 and another derivative (JB-9322) showed dose-dependent antinociceptive activity 15 to 30 min after systemic dosing in mice, but these effects were accompanied by seizures and death beginning 45 min after dosing. Other drugs showed a similar pattern of antinociceptive and toxic effects. In addition, loxtidine produced seizures without antinociception, whereas zolantidine produced neither effect after systemic dosing in mice. Although several of the drugs tested have histamine H(2) receptor antagonist activity, neither the antinociception nor the toxicity was correlated with histamine H(2) receptor activity. The present results are the first to demonstrate the existence of brain-penetrating antinociceptive agents chemically related to zolantidine and improgan, but further studies are needed to understand the mechanisms of both the pain relief and toxicity produced by these agents.

Topics: Algorithms; Analgesics; Animals; Behavior, Animal; Benzothiazoles; Brain; Cimetidine; Dose-Response Relationship, Drug; Histamine H2 Antagonists; Injections, Intraventricular; Male; Mice; Molecular Structure; Pain; Pain Measurement; Phenoxypropanolamines; Piperidines; Quinazolines; Quinazolinones; Rats; Rats, Sprague-Dawley; Thiazoles; Time Factors; Triazoles

F 13640 is a newly discovered high-efficacy 5-HT(1A) receptor agonist that produces exceptional analgesia in animal models of tonic and chronic, nociceptive and neuropathic pains by novel molecular and neuroadaptive mechanisms. Here we examined the effects of F 13640 and remifentanil (0.63 mg/kg with either compound) when injected i.p. either before or 15 min after rats underwent orthopedic surgery. Surgery consisted of the drilling of a hole in the calcaneus bone and of an incision of the skin, fascia and plantar muscle of one foot. During surgery, the concentration of volatile isoflurane was progressively incremented depending on the animal's response to surgical maneuvers. Other experiments examined the dose-dependent effects of F 13640 (0.04 to 0.63 mg/kg) on surgical pain as well as on the Minimum Alveolar Concentration of isoflurane. Both F 13640 and remifentanil markedly reduced the intra-operative isoflurane requirement. F 13640 also reduced measures of postoperative pain (i.e., paw elevation and flexion). With these postoperative measures, remifentanil produced short-lived analgesia followed by hyperalgesia. F 13640 significantly reduced both surgical pain and the isoflurane Minimum Alveolar Concentration from 0.16 mg/kg onward. F 13640 produced powerful intra- and postoperative analgesia in rats undergoing orthopedic surgery. Unlike the opioid, remifentanil, F 13640 caused no hyperalgesia with ongoing postoperative pain, and should remain effective with protracted postoperative use.

Topics: Analgesia; Analgesics, Non-Narcotic; Analgesics, Opioid; Analysis of Variance; Anesthetics, Inhalation; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Hyperalgesia; Isoflurane; Male; Monitoring, Intraoperative; Orthopedic Procedures; Pain; Pain Measurement; Pain Threshold; Pain, Postoperative; Piperazines; Piperidines; Pulmonary Alveoli; Pyridines; Rats; Rats, Sprague-Dawley; Remifentanil; Serotonin Antagonists; Vocalization, Animal

A recent model of acute incisional pain has been characterized that strongly parallels the postoperative period in patients experiencing evoked pain. In that setting, abundant literature has revealed antihypersensitive effects produced by intrathecally administered alpha2-adrenergic receptor agonists, such as clonidine, in both animals and humans. Recent reports have suggested an obligatory role of spinal acetylcholine receptors in the analgesic action of intrathecal clonidine. The authors sought to determine the involvement of spinal muscarinic and nicotinic receptor subpopulations in the antihypersensitivity effect of intrathecal clonidine in a rodent model for human postoperative pain.. After intrathecal catheterization, rats underwent superficial plantar incision. Clonidine or a combination of clonidine and muscarinic receptor subtype antagonists (M1, M2, M3, and M4) or nicotinic receptor subtype antagonists (alpha4beta2 and alpha7) were intrathecally administered, and withdrawal thresholds to mechanical stimuli were examined.. Spinal clonidine maximally reduced hypersensitivity adjacent to the wound 30 min after its injection. When animals were intrathecally pretreated with the M1 muscarinic antagonist toxin MT-7, the M3 muscarinic antagonist 4-diphenylacetoxy-N-methylpiperidine, and the M4 muscarinic antagonist toxin MT-3, clonidine lost its antihypersensitive action. When animals were intrathecally pretreated with the alpha4beta2 nicotinic receptor antagonist dihydro-beta-erythroidine, but not with the alpha7 nicotinic receptor antagonist methyllycaconitine, the antihypersensitivity action of clonidine was abolished.. These data indicate for the first time that the clonidine-induced increase in punctuate mechanical threshold is mediated via the activation of all but M2 muscarinic receptor subtypes, and via the activation of alpha4beta2 but not alpha7 nicotinic receptor subtypes in a rodent model for human postoperative pain.

Topics: Aconitine; Adrenergic alpha-Agonists; Animals; Behavior, Animal; Clonidine; Diamines; Dihydro-beta-Erythroidine; Injections, Spinal; Male; Muscarinic Agonists; Nicotinic Agonists; Pain; Piperidines; Rats; Rats, Sprague-Dawley; Receptor, Muscarinic M1; Receptor, Muscarinic M2; Receptors, Muscarinic; Receptors, Nicotinic; Spine

(-)-cis-1-Methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol (SB-612111) is a novel human opiate receptor-like orphan receptor (ORL-1) antagonist that has high affinity for the clonal human ORL-1 receptor (hORL-1 K(i) = 0.33 nM), selectivity versus mu-(174-fold), delta-(6391-fold), and kappa (486-fold)-opioid receptors and is able to inhibit nociceptin signaling via hORL-1 in a whole cell gene reporter assay. SB-612111 has no measurable antinociceptive effects in vivo in the mouse hot-plate test after intravenous administration but is able to antagonize the antimorphine action of nociceptin [ED(50) = 0.69 mg/kg, 95% confidence limit (CL) = 0.34-1.21]. SB-62111 administration can also reverse tolerance to morphine in this model, established via repeated morphine administration. In addition, intravenous SB-612111 can antagonize nociceptin-induced thermal hyperalgesia in a dose-dependent manner (ED(50) = 0.62 mg/kg i.v., 95% CL = 0.22-1.89) and is effective per se at reversing thermal hyperalgesia in the rat carrageenan inflammatory pain model. These data show that an ORL-1 receptor antagonist may be a useful adjunct to chronic pain therapy with opioids and can be used to treat conditions in which thermal hyperalgesia is a significant component of the pain response.

Topics: Animals; Binding Sites; CHO Cells; Cricetinae; Cycloheptanes; Drug Tolerance; Humans; Morphine; Narcotic Antagonists; Nociceptin Receptor; Pain; Piperidines; Receptors, Opioid

Arachidonylethanolamide (anandamide, AEA) is believed to be the endogenous ligand of the cannabinoid CB(1) and CB(2) receptors. CB(1) receptors have been found localized on fibers in the spinal trigeminal tract and spinal trigeminal nucleus caudalis. Known behavioral effects of anandamide are antinociception, catalepsy, hypothermia, and depression of motor activity, similar to Delta(9)-tetrahydocannanbinol, the psychoactive constituent of cannabis. It may be a possible therapeutic target for migraine. In this study, we looked at the possible role of the CB(1) receptor in the trigeminovascular system, using intravital microscopy to study the effects of anandamide against various vasodilator agents. Anandamide was able to inhibit dural blood vessel dilation brought about by electrical stimulation by 50%, calcitonin gene-related peptide (CGRP) by 30%, capsaicin by 45%, and nitric oxide by 40%. CGRP(8-37) was also able to attenuate nitric oxide (NO)-induced dilation by 50%. The anandamide inhibition was reversed by the CB(1) receptor antagonist AM251. Anandamide also reduced the blood pressure changes caused by CGRP injection, this effect was not reversed by AM251. It would seem that anandamide acts both presynaptically, to prevent CGRP release from trigeminal sensory fibers, and postsynaptically to inhibit the CGRP-induced NO release in the smooth muscle of dural arteries. CB(1) receptors seem to be involved in the NO/CGRP relationship that exists in causing headache and dural blood vessel dilation. It also seems that some of the blood pressure changes caused by anandamide are mediated by a noncannabinoid receptor, as AM251 was unable to reverse these effects. It can be suggested that anandamide is tonically released to play some form of modulatory role in the trigeminovascular system.

Topics: Animals; Arachidonic Acids; Blood Pressure; Calcitonin Gene-Related Peptide; Capsaicin; Electric Stimulation; Endocannabinoids; Hypotension; Male; Neurons; Nitroprusside; Pain; Peptide Fragments; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Trigeminal Caudal Nucleus; Vasodilation

Topics: Analgesics, Opioid; Anesthetics, Intravenous; Humans; Pain; Piperidines; Propofol; Remifentanil

1. The contribution of endogenous endothelins to nociceptive responses elicited by ovalbumin (OVA) in the hind-paw of mice sensitised to this antigen (50 microg OVA+5 mg Al(OH)(3), s.c., 14 days beforehand) was investigated. 2. Sensitised mice exhibited greater nocifensive responsiveness to intraplantar (i.pl.) OVA (total licking time over first 30 min: 85.2+/-14.6 s at 0.3 microg; 152.6+/-35.6 s at 1 microg) than nonsensitised animals (29.3+/-7.4 s at 1 microg). Nocifensive responses of sensitised mice to 0.3 microg OVA were inhibited by morphine (3 mg kg(-1), s.c.) or local depletion of mast cells (four daily i.pl. injections of compound 48/80). 3. Pretreatment with i.v. bosentan (mixed ET(A)/ET(B) receptor antagonist; 52 micromol kg(-1)) or A-122722.5 (selective ET(A) receptor antagonist; 6 micromol kg(-1)) reduced OVA-induced licking from 124.8+/-20.6 s to 45.7+/-13.0 s and 64.2+/-12.1 s, respectively, whereas A-192621.1 (selective ET(B) receptor antagonist; 25 micromol kg(-1)) enhanced them to 259.2+/-39.6 s. 4. Local i.pl. pretreatment with BQ-123 or BQ-788 (selective ET(A) or ET(B) receptor antagonists, respectively, each at 3 nmol) reduced OVA-induced licking (from 106.2+/-15.2 to 57.0+/-9.4 s and from 118.6+/-10.5 to 76.8+/-14.7 s, respectively). Sarafotoxin S6c (selective ETB receptor agonist, 30 pmol, i.pl., 30 min after OVA) induced nocifensive responses in OVA-sensitised, but not in nonsensitised, animals. 5. Compound 48/80 (0.3 microg, i.pl.) induced nocifensive responses per se and potentiated those induced by i.pl. capsaicin (0.1 microg). Treatment with BQ-123 (3 nmol, i.pl.) reduced only the hyperalgesic effect of compound 48/80, whereas BQ-788 (3 nmol) was ineffective. 6. Thus, immune-mediated Type I hypersensitivity reactions elicit mast cell- and endothelin-dependent nociception in the mouse hind-paw, which are mediated locally by both ET(A) and ET(B) receptors. The nocifensive response to antigen is amenable to blockade by systemic treatment with dual ET(A)/ET(B) or selective ET(A) receptor antagonists, but is sharply potentiated by systemic selective ET(B) receptor antagonist treatment. The apparently distinct roles played by ET(B) receptors in this phenomenon at local and other sites remain to be characterised.

Topics: Animals; Antigens; Bosentan; Dose-Response Relationship, Drug; Endothelins; Hyperalgesia; Hypersensitivity; Indicators and Reagents; Male; Mice; Oligopeptides; Ovalbumin; p-Methoxy-N-methylphenethylamine; Pain; Peptides, Cyclic; Piperidines; Sulfonamides; Viper Venoms

Surgical pain typically combines superficial and deep pain. We wished to generate pain that resembled surgical pain, reliably and reproducibly, in volunteers.. We constructed a computer-controlled pneumatic device to apply pressure to the anterior tibia. The reproducibility of the pain was tested by rating the pressure that caused pain rated 4-5 on a visual analogue scale (VAS) on days 0, 7, and 24 in 10 volunteers. The effect of remifentanil (0.025, 0.05, 0.075, and 0.1 microg kg-1 min-1) on pain tolerance in another set of volunteers (n=11) was used as an indirect measure of the reliability of pain production.. The pressure needed (0.7 (0.3) to 0.9 (0.4) atm (mean (SD)) to induce pain rated 4-5 (VAS) did not vary, showing long-term reproducibility of the method. When pressure was applied to cause increasing pain in volunteers (n=11) 0.05 microg kg-1 min-1 remifentanil increased pain tolerance by 50%. An approximate doubling of the dose (0.1 microg kg-1 min-1) increased pain tolerance significantly more. The linear logarithmic dose-effect relationship shows that the device causes pain reliably, and this can be reduced with opioid treatment.. This pneumatic device can apply pain reliably and reproducibly.

Topics: Adult; Analgesics, Opioid; Dose-Response Relationship, Drug; Equipment Design; Humans; Infusions, Intravenous; Magnetic Resonance Imaging; Male; Pain; Pain Threshold; Piperidines; Pressure; Remifentanil; Reproducibility of Results; Tibia

We characterized the effect of a novel selective histamine H1 receptor antagonist, (R)-1-(3-(10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5-ylidene)-1-propyl)-3-piperidine carboxylic acid (ReN-1869), on the responses of dorsal horn neurons in anesthetized rats after carrageenan induced-inflammation and peripheral neuropathy (L5/6 spinal nerve ligation; SNL). ReN-1869 was administered systemically (0.1-4 mg/kg), and drug effects were assessed using a wide range of peripheral electrical and natural stimuli (brush, von Frey filaments, and heat). Comparisons were made between unoperated naive groups and either carrageenan inflamed or SNL rats. ReN-1869 produced little effect on the electrically evoked responses (wind-up, Abeta-, Adelta-, and C-fiber-evoked responses); however, it significantly attenuated neuronal responses to noxious heat in carrageenan and SNL rats. A robust effect was seen with the low-threshold mechanical punctate (von Frey 9 g) stimuli, which were selectively inhibited by ReN-1869 after tissue and nerve injury. These inhibitory actions were in marked contrast to the naive animal group, where only nonsignificant effects were observed. To investigate whether the actions of ReN-1869 are mediated via the antagonism of histamine H1 receptors, the effects of this novel compound were compared with that of another H1 receptor antagonist, mepyramine (1-20 mg/kg). Systemic mepyramine produced strong inhibitions of the 9-g von Frey-evoked responses in carrageenan and SNL rats. The similar pharmacological profile of these two compounds suggests for a similar mechanism of action. We propose that ReN-1869 may represent a novel agent for the treatment of certain modalities of persistent pain states, in particular for the treatment of mechanical allodynia.

Topics: Analgesics; Animals; Disease Models, Animal; Electrophysiology; Histamine H1 Antagonists; Inflammation; Male; Neurons; Pain; Peripheral Nervous System Diseases; Piperidines; Posterior Horn Cells; Pyrilamine; Rats; Rats, Sprague-Dawley; Spinal Cord

Topics: Analgesics; Burning Mouth Syndrome; Europe; Facial Pain; Humans; Inflammation; Pain; Peripheral Nerve Injuries; Piperidines; Pyridines; Temporomandibular Joint Disorders; Trust

Peripheral nerve injury in humans can produce a persistent pain state characterized by spontaneous pain and painful responses to normally innocuous stimuli (allodynia). Here we attempt to identify some of the neurophysiological and neurochemical mechanisms underlying neuropathic pain using an animal model of peripheral neuropathy induced in male Sprague-Dawley rats by placing a 2-mm polyethylene cuff around the left sciatic nerve according to the method of Mosconi and Kruger. von Frey hair testing confirmed tactile allodynia in all cuff-implanted rats before electrophysiological testing. Rats were anesthetized and spinalized for extracellular recording from single spinal wide dynamic range neurons (L(3-4)). In neuropathic rats (days 11-14 and 42-52 after cuff implantation), ongoing discharge was greater and hind paw receptive field size was expanded compared to control rats. Activation of low-threshold sensory afferents by innocuous mechanical stimulation (0.2 N for 3 s) in the hind paw receptive field evoked the typical brief excitation in control rats. However, in neuropathic rats, innocuous stimulation also induced a nociceptive-like afterdischarge that persisted 2-3 min. This afterdischarge was never observed in control rats, and, in this model, is the distinguishing feature of the spinal neural correlate of tactile allodynia. Electrical stimulation of the sciatic nerve at 4 and at 20 Hz each produced an initial discharge that was identical in control and in neuropathic rats. This stimulation also produced an afterdischarge that was similar at the two frequencies in control rats. However, in neuropathic rats, the afterdischarge produced by 20-Hz stimulation was greater than that produced by 4-Hz stimulation. Given that acutely spinalized rats were studied, only peripheral and/or spinal mechanisms can account for the data obtained; as synaptic responses from C fibers begin to fail above approximately 5-Hz stimulation [Pain 46 (1991) 327], the afterdischarge in response to 20-Hz stimulation suggests a change mainly in myelinated afferents and a predominant role of these fibers in eliciting this afterdischarge. These data are consistent with the suggestion that peripheral neuropathy induces phenotypic changes predominantly in myelinated afferents, the sensory neurons that normally respond to mechanical stimulation. The NK-1 receptor antagonist, CP-99,994 (0.5 mg/kg, i.v.), depressed the innocuous pressure-evoked afterdischarge but not the brief initial d

Topics: Afferent Pathways; Animals; Constriction; Disease Models, Animal; Dose-Response Relationship, Radiation; Electrophysiology; Evoked Potentials; Functional Laterality; Hindlimb; Male; Nerve Fibers, Myelinated; Neurokinin-1 Receptor Antagonists; Pain; Pain Measurement; Pain Threshold; Peripheral Nervous System Diseases; Physical Stimulation; Piperidines; Posterior Horn Cells; Rats; Rats, Sprague-Dawley; Receptors, Neurokinin-1; Sciatic Nerve; Spinal Cord; Time Factors

The roles of the two cannabinoid receptor subtypes, CB-1 and CB-2, have not been clarified in cannabinoid-mediated analgesia. We investigated the efficacy of the non-selective cannabinoid receptor agonist CP55,940 in the modulation of responses in the rat to both acute pain (tail flick) and neuropathic pain (tactile allodynia following chronic L5/6 spinal nerve ligation). Responses were also assessed in the presence of the CB-1 antagonist SR141716A (SR1) and the CB-2 antagonist SR144528 (SR2). CP55,940 attenuated tactile allodynia (ED(50) 0.04 mg/kg i.t. (95% CI 0.032-0.044 mg/kg), 0.12 mg/kg i.p. (95% CI 0.10-0.15 mg/kg)) and induced thermal antinociception (ED(50) tail flick 0.07 mg/kg i.t. (95% CI 0.05-0.10 mg/kg), 0.17 mg/kg i.p. (95% CI 0.11-0.26 mg/kg)). SR1 0.5 mg/kg i.t. attenuated the antinociceptive effect of CP55,940 in both modalities. However, SR1 1.0 mg/kg i.p. decreased tail flick latency but had no effect on tactile allodynia antinociception. In contrast, SR2 1.0 mg/kg i.p. significantly decreased the effect of i.p. CP55,940 on both tail flick antinociception and tactile allodynia (P<0.005). The combination of SR1 and SR2 (i.p.) had an additive effect in decreasing the antinociception induced by CP55,940 on tail flick responses (P<0.005). These results suggest a role for CB-2 receptor-mediated antinociception in both acute and neuropathic pain in addition to centrally located CB-1 mechanisms.

Topics: Analgesics; Analysis of Variance; Animals; Behavior, Animal; Camphanes; Cyclohexanols; Dose-Response Relationship, Drug; Drug Administration Routes; Drug Interactions; Ligation; Male; Nociceptors; Pain; Pain Measurement; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Reaction Time; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Rimonabant; Spinal Nerves; Time Factors

Pharmacological blockade of N-methyl-D-aspartate (NMDA) receptors can modulate morphine analgesia in experimental animals and humans. However, this literature is highly inconsistent, with NMDA receptor antagonists variously shown to potentiate, attenuate or produce no effect on morphine analgesic magnitude. A number of factors influencing this modulation have been proposed, but no one has examined such factors simultaneously, and all existing studies in mice were conducted exclusively in male subjects. Thus, the influence of systemic administration of site-specific NMDA receptor antagonists-including dextromethorphan, dextrorphan, MK-801, LY235959, L-701,324, and Ro 25-6981-on morphine analgesia (15-45 mg/kg; 15, 30 and 60 min post-injection) was studied in male and female mice using the 49 degrees C tail-withdrawal test. We found that oral and intraperitoneal dextromethorphan, a low-affinity non-competitive antagonist, dose-dependently potentiated low-dose morphine analgesia but attenuated high-dose morphine analgesia. Dextrorphan and MK-801 were found to potentiate low- but not high-dose morphine analgesia. The competitive glutamate-site antagonist, LY235959, and glycine-site antagonist, L-701,324, potentiated morphine analgesia at all doses. In contrast, the polyamine (NR2B) site antagonist, Ro 25-6981, attenuated morphine analgesia at all doses. Strikingly, the non-competitive antagonists produced no modulation of morphine analgesia whatsoever in female mice, whereas no sex differences were observed using competitive or NR2B antagonists. These findings indicate that NMDA modulation of morphine analgesia is critically influenced by sex, site of antagonism, morphine dose and time after injection. Our data suggest that NMDA antagonism via competitive or glycine site antagonism might result in more reliable clinical effects on morphine analgesia in both sexes.

Topics: Animals; Central Nervous System; Dextromethorphan; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Interactions; Excitatory Amino Acid Antagonists; Female; Isoquinolines; Male; Mice; Morphine; Pain; Phenols; Piperidines; Quinolones; Receptors, N-Methyl-D-Aspartate; Sex Characteristics; Time Factors

Accumulating evidence suggests that cannabinoids can produce antinociception through peripheral mechanisms. In the present study, we determined whether cannabinoids attenuated existing hyperalgesia produced by a mild heat injury to the glabrous hindpaw and whether the antihyperalgesia was receptor-mediated. Anesthetized rats received a mild heat injury (55 degrees C for 30 s) to one hindpaw. Fifteen minutes after injury, animals exhibited hyperalgesia as evidenced by lowered withdrawal latency to radiant heat and increased withdrawal frequency to a von Frey monofilament (200 mN force) delivered to the injured hindpaw. Separate groups of animals were then treated with an intraplantar (i.pl.) injection of vehicle or the cannabinoid receptor agonist WIN 55,212-2 at doses of 1, 10, or 30 microg in 100 microl. WIN 55,212-2 attenuated both heat and mechanical hyperalgesia dose-dependently. The inactive enantiomer WIN 55,212-3 did not alter mechanical or heat hyperalgesia, suggesting the effects of WIN 55,212-2 were receptor-mediated. The CB1 receptor antagonist AM 251 (30 microg) co-injected with WIN 55,212-2 (30 microg) attenuated the antihyperalgesic effects of WIN 55,212-2. The CB2 receptor antagonist AM 630 (30 microg) co-injected with WIN 55,212-2 attenuated only the early antihyperalgesic effects of WIN 55,212-2. I.pl. injection of WIN 55,212-2 into the contralateral paw did not alter the heat-injury induced hyperalgesia, suggesting that the antihyperalgesia occurred through a peripheral mechanism. These data demonstrate that cannabinoids primarily activate peripheral CB1 receptors to attenuate hyperalgesia. Activation of this receptor in the periphery may attenuate pain without causing unwanted side effects mediated by central CB1 receptors.

Topics: Animals; Benzoxazines; Burns; Cannabinoid Receptor Agonists; Cannabinoid Receptor Antagonists; Disease Models, Animal; Hot Temperature; Hyperalgesia; Indoles; Male; Morpholines; Naphthalenes; Nerve Fibers, Myelinated; Nerve Fibers, Unmyelinated; Nociceptors; Pain; Pain Measurement; Physical Stimulation; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Receptors, Cannabinoid; Reflex; Skin

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

The selective, high-efficacy 5-HT(1A) receptor agonist, (3-chloro-4-fluoro-phenyl)-[4-fluoro-4-[[(5-methyl-pyridin-2-ylmethyl)-amino]-methyl]piperidin-1-yl]-methanone (F 13640) has been reported to produce long-term analgesia in rodent models of chronic nociceptive and neuropathic pain; it also preempts allodynia following spinal cord injury. Here, rats underwent spinal cord injury, fully developed allodynia, and were infused with saline or 0.63 mg/day of F 13640 for 56 days. Infusion was then discontinued, and further assessments of allodynia (vocalization threshold to von Frey filament stimulation, responses to brush and cold) were conducted for another 70 days. F 13640-induced analgesia persisted during this post-treatment period. The data offer initial evidence that high-efficacy 5-HT(1A) receptor activation produces an unprecedented curative-like action on pathological pain.

Topics: Analgesics; Animals; Behavior, Animal; Cold Temperature; Female; Infusions, Intravenous; Pain; Pain Measurement; Pain Threshold; Piperidines; Pyridines; Rats; Rats, Sprague-Dawley; Serotonin 5-HT1 Receptor Agonists; Spinal Cord Injuries; Touch; Vocalization, Animal

Several compounds with a 4-aminopiperidine scaffold decorated on both nitrogen atoms by alkyl or acyl moieties containing the structural motifs of verapamil and of flunarizine, as well as those that are more frequent in known N-type calcium channel antagonists, have been synthesized. Antinociceptive activity on the mouse hot-plate test was used to select molecules to be submitted to further studies. Active compounds were tested in vitro on a PC12 rat pheochromocytoma clonal cell line, to evaluate their action on N-type calcium channels, and on a rat model of neuropathic pain. Two compounds that show N-type calcium channel antagonism and are endowed with potent action on pain and neuropathic pain (3 and 18) have been selected for further studies.

Topics: Analgesics; Animals; Binding Sites; Butanones; Calcium; Calcium Channel Blockers; Calcium Channels, N-Type; Cerebral Ventricles; Drug Design; In Vitro Techniques; Male; Mice; Pain; Pain Measurement; Pain Threshold; PC12 Cells; Peripheral Nervous System Diseases; Piperidines; Radioligand Assay; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship

We examined the involvement of the spinal muscarinic receptors in the clonidine-induced antiallodynic effects. Mechanical sensitivity was assessed by stimulating the hind paw with von Frey filaments. In streptozotocin-treated (200 mg/kg, i.v.) diabetic mice, hypersensitivity to mechanical stimulation appeared 3 days after streptozotocin administration, and persisted for 11 days. This mechanical hypersensitivity (allodynia) was inhibited by the intrathecal (i.t.) injection of clonidine. The muscarinic receptor antagonist atropine (i.t.) and alpha2-adrenoreceptor antagonist yohimbine (i.t. or subcutaneous injection) abolished the antiallodynic effect of clonidine. The effect was mimicked by the muscarinic M1 receptor antagonist pirenzepine, but not by the muscarinic M2 receptor antagonist methoctoramine or the muscarinic M3 receptor antagonist 4-DAMP (4-diphenyl-acetoxy-N-methylpiperidine methiodide). In addition, the mechanical hypersensitivity in diabetic mice was reduced by the selective muscarinic M1 receptor agonist McN-A-343 (4-(m-chlorophenyl-carbamoyloxy)-2-butynyltrimethylammonium chloride) (i.t.). These results suggest that spinal muscarinic M1 receptors participate in the antiallodynic effect of clonidine in diabetic mice.

Topics: (4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride; Analgesics; Animals; Atropine; Blood Glucose; Clonidine; Diabetes Mellitus, Experimental; Diamines; Injections, Spinal; Male; Mice; Motor Activity; Muscarinic Agonists; Muscarinic Antagonists; Pain; Pain Threshold; Piperidines; Pirenzepine; Receptor, Muscarinic M1; Receptor, Muscarinic M2; Receptor, Muscarinic M3; Spinal Cord; Streptozocin; Stress, Mechanical; Time Factors

Different analytical concepts were introduced to quantify the changes of the electroencephalogram. The Datex-Ohmeda S/5 Entropy Module (Datex-Ohmeda Division, Instrumentarium Corp., Helsinki, Finland) was the first commercial monitor based on the entropy generating two indices, the state entropy (SE) and the response entropy (RE). The aim of the current study was to compare the accuracy of SE and RE with the Bispectral Index(R) monitor (BIS(R); Aspect Medical Systems, Newton, MA) during propofol-remifentanil anesthesia.. The authors investigated 20 female patients during minor gynecologic surgery. SE, RE, BIS, mean arterial blood pressure, heart rate, and sedation level were recorded every 20 s during stepwise increase (target-controlled infusion, 0.5 microg/ml) of propofol until the patients lost response. Five minutes after loss of response, remifentanil infusion (0.4 microg . kg(-1) . min(-1)) was started. Spearman correlation coefficient and prediction probability were calculated for sedation levels with SE, RE, BIS, mean arterial blood pressure, and heart rate. The ability of the investigated parameters to distinguish between the anesthesia steps awake versus loss of response, awake versus anesthesia, anesthesia versus first reaction, and anesthesia versus extubation was analyzed with the prediction probability.. SE correlates best with sedation levels, but no significant differences of the prediction probability values among SE, RE, and BIS were found. The prediction probability for all investigated steps of anesthesia did not show significant differences among SE, RE, and BIS. SE, RE, and BIS were superior to mean arterial blood pressure and heart rate.. SE, RE, and BIS revealed similar information about the level of sedation and allowed the authors to distinguish between different steps of anesthesia. Both monitors provided useful additional information for the anesthesiologist.

Topics: Acoustic Stimulation; Adult; Algorithms; Anesthesia, General; Anesthesia, Intravenous; Anesthetics, Intravenous; Blood Pressure; Conscious Sedation; Consciousness; Electroencephalography; Entropy; Female; Gynecologic Surgical Procedures; Heart Rate; Humans; Intubation, Intratracheal; Logistic Models; Middle Aged; Monitoring, Intraoperative; Pain; Physical Stimulation; Piperidines; Predictive Value of Tests; Propofol; Remifentanil

Endothelin-1 (ET-1) in the central nervous system has been suggested to produce suppressive effects on pain transmission. We investigated the manner by which ET-1 exerts this action. ET-1 administered intracerebroventricularly produced a dose-dependent antinociceptive effect in a thermal pain test that utilized a spinal reflex to determine nociceptive thresholds. This suggested that the antinociceptive effect of ET-1 involved a descending pain inhibitory system. The antinociceptive effect was blocked by an ETA receptor antagonist but not by an ETB receptor antagonist, indicating that the action was mediated through the ETA receptor. Antagonists of opioid receptors, serotonin receptors, alpha-2 adrenergic receptors, oxytocin receptors, and dopamine receptors did not block the antinociceptive effect of ET-1. Thus, major descending inhibitory systems were probably not involved. The antinociceptive effect was blocked by intracerebroventricular administration of an alpha-1 adrenergic receptor antagonist. This indicated that the antinociceptive effect involved the activation of a supraspinal noradrenergic pathway, which in turn may activate a still unknown descending pain inhibitory system.

Topics: Adrenergic alpha-1 Receptor Antagonists; Adrenergic alpha-Antagonists; Analgesics, Non-Narcotic; Animals; Brain; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Injections, Intraventricular; Male; Mice; Mice, Inbred C57BL; Neural Inhibition; Neural Pathways; Oligopeptides; Pain; Pain Measurement; Pain Threshold; Peptides, Cyclic; Piperidines; Prazosin; Reaction Time; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Adrenergic, alpha-1; Yohimbine

The present studies were conducted to test the hypothesis that systemically inactive doses of cannabinoids suppress inflammation-evoked neuronal activity in vivo via a peripheral mechanism. We examined peripheral cannabinoid modulation of spinal Fos protein expression, a marker of neuronal activity, in a rat model of inflammation. Rats received unilateral intraplantar injections of carrageenan (3%). In behavioral studies, carrageenan induced allodynia and mechanical hyperalgesia in response to stimulation with von Frey monofilaments. The cannabinoid agonist WIN55,212-2 (30 microg intraplantarly), administered concurrently with carrageenan, attenuated carrageenan-evoked allodynia and hyperalgesia relative to control conditions. In immunocytochemical studies, WIN55,212-2 suppressed the development of carrageenan-evoked Fos protein expression in the lumbar dorsal horn of the spinal cord relative to vehicle treatment. The same dose administered systemically or to the noninflamed contralateral paw failed to alter either carrageenan-evoked allodynia and hyperalgesia or carrageenan-evoked Fos protein expression, consistent with a peripheral site of action. The suppressive effects of WIN55,212-2 (30 microg intraplantarly) on carrageenan-evoked Fos protein expression and pain behavior were blocked by local administration of either the CB(2) antagonist SR144528 (30 microg intraplantarly) or the CB(1) antagonist SR141716A (100 microg intraplantarly). WIN55,212-3, the enantiomer of the active compound, also failed to suppress carrageenan-evoked Fos protein expression. These data provide direct evidence that a peripheral cannabinoid mechanism suppresses the development of inflammation-evoked neuronal activity at the level of the spinal dorsal horn and implicate a role for CB(2) and CB(1) in peripheral cannabinoid modulation of inflammatory nociception.

Topics: Analgesics; Animals; Behavior, Animal; Benzoxazines; Camphanes; Cannabinoids; Carrageenan; Disease Models, Animal; Drug Administration Routes; Drug Interactions; Edema; Functional Laterality; Gene Expression Regulation; Immunohistochemistry; Inflammation; Male; Mechanoreceptors; Morpholines; Naphthalenes; Pain; Pain Measurement; Physical Stimulation; Piperidines; Proto-Oncogene Proteins c-fos; Pyrazoles; Rats; Rats, Sprague-Dawley; Rimonabant; Spinal Cord; Time Factors

This study sought to establish whether sensory neuropeptides and the capsaicin-sensitive fibres are involved in the nociception and oedema formation caused by intraplantar (i.pl.) injection of glutamate into the mouse paw. The i.pl. co-injection of the selective neurokinin (NK) NK(2) (SR 48968, 0.05-0.5 nmol/paw), and to a lesser extent the selective NK(1) (FK 888, 0.25-1.0 nmol/paw) receptor antagonists, resulted in a significant inhibition of glutamate-induced nociception. The percentages of inhibition were 82 and 37%, respectively. In contrast, the selective NK(3) receptor antagonist (SR 142801, 0.25-1.0 nmol/paw) failed to significantly affect glutamate-induced nociception. SR 48968, but not FK 888 or SR 142801, significantly inhibited (36%) glutamate-induced paw oedema formation. The i.pl. injection of kinin B(1) receptor antagonist des-Arg(9)-[Leu(8)]-BK (0.2-0.8 nmol/paw), but not the B(2) receptor antagonist HOE 140 (1.0-4.0 nmol/paw), together with glutamate, also inhibited glutamate-induced nociception (53%) in a graded manner, without affecting glutamate-induced paw oedema. The i.pl. co-injection of the calcitonin gene-related peptide (CGRP) receptor antagonist CGRP(8-37) (1 nmol/paw) failed to significantly inhibit glutamate-induced nociception or oedema. Finally, neonatal-capsaicin (50 mg/kg, s.c.) treatment inhibited glutamate-induced nociception by 69% and to a lesser extent glutamate-mediated oedema formation (30%). Collectively, the current results indicate that the nociception caused by i.pl. injection of glutamate in mice is clearly mediated by capsaicin-sensitive fibres and by release of neurokinins from sensory neurones that activate NK(2) receptors and to a lesser extent NK(1) receptors. Furthermore, kinins acting at B(1) (but not at B(2)) receptors also largely account for glutamate-mediated nociceptive behaviour response. In contrast, glutamate-induced paw oedema seems to be primarily mediated via activation of NK(2) receptors and stimulation of capsaicin-sensitive C-fibres. CGRP receptors do not seem to be involved in either of the glutamate responses.

Topics: Animals; Benzamides; Bradykinin Receptor Antagonists; Calcitonin Gene-Related Peptide; Capsaicin; Dipeptides; Edema; Foot; Glutamic Acid; Indoles; Male; Mice; Nerve Fibers; Neurokinin-1 Receptor Antagonists; Nociceptors; Pain; Piperidines; Receptor, Bradykinin B1; Receptor, Bradykinin B2; Receptors, Calcitonin Gene-Related Peptide; Receptors, Neurokinin-1; Receptors, Neurokinin-2

5-HT(1A) receptor activation by the very-high-efficacy, selective 5-HT(1A) receptor agonist F 13640 [(3-Chloro-4-fluoro-phenyl)-[4-fluoro-4-([(5-methyl-pyridin-2-ylmethyl)-amino]-methyl)piperidin-1-yl]-methanone] was recently discovered to constitute a novel central mechanism of broad-spectrum analgesia that, remarkably, grows rather than decays with chronicity. However, in rodents not exposed to nociception, F 13640 induces its analgesic effect only after having initially induced hyperalgesia. Numerical simulations implementing a signal transduction theory here show that the progressive increase in the intensity of nociceptive stimulation which F 13640 presumably mimics should eventually produce a large analgesic effect without initially causing marked pain. In vivo studies examined the effects of progressively increasing doses of F 13640 on the threshold of mechanically induced vocalization and, also, on the 5-HT syndrome in rats. The infusion of increasing (0.04-0.63 mg/rat/day) doses of F 13640 over a 5-week period induced a large analgesia preceded by a hyperalgesic effect that was small and comparable to that induced by initial exposure to a low, 0.04 mg/rat/day dose. Furthermore, increasing the dose of F 13640 induced tachyphylaxis to the 5-HT syndrome. Producing the mirror opposite of morphine's neuroadaptive actions, F 13640 causes an analgesia that becomes more powerful with chronic administration, and this at the expense of the initial hyperalgesia which it may also produce.

Topics: Algorithms; Analgesics; Animals; Body Temperature; Dose-Response Relationship, Drug; Drug Tolerance; Hyperalgesia; Male; Pain; Pain Threshold; Piperidines; Pyridines; Rats; Rats, Sprague-Dawley; Signal Transduction; Time Factors

Drug addiction poses serious social, medical, and economic problems, but effective treatments for drug addiction are still limited. Cocaine and morphine elevate dopamine levels in the nucleus accumbens (NAc), and the overwhelming actions of dopamine are implicated in reinforcement and addiction of abusive drugs. In our previous studies, we reported the regulatory role of acetylcholine (ACh) in the NAc function by selectively ablating the NAc cholinergic neurons with use of immunotoxin-mediated cell targeting. These studies indicated that ACh and dopamine acted convergently but oppositely on the NAc circuit and that cholinergic cell ablation enhanced long-lasting behavioral changes of cocaine addiction. In this investigation, we showed that immunotoxin-mediated ablation of the NAc cholinergic neurons enhanced not only the sensitivity to morphine in conditioned place preference but also negative reinforcement of morphine withdrawal in conditioned place aversion. Remarkably, acetylcholinesterase (AChE) inhibitors that act on the brain AChE suppressed both cocaine- and morphine-induced conditioned place preference and blocked the induction and persistence of cocaine-evoked hyperlocomotion. Importantly, this inhibition was abolished by ablation of the NAc cholinergic neurons. These results demonstrate that centrally active AChE inhibitors prevent long-lasting behavioral abnormalities associated with cocaine and morphine addictions by potentiating the actions of ACh released from the NAc cholinergic neurons. Centrally active AChE inhibitors could thus be approached as novel and potential therapeutic agents for drug addiction.

Topics: Acetylcholine; Animals; Cholinesterase Inhibitors; Cocaine; Cocaine-Related Disorders; Conditioning, Psychological; Donepezil; Indans; Male; Mice; Mice, Inbred C57BL; Morphine; Morphine Dependence; Nucleus Accumbens; Pain; Piperidines; Substance Withdrawal Syndrome

(3-Chloro-4-fluoro-phenyl)-[4-fluoro-4-[[(5-methyl-pyridin-2-ylmethyl)-amino]-methyl]piperidin-1-yl]-methadone (F 13640) is a recently discovered high-efficacy 5-hydroxytryptamine (HT)1A receptor agonist that produces central analgesia through the neuroadaptive mechanisms of inverse tolerance and cooperation. In a rat model of trigeminal neuropathic pain, the chronic constriction injury of the infraorbital nerve causes allodynia-like behavior that develops within 2 weeks and remains stable thereafter. We report that early after surgery, during which time allodynia develops, the continuous 2-week infusion of 0.63 mg/day F 13640 inhibited the allodynia-like behavior, whereas 5 mg/day morphine showed no significant effect. When F 13640 infusion was initiated late after surgery, when allodynia was well established, it produced an antiallodynic effect that was apparent during the entire infusion period. In contrast, morphine infusion caused an initially marked antiallodynic effect to which tolerance developed within the 2-week infusion period. The GABA-B receptor agonist baclofen (1.06 mg/day) that has a recognized usefulness in the treatment of trigeminal neuralgia, demonstrated effectiveness in both conditions. The data are consistent with a theory of nociceptive signal transduction, as well as with previous data, in demonstrating the neuroadaptive mechanisms of inverse tolerance and cooperation. That is, in contrast with morphine, the antiallodynic effect induced by 5-HT1A receptor activation does not decay, but, if anything, grows with chronicity. Also, 5-HT1A receptor activation seemed to cooperate with nociceptive stimulation in, paradoxically, inducing an antiallodynic effect. The data presented here suggest that F 13640 may perhaps offer a lasting treatment of trigeminal neuralgia.

Topics: Analgesics, Opioid; Analysis of Variance; Animals; Behavior, Animal; Disease Models, Animal; Male; Pain; Pain Measurement; Piperidines; Pyridines; Rats; Rats, Sprague-Dawley; Trigeminal Neuralgia

Pain associated with cancer and chronic musculoskeletal disorders can be difficult to control. We used murine models of cancer and inflammatory muscle pain to examine whether the cannabinoid receptor agonist WIN55,212-2 reduces hyperalgesia originating in deep tissues. C3H/He mice were anesthetized and implanted with osteolytic NCTC clone 2472 cells into the humeri or injected with 4% carrageenan into the triceps muscles of both forelimbs. At the time of peak hyperalgesia, WIN55,212-2 (1-30mg/kg) or vehicle was administered intraperitoneally and forelimb grip force was measured 0.5-24h later. WIN55,212-2 produced time- and dose-related antihyperalgesia in both models. A 10mg/kg dose of WIN55,212-2 fully reversed carrageenan-evoked muscle hyperalgesia. However, 30mg/kg of WIN55,212-2 attenuated tumor-evoked hyperalgesia only approximately 50%. After controlling for the difference in magnitude of hyperalgesia between the two models, WIN55,212-2 was still more potent at reducing hyperalgesia in the inflammatory model. In the cancer pain model, the antihyperalgesic effect of WIN55,212-2 was partially blocked by pretreatment with the selective CB1 (SR141716A) but not the CB2 (SR144528) receptor antagonist. In contrast, both antagonists blocked antihyperalgesic effects of WIN55,212-2 on carrageenan-evoked muscle hyperalgesia. Catalepsy and loss of motor coordination, known side effects of cannabinoids, did not account for the antihyperalgesia produced by WIN55,212-2. These data show that cannabinoids attenuate deep tissue hyperalgesia produced by both cancer and inflammatory conditions. Interestingly, cannabinoids differentially modulated carrageenan- and tumor-evoked hyperalgesia in terms of potency and receptor subtypes involved suggesting that differences in underlying mechanisms may exist between these two models of deep tissue pain.

Topics: Animals; Benzoxazines; Calcium Channel Blockers; Camphanes; Cannabinoids; Carrageenan; Catalepsy; Disease Models, Animal; Dopamine Antagonists; Dose-Response Relationship, Drug; Drug Interactions; Fibrosarcoma; Haloperidol; Hand Strength; Humerus; Hyperalgesia; Male; Mice; Mice, Inbred C3H; Morpholines; Myositis; Naphthalenes; Neoplasm Transplantation; Neoplasms; Pain; Piperidines; Psychomotor Performance; Pyrazoles; Receptors, Cannabinoid; Receptors, Drug; Rimonabant

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

Activation of cannabinoid CB(2) receptors attenuates thermal nociception in untreated animals while failing to produce centrally mediated effects such as hypothermia and catalepsy [Pain 93 (2001) 239]. The present study was conducted to test the hypothesis that activation of CB(2) in the periphery suppresses the development of inflammatory pain as well as inflammation-evoked neuronal activity at the level of the CNS. The CB(2)-selective cannabinoid agonist AM1241 (100, 330 micrograms/kg i.p.) suppressed the development of carrageenan-evoked thermal and mechanical hyperalgesia and allodynia. The AM1241-induced suppression of carrageenan-evoked behavioral sensitization was blocked by the CB(2) antagonist SR144528 but not by the CB(1) antagonist SR141716A. Intraplantar (ipl) administration of AM1241 (33 micrograms/kg ipl) suppressed hyperalgesia and allodynia following administration to the carrageenan-injected paw but was inactive following administration in the contralateral (noninflamed) paw, consistent with a local site of action. In immunocytochemical studies, AM1241 suppressed spinal Fos protein expression, a marker of neuronal activity, in the carrageenan model of inflammation. AM1241 suppressed carrageenan-evoked Fos protein expression in the superficial and neck region of the dorsal horn but not in the nucleus proprius or the ventral horn. The suppression of carrageenan-evoked Fos protein expression induced by AM1241 was blocked by coadministration of SR144528 in all spinal laminae. These data provide evidence that actions at cannabinoid CB(2) receptors are sufficient to suppress inflammation-evoked neuronal activity at rostral levels of processing in the spinal dorsal horn, consistent with the ability of AM1241 to normalize nociceptive thresholds and produce antinociception in inflammatory pain states.

Topics: Analgesics; Animals; Camphanes; Cannabinoids; Carrageenan; Disease Models, Animal; Drug Interactions; Hyperalgesia; Inflammation; Male; Nociceptors; Pain; Pain Threshold; Piperidines; Posterior Horn Cells; Proto-Oncogene Proteins c-fos; Pyrazoles; Rats; Rats, Sprague-Dawley; Reaction Time; Receptor, Cannabinoid, CB2; Receptors, Cannabinoid; Receptors, Drug; Rimonabant

Somatic noxious stimulation can evoke profound cardiovascular responses by altering activity in the autonomic nervous system. This noxious stimulation attenuates the cardiac vagal baroreflex, a key cardiovascular homeostatic reflex. This attenuation is mediated via NK1 receptors expressed on GABAergic interneurones within the nucleus of the solitary tract (NTS). We have investigated the effect of noxious stimulation and exogenous substance P (SP) on the sympathetic component of the baroreflex. We recorded from the sympathetic chain in a decerebrate, artificially perfused rat preparation. Noxious hindlimb pinch was without effect on the sympathetic baroreflex although the cardiac vagal baroreflex gain was decreased (56 %, P < 0.01). Bilateral NTS microinjection of SP (500 fmol) produced a similar selective attenuation of the cardiac vagal baroreflex gain (62 %, P < 0.005) without effect on the sympathetic baroreflex. Recordings from the cardiac sympathetic and vagal nerves confirmed the selectivity of the SP inhibition. Control experiments using a GABAA receptor agonist, isoguvacine, indicated that both components of the baroreflex (parasympathetic and sympathetic) could be blocked from the NTS injection site. The NTS microinjection of a NK1 antagonist (CP-99,994) in vivo attenuated the tachycardic response to hindlimb pinch. Our data suggest that noxious pinch releases SP within the NTS to selectively attenuate the cardiac vagal, but not the sympathetic, component of the baroreflex. This selective withdrawal of the cardiac vagal baroreflex seems to underlie the pinch-evoked tachycardia seen in vivo. Further, these findings confirm that baroreflex sympathetic and parasympathetic pathways diverge, and can be independently controlled, within the NTS.

Topics: Animals; Baroreflex; GABA Agonists; Heart; Hindlimb; Isonicotinic Acids; Male; Microinjections; Nociceptors; Pain; Parasympathetic Nervous System; Physical Stimulation; Piperidines; Rats; Rats, Wistar; Receptors, Neurokinin-1; Solitary Nucleus; Substance P; Sympathetic Nervous System; Tachycardia; Vagus Nerve

In the rat, antinociception of supraspinal origin is observed in response to administration of cocaine or an antagonist of the NMDA receptor for glutamate. The current study was conducted to determine if endocannabinoids are involved in the antinociceptive effect of cocaine, or antagonism of NMDA receptor binding. Intraperitoneal (i.p.) administration to male rats of cocaine, or the NMDA receptor antagonist, MK-801, resulted in a significant antinociceptive response of supraspinal origin, as indicated by a significant increase in reaction time in the hot plate test of analgesia (increase in the amount of time before the animal reacted to the hot plate by licking its paws or jumping). Treatment with SR141716A, a specific antagonist of the cannabinoid (CB1) receptor, resulted in a complete reversal of cocaine-induced antinociception when administered at a dose of 5.0mg/kg. Although the 2.5 and 5.0mg/kg doses of SR141716A produced a significant reduction in the antinociceptive effect of MK-801, the effect was incomplete since the reaction time in the hot plate test remained greater than that observed in vehicle-treated controls. These findings suggest that activation of the CB1 receptor participates significantly in antinociception resulting from treatment with cocaine and with the NMDA receptor antagonist, MK-801. The partial reversal of the antinociceptive effect of MK-801 by CB1 receptor antagonism indicates other mediators of nociception, in addition to the endocannabinoids, appear to be active in the antinociceptive response to NMDA receptor antagonism.

Topics: Anesthetics, Local; Animals; Cannabinoid Receptor Modulators; Cocaine; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Interactions; Excitatory Amino Acid Antagonists; Male; Pain; Pain Measurement; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Reaction Time; Receptors, Cannabinoid; Receptors, Drug; Receptors, N-Methyl-D-Aspartate; Rimonabant

The analgesic potential of cannabinoids may be hampered by their ability to produce aversive emotion when administered systemically. We investigated the hypothesis that the midbrain periaqueductal grey (PAG) is a common substrate mediating the anti-nociceptive and potential aversive effects of cannabinoids. The rat formalin test was used to model nociceptive behaviour. Intra-PAG microinjection of the excitatory amino acid D,L-homocysteic acid (DLH) was used to induce an aversive, panic-like reaction characteristic of the defensive "fight or flight" response. Administration of the cannabinoid receptor agonist HU210 (5 microg/rat) into the dorsal PAG significantly reduced the second phase of formalin-evoked nociceptive behaviour, an effect which was blocked by co-administration of the CB(1) receptor antagonist SR141716A (50 microg/rat). This anti-nociceptive effect was accompanied by an HU210-induced attenuation of the formalin-evoked increase in Fos protein expression in the caudal lateral PAG. Intra-dorsal PAG administration of HU210 (0.1, 1 or 5 microg/rat) significantly reduced the aversive DLH-induced explosive locomotor response. The anti-nociceptive effect of HU210 is likely to result from activation of the descending inhibitory pain pathway. Mechanisms mediating the anti-aversive effects of cannabinoids in the PAG remain to be elucidated. These data implicate a role for the PAG in both cannabinoid-mediated anti-nociceptive and anti-aversive responses.

Topics: Analysis of Variance; Animals; Behavior, Animal; Cannabinoid Receptor Agonists; Disinfectants; Dose-Response Relationship, Drug; Dronabinol; Drug Combinations; Escape Reaction; Excitatory Amino Acid Antagonists; Formaldehyde; Homocysteine; Immunohistochemistry; Male; Microinjections; Movement; Pain; Pain Measurement; Periaqueductal Gray; Piperidines; Proto-Oncogene Proteins c-fos; Pyrazoles; Rats; Rats, Sprague-Dawley; Rimonabant; Time Factors

Analgesic effects of cannabimimetic compounds have been known to be related to their central effects. Cannabinoid receptors also exist in the periphery but their role in pain perception has been remained to be clarified. Therefore, we assessed topical antinociceptive effects of WIN 55, 212-2, a mixed CB(1) and CB(2) receptors agonist, in mice using tail-flick test. Immersion of the tail of mouse into the WIN 55, 212-2 solution produced dose-dependent antinociception. This antinociceptive activity was limited to the portion of the tail exposed to WIN 55, 212-2. The antinociceptive response was dependent on duration of exposure to WIN 55, 212-2 solution. The topical antinociceptive effects of WIN 55, 212-2 were dose dependently blocked by topical pretreatment of CB(1) receptor-selective antagonist, AM 251. Thus, topical antinociceptive action of WIN 55, 212-2 involve CB(1) receptors. Intrathecal (i.th.) administration of WIN 55, 212-2 produced a dose-dependent antinociceptive effect. Interestingly, ineffective i.th. doses of WIN 55, 212-2 produced a marked antinociception when combined with topical application of WIN 55, 212-2 and topical antinociceptive effect was potentiated. The dose-response curve of i.th. WIN 55, 212-2 was shifted to the left 15-fold by topical WIN 55, 212-2. This finding suggests that there is an antinociceptive synergy between peripheral and spinal sites of cannabinoid action and it also implicates that local activation of cannabinoid system may regulate pain initiation in cutaneous tissue. Our findings support that cannabinoid system participates in buffering the emerging pain signals at the peripheral sites in addition to their spinal and supraspinal sites of action. In addition, an antinociceptive synergy between topical and spinal cannabinoid actions exists. These results also indicate that topically administered cannabinoid agonists may reduce pain without the dysphoric side effects and abuse potential of centrally acting cannabimimetic drugs.

Topics: Administration, Topical; Analgesics; Animals; Benzoxazines; Cannabinoids; Dose-Response Relationship, Drug; Injections, Spinal; Mice; Mice, Inbred BALB C; Morpholines; Naphthalenes; Nociceptors; Pain; Pain Measurement; Piperidines; Pyrazoles; Receptors, Cannabinoid; Receptors, Drug; Spinal Cord

Central neuropathic pain after spinal cord injury (SCI) presents a challenging clinical problem with limited treatment options. [(3-chloro-4-fluoro-phenyl)-[4-fluoro-4-([(5-methyl-pyridin-2-ylmethyl)-amino]-methyl)piperidin-1-yl]]-methadone (F 13640) is a recently discovered very-high-efficacy, selective 5-HT1A receptor agonist that produces a remarkably powerful, central analgesia through unprecedented neuroadaptive mechanisms. In a rat model of spinal cord injury pain, we previously found that chronic infusion of F 13640 alleviated pain-like behaviors. Here, we report that infusion of 0.63 mg/day of F 13640 for 8 weeks starting 24 h before the induction of injury significantly attenuates the development of chronic allodynia-like behavior in rats sustaining a photochemically-induced, ischaemic injury of the dorsal laminae of the L3-L5 segments of the spinal cord. Importantly, the preemptive effect of F 13640 persisted for 2 months after treatment was discontinued. The data warrant the study of the possible effects of the early administration of F 13640 in patients sustaining spinal cord injury.

Topics: Animals; Behavior, Animal; Cold Temperature; Female; Motor Activity; Pain; Pain Measurement; Pain Threshold; Photochemistry; Physical Stimulation; Piperidines; Pyridines; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT1A; Serotonin Receptor Agonists; Spinal Cord Injuries; Time Factors; Vocalization, Animal

Tachykinins are known to be involved in the processing of information leading to central sensitization and nociception. Using an animal model of repetitive colorectal distensions (CRD), we investigated the effect of spinal administration of tachykinin receptor antagonists in the mediation of visceral hypersensitivity. Intrathecal administration of the NK(1) receptor antagonist RP-67,580 (6.5 nmol) and the NK(3) receptor antagonist R-820 (6.5 nmol) completely blocked the CRD-induced hyperalgesia for both noxious and innocuous stimuli. The intrathecal administration of SR-48,968, a tachykinin NK(2) receptor antagonist, did not affect the visceral pain threshold of hypersensitive animals. Thus, the results from the present experiment support the concept that tachykinins with actions at spinal NK(1) and NK(3) but not NK(2) receptor sites are involved in visceral hypersensitivity mediated by nociceptive and non-nociceptive afferent inputs.

Topics: Animals; Benzamides; Digestive System; Hyperalgesia; Indoles; Injections, Spinal; Isoindoles; Male; Neurokinin-1 Receptor Antagonists; Nociceptors; Oligopeptides; Pain; Pain Threshold; Physical Stimulation; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Neurokinin-1; Receptors, Neurokinin-2; Receptors, Neurokinin-3; Receptors, Tachykinin; Visceral Afferents

The antinociceptive activity of (-)-spectaline (1), a piperidine alkaloid isolated from Cassia leptophylla Vog. (Leguminosae), was investigated. We have also studied the acute oral toxicity of 1 in mice and it did not show any signals of toxicity in doses lower than 400 micromol/kg. The antinociceptive effect of 1 was evaluated on chemical (acetic acid, formalin and capsaicin) and thermal (hot plate and tail flick) pain models in mice, using classical standard drugs. Dipyrone ID (50) = 14.68 micromol/kg (4.8 mg/kg), indomethacin ID (50) = 0.78 micromol/kg (0.28 mg/kg) and (-)-spectaline ID (50) = 48.49 micromol/kg (15.75 mg/kg), all produced a significant inhibition of acetic acid-induced abdominal writhing in mice. (-)-Spectaline was inactive in the hyperalgesic model of formalin and did not show any central analgesic activity (hot plate and tail flick models). In the capsaicin-induced neurogenic pain model, (-)-spectaline presented an important inhibitory effect with an ID (50) = 20.81 microg/paw and dipyrone ID (50) = 19.89 microg/paw. The ensemble of results permitted us to identify 1 as an antinociceptive compound. The mechanism underlying this antinociceptive effect of 1 remains unknown, but the results suggest that such an effect could be related to pathways associated to vanilloid receptor systems.

Topics: Acetic Acid; Alkaloids; Analgesics; Animals; Capsaicin; Cassia; Dipyrone; Dose-Response Relationship, Drug; Flowers; Formaldehyde; Fruit; Hot Temperature; Indomethacin; Male; Mice; Pain; Phytotherapy; Piperidines; Plant Extracts

Topics: Acute Disease; Aged; Aged, 80 and over; Analgesics, Opioid; Female; Humans; Pain; Pancreatitis; Piperidines; Remifentanil

Kappa-opioid receptors (KOR) have been implicated in neuroprotection from ischemic neuronal injury, but less work has been performed with transient focal cerebral ischemia to determine the role of KOR during reperfusion. We tested the effects of a selective and specific KOR agonist, BRL 52537 hydrochloride [(+/-)-1-(3,4-dichlorophenyl)acetyl-2-(1-pyrrolidinyl)methylpiperidine], and the standard KOR antagonist, nor-binaltorphimine dihydrochloride [nor-BNI; 17,17'-(dicyclopropylmethyl)-6,6',7,7'-6,6'-imino-7,7'-binorphinan-3,4',14,14'-tetrol], on functional and histological outcome after transient focal ischemia in the rat. By use of the intraluminal filament technique, halothane-anesthetized adult male Wistar rats were subjected to 2 h of middle cerebral artery occlusion confirmed by laser Doppler flowmetry. In a blinded, randomized fashion, rats were treated with 1). saline (vehicle) 15 min before reperfusion followed by saline at reperfusion for 22 h, 2). saline 15 min before reperfusion followed by BRL 52537 (1 mg x kg(-1) x h(-1)) at reperfusion for 22 h, 3). saline 15 min before reperfusion followed by nor-BNI (1 mg x kg(-1) x h(-1)) at reperfusion for 22 h, or 4) nor-BNI (1 mg/kg) 15 min before reperfusion followed by BRL 52537 (1 mgx kg(-1)x h(-1)) and nor-BNI (1 mg x kg(-1) x h(-1)) at reperfusion for 22 h. Infarct volume (percentage of ipsilateral structure) analyzed at 4 days of reperfusion was significantly attenuated in saline/BRL 52537 rats (n = 8; cortex, 10.2% +/- 4.3%; caudoputamen [CP], 23.8% +/- 6.7%) (mean +/- SEM) compared with saline/saline treatment (n = 8; cortex, 28.6% +/- 4.9%; CP, 53.3% +/- 5.8%). Addition of the specific KOR antagonist nor-BNI to BRL 52537 completely prevented the neuroprotection (n = 7; cortex, 28.6% +/- 5.3%; CP, 40.9% +/- 6.2%) conferred by BRL 52537. BRL 52537 did not produce postischemic hypothermia. These data demonstrate that KORs may provide a therapeutic target during early reperfusion after ischemic stroke.. The neuroprotective effect of selective kappa-opioid agonists in transient focal ischemia is via a selective action at the kappa-opioid receptors.

Topics: Animals; Behavior, Animal; Cerebral Cortex; Cranial Nerves; Functional Laterality; Gait; Hemodynamics; Ischemic Attack, Transient; Laser-Doppler Flowmetry; Male; Middle Cerebral Artery; Muscle Tonus; Naltrexone; Neuroprotective Agents; Pain; Piperidines; Putamen; Pyrrolidines; Rats; Rats, Wistar; Receptors, Opioid, kappa; Weight Loss

Topics: Analgesia, Obstetrical; Analgesia, Patient-Controlled; Analgesics, Opioid; Female; Humans; Nurse Midwives; Obstetric Labor Complications; Pain; Patient Selection; Piperidines; Pregnancy; Remifentanil

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

We present a method for investigating the dynamic pharmacological modulation of pain-related brain activity, measured by BOLD-contrast fMRI. Noxious thermal stimulation was combined with a single infusion and washout of remifentanil, a short-acting opioid analgesic agent. The temporal profile of the effect site concentration of remifentanil, estimated from a pharmacokinetic model, was incorporated into a linear model of the fMRI data. The methodology was tested in nine healthy male subjects. During each imaging session the subjects received noxious thermal stimulation to the back of the left hand, prior to infusion, during infusion to a remifentanil effect site concentration of 1.0 ng/ml, and during washout of the remifentanil. Infusions were repeated with saline. Remifentanil-induced analgesia was confirmed from subjective pain intensity scores. Pain-related brain activity was identified in a matrix of regions using a linear model of the transient BOLD responses to noxious stimulation. Of those regions, there was a significant fractional reduction in the amplitude of the pain-related BOLD response in the insular cortex contralateral to the stimulus, the ipsilateral insular cortex, and the anterior cingulate cortex. Statistical parametric mapping of the component of pain-related BOLD responses that was linearly scaled by remifentanil concentration confirmed the contralateral insular cortex as the pain-processing region most significantly modulated by remifentanil compared to saline. The mapping of specific modulation of pain-related brain activity is directly relevant for understanding pharmacological analgesia. The method of examining time-dependent pharmacological modulation of specific brain activity may be generalized to other drugs that modulate brain activity other than that associated with pain.

Topics: Analgesics, Opioid; Brain; Brain Mapping; Cerebrovascular Circulation; Humans; Magnetic Resonance Imaging; Male; Models, Neurological; Oxygen; Pain; Pain Measurement; Piperidines; Remifentanil; Time Factors

Improgan, a nonopioid antinociceptive agent, activates descending, pain-relieving mechanisms in the brain stem, but the receptor for this compound has not been identified. Because cannabinoids also activate nonopioid analgesia by a brain stem action, experiments were performed to assess the significance of cannabinoid mechanisms in improgan antinociception. The cannabinoid CB(1) antagonist N-(piperidin-1-yl)-5-(4-chloro phenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716A) induced dose-dependent inhibition of improgan antinociception on the tail-flick test after i.c.v. administration in rats. The same treatments yielded comparable inhibition of cannabinoid [R-(+)-(2,3-dihydro-5-methyl-3-[(4-mor pholinyl)methyl]pyrol[1,2,3-de]-1,4-benzoxazin-6-yl)(1-naphthalenyl)methanone monomethanesulfonate, WIN 55,212-2] analgesia. Inhibition of improgan and WIN 55,212-2 antinociception by SR141716A was also observed in Swiss-Webster mice. Radioligand binding studies showed no appreciable affinity of improgan on rat brain, mouse brain, and human recombinant CB(1) receptors, ruling out a direct action at these sites. To test the hypothesis that CB(1) receptors indirectly participate in improgan signaling, the effects of improgan were assessed in mice with a null mutation of the CB(1) gene with and without SR141716A pretreatment. Surprisingly, improgan induced complete antinociception in both CB(1) (-/-) and wild-type control [CB(1) (+/+)] mice. Furthermore, SR141716A inhibited improgan antinociception in CB(1) (+/+) mice, but not in CB(1) (-/-) mice. Taken together, the results show that SR141716A reduces improgan antinociception, but neither cannabinoids nor CB(1) receptors seem to play an obligatory role in improgan signaling. Present and previous studies suggest that Delta(9)-tetrahydrocannabinol may act at both CB(1) and other receptors to relieve pain, but no evidence was found indicating that improgan uses either of these mechanisms. SR141716A will facilitate the study of improgan-like analgesics.

Topics: Analgesics; Animals; Brain; Cannabinoid Receptor Modulators; Cannabinoids; Cerebral Ventricles; Cimetidine; Dronabinol; Endocannabinoids; Hot Temperature; Injections, Intraventricular; Male; Mice; Pain; Piperidines; Pyrazoles; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptors, Cannabinoid; Receptors, Drug; Rimonabant; Time Factors

There is limited information regarding the integration of visceral and somatic afferents within the nucleus of the solitary tract (NTS). We studied the interaction of nociceptive and baroreceptive inputs in this nucleus in an in situ arterially perfused, un-anaesthetized decerebrate preparation of rat. At the systemic level, the gain of the cardiac component of the baroreceptor reflex was attenuated significantly by noxious mechanical stimulation of a forepaw. This baroreceptor reflex depression was mimicked by NTS microinjection of substance P and antagonized by microinjection of either bicuculline (a GABAA receptor antagonist) or a neurokinin type 1 (NK1) receptor antagonist (CP-99994). The substance P effect was also blocked by a bilateral microinjection of bicuculline, at a dose that was without effect on basal baroreceptor reflex gain. Baroreceptive NTS neurons were defined by their excitatory response following increases in pressure within the ipsilateral carotid sinus. In 27 of 34 neurons the number of evoked spikes from baroreceptor stimulation was reduced significantly by concomitant electrical stimulation of the brachial nerve (P < 0.01). Furthermore, the attenuation of baroreceptor inputs to NTS neurons by brachial nerve stimulation was prevented by pressure-ejection of bicuculline from a multi-barrelled microelectrode (n = 8). In a separate population of 17 of 45 cells tested, brachial nerve stimulation evoked an excitatory response that was antagonized by blockade of NK1 receptors. We conclude that nociceptive afferents activate NK1 receptors, which in turn excite GABAergic interneurons impinging on cells mediating the cardiac component of the baroreceptor reflex.

Topics: Animals; Baroreflex; Bicuculline; Electrophysiology; GABA Antagonists; gamma-Aminobutyric Acid; Microinjections; Neural Inhibition; Neurokinin-1 Receptor Antagonists; Nociceptors; Pain; Pain Measurement; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, GABA-A; Receptors, Neurokinin-1; Solitary Nucleus; Substance P

The present study examines the effect of combinations of gabapentin (Neurontin) and a selective neurokinin (NK)(1) receptor antagonist, 1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-[(1-phenylethyl)amino]ethyl]-2-benzofuranylmethyl ester (CI-1021), in two models of neuropathic pain. Dose responses to both gabapentin and CI-1021 were performed against static allodynia induced in the streptozocin and chronic constriction injury (CCI) models. Theoretical additive lines were calculated from these data. Dose responses to various fixed dose ratios of a gabapentin/CI-1021 combination were then examined in both models. In the streptozocin model, administration of gabapentin/CI-1021 combinations at fixed dose ratios of 1:1 and 60:1 resulted in an additive effect with dose response similar to the theoretical additive line. However, a synergistic interaction was seen after fixed dose ratios of 10:1, 20:1, and 40:1 with static allodynia completely blocked and the dose responses shifted approximately 8-, 30-, and 10-fold leftward, respectively, from the theoretical additive values. In the CCI model, after fixed dose ratios of 5:1 and 20:1, combinations of gabapentin and CI-1021 produced an additive response. At the fixed dose ratio of 10:1 static allodynia was completely blocked with an approximate 10-fold leftward shift of the dose response from the theoretical additive value, indicating synergy. The combination of gabapentin with a structurally unrelated NK(1) receptor antagonist, (2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine (CP-99,994), also produced synergy, at a fixed dose ratio of 20:1. This ratio completely blocked streptozocin-induced static allodynia and was approximately shifted leftward 5-fold from the theoretical additive value. These data suggest a synergistic interaction between gabapentin and NK(1) receptor antagonists in animal models of neuropathic pain.

Topics: Acetates; Amines; Animals; Benzofurans; Carbamates; Cyclohexanecarboxylic Acids; Diabetes Mellitus, Experimental; Dose-Response Relationship, Drug; Drug Synergism; Excitatory Amino Acid Antagonists; Gabapentin; gamma-Aminobutyric Acid; Male; Neurokinin-1 Receptor Antagonists; Pain; Pain Measurement; Peripheral Nervous System Diseases; Piperidines; Rats; Rats, Sprague-Dawley

We report the discovery of F 13640 and evidence suggesting this agent to produce powerful, broad-spectrum analgesia by novel molecular and neuroadaptative mechanisms. F 13640 stimulates G(alphaomicron) protein coupling to 5-HT(1A) receptors to an extent unprecedented by selective, non-native 5-HT(1A) ligands. Fifteen minutes after its injection in normal rats, F 13640 (0.01-2.5 mg/kg) decreases the vocalization threshold to paw pressure; 15 min upon injection in rats that are exposed to formalin-induced tonic nociception, F 13640 inhibits pain behavior. The initial hyperalgesia induced by 0.63 mg/kg F 13640 was followed, 8 hrs later, by paradoxical hypo-algesia; 5 mg/kg of morphine produces the opposite effects (i.e., hypo-algesia followed by hyper-algesia). Repeated F 13640 injections cause an increase in the basal vocalization threshold and a reduction of F 13640-produced hyperalgesia; in these conditions, morphine causes basal hyperalgesia and antinociceptive tolerance. Continuous two-week infusion of F 13640 (0.63 mg/day) exerts little effect on the threshold in normal rats, but markedly reduces analgesic self-administration in arthritic rats. F 13640 infusion also decreases allodynic responses to tactile and thermal stimulations in rats sustaining spinal cord or sciatic nerve injury. In these models of chronic nociceptive and neuropathic pain, the analgesia afforded by F 13640 consistently surpasses that of morphine (5 mg/day), imipramine (2.5 mg/day), ketamine (20 mg/day) and gabapentin (10 mg/day). Very-high-efficacy 5-HT(1A) receptor activation constitutes a novel mechanism of central analgesia that grows rather than decays with chronicity, that is amplified by nociceptive stimulation, and that may uniquely relieve persistent nociceptive and neuropathic pains.

Topics: Acetates; Adrenergic Uptake Inhibitors; Amines; Aminopyridines; Analgesia; Analgesics; Animals; Cells, Cultured; CHO Cells; Cricetinae; Cyclohexanecarboxylic Acids; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Routes; Drug Administration Schedule; Drug Synergism; Female; Fentanyl; Gabapentin; gamma-Aminobutyric Acid; Guanosine 5'-O-(3-Thiotriphosphate); Hyperalgesia; Imipramine; Ketamine; Male; Morphine; Pain; Pain Measurement; Pain Threshold; Piperidines; Pyridines; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptors, Serotonin; Receptors, Serotonin, 5-HT1; Serotonin Agents; Time Factors; Transfection

Bioactivity guided isolation of the bark of Careya arborea afforded piperine--an alkaloid chemically known as 1-[5-(1,3-benzodioxol-5-yl)-1-oxo-2,4-pentadienyl]piperidine, which was found to possess significant central and peripheral analgesic activity. At oral doses of 10, 20 and 30 mg/kg body weight, piperine exhibited 41 (p < 0.01), 45 (p < 0.01) and 53% (p < 0.001) inhibition of acetic acid induced writhing in mice respectively. At doses of 20 and 30 mg/kg body weight, the compound also showed 31.8 (p < 0.05) and 52.4% (p < 0.01) prolongation of tail flicking time of mice 30 min after the treatments determined by the radiant heat method.

Topics: Acetic Acid; Alkaloids; Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Bangladesh; Behavior, Animal; Benzodioxoles; Female; Lecythidaceae; Magnetic Resonance Spectroscopy; Male; Mass Spectrometry; Mice; Pain; Pain Measurement; Piperidines; Plant Epidermis; Plant Extracts; Polyunsaturated Alkamides; Reaction Time

The effects of acute intraperitoneal injections of the 5-HT(1A) receptor agonists F 13640 [(3-chloro-4-fluoro-phenyl)-[4-fluoro-4-[[(5-methyl-pyridin-2-ylmethyl)-amino]-methyl]piperidin-1-yl]-methadone] and F 13714 [3-chloro-4-fluorophenyl-(4-fluoro-4-[[(5-methyl-6-methylamino-pyridin-2-ylmethyl)-amino]-methyl]-piperidin-1-yl-methanone] were studied in comparison with those of baclofen and morphine on responsiveness to von Frey hair stimulation after chronic constriction injury to the rat's infraorbital nerve (IoN-CCI). Following IoN-CCI, an ipsilateral hyperresponsiveness developed that remained stable in control rats throughout the period of drug testing. F 13640, F 13714, baclofen and morphine dose-dependently decreased the hyperresponsiveness; normalization of the response occurred at doses 0.63, 0.04, 5 and 10 mg/kg, respectively. Confirming earlier data, baclofen's effects further validate IoN-CCI as a model of trigeminal neuralgia. The effects of F 13640 and F 13714 are initial evidence that 5-HT(1A) receptor agonists produce profound analgesia in the IoN-CCI model. The present data extend recent evidence that high-efficacy 5-HT(1A) receptor activation constitutes a new mechanism of central analgesia the spectrum of which may also encompass trigeminal neuropathic pain.

Topics: Aminopyridines; Animals; Baclofen; Behavior, Animal; Disease Models, Animal; Dose-Response Relationship, Drug; Male; Morphine; Muscle Relaxants, Central; Narcotics; Pain; Piperidines; Pyridines; Rats; Rats, Sprague-Dawley; Receptors, Serotonin; Receptors, Serotonin, 5-HT1; Serotonin Receptor Agonists; Stress, Mechanical; Trigeminal Neuralgia

Topics: Aged; Analgesics; Colonoscopy; Drug Evaluation; Humans; Hypnotics and Sedatives; Middle Aged; Nausea; Pain; Patient Satisfaction; Piperidines; Propofol; Remifentanil

The tricyclic compound (R)-1-(3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-propyl)-3-piperidine carboxylic acid (ReN 1869) is a novel, selective histamine H(1) receptor antagonist. It is orally available, well tolerated, easily enters the central nervous system (CNS) but no adverse effects are seen in mice at 300 mg/kg. ReN 1869 at 0.01-10 mg/kg is antinociceptive in tests of chemical nociception in rodents (formalin, capsaicin, phenyl quinone writhing) but not in thermal tests (hot plate and tail flick). ReN 1869 amplifies the analgesic action of morphine but does not show tolerance after chronic dosing. Moreover, the compound is effective against inflammation of neurogenic origin (antidromic nerve stimulation, histamine-evoked edema) but not in carrageenan-induced inflammation. We suggest that ReN 1869, via H(1) blockade, counteracts the effect of histamine liberated from activated mast cells and inhibits pain transmission in the dorsal spinal cord. ReN 1869 represents a new class of antihistamines with pain-relieving properties that probably is mediated centrally through histamine H(1) receptors but alternative mechanisms of action cannot be excluded.

Topics: Animals; Benzoquinones; Binding Sites; Calcitonin Gene-Related Peptide; Calcium; Calcium Channels; Capsaicin; Carrageenan; Central Nervous System; CHO Cells; Cricetinae; Disease Models, Animal; Edema; Extravasation of Diagnostic and Therapeutic Materials; Gene Expression; Guinea Pigs; Histamine; Histamine H1 Antagonists; In Vitro Techniques; Mice; Neurogenic Inflammation; Pain; Pain Measurement; Piperidines; Proto-Oncogene Proteins c-fos; Pyrilamine; Rats; Rats, Sprague-Dawley; Receptors, Histamine H1; Species Specificity; Spinal Cord; Transfection; Tritium

1. Orphanin FQ (OFQ), an endogenous peptide for ORL1 receptors, has been identified. Although the actions of OFQ have much in common with those of opioid peptides at the cellular level, behavioral studies in rodents seem conflicting. 2. The aim of this study was to investigate the potential pronociceptive or antinociceptive function of peripheral ORL1 receptors in primates. Experiments were conducted to verify whether local administration of OFQ can attenuate capsaicin-induced nociception and whether peripheral ORL1 receptors selectively mediate the local action of OFQ in monkeys. 3. Capsaicin (100 microg) was administered subcutaneously in the tail to locally evoke a nociceptive response (thermal allodynia/hyperalgesia), which was manifested as a reduced tail-withdrawal latency in normally innocuous 46 degreeC warm water. 4. Co-administration of OFQ (1--30 microg) with capsaicin in the tail dose-dependently inhibited thermal nociception. However, a locally effective dose of OFQ (30 microg), when applied in the back, did not inhibit capsaicin-induced nociception. 5. OFQ-induced local antinociception was antagonized by a small dose (10 microg) of J-113397, a selective ORL1 receptor antagonist, in the tail. Similarly, s.c. administration of 10 microg of J-113397 in the back did not antagonize local antinociception of OFQ. 6. In addition, s.c. administration of either OFQ or J-113397 in the tail alone did not change its thermal nociceptive threshold. Local administration of opioid receptor antagonists selective for mu, kappa, and delta opioid receptors did not antagonize OFQ-induced local antinociception. Local administration of J-113397 also did not interfere with the local actions of mu, kappa, and delta opioid agonists in the tail. 7. These results provide the first functional evidence that activation of peripheral ORL1 receptors produces thermal antinociception in primates and this action is independent of antinociception produced at classical opioid receptors.

Topics: Animals; Benzimidazoles; Capsaicin; Female; Heating; Macaca mulatta; Male; Nociceptin; Nociceptin Receptor; Opioid Peptides; Pain; Piperidines; Receptors, Opioid; Tail

Irritable bowel syndrome (IBS) is a common disorder mainly characterized by altered bowel habits and visceral pain. In this study, we investigated the role of tachykinin NK1 receptors in the visceral pain response (abdominal muscle contraction) caused by colorectal distention in rabbits previously subjected to colonic irritation, using the selective tachykinin NK1 receptor antagonists TAK-637 [(aR,9R)-7-[3,5-Bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4] diazocino[2,1-g][1,7]naphthyridine-6,13-dione] and (+/-)-CP-99,994 (+/-)-(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine. Intracolorectal administration of 0.8% acetic acid solution enhanced the nociceptive response to colorectal distention, producing a significant increase in the number of abdominal muscle contractions. Under these conditions, intraduodenal TAK-637 (0.1-3 mg/kg) dose dependently decreased the number of distention-induced abdominal contractions, and a significant inhibitory effect was observed with doses of 0.3 to 3 mg/kg. Another tachykinin NK1 antagonist, (+/-)-CP-99,994, also reduced the number of abdominal contractions. In contrast, the enantiomer of TAK-637 (which has very weak tachykinin NK1 receptor antagonistic activity), trimebutine maleate, ondansetron, and atropine sulfate did not inhibit the abdominal response. The main metabolite of TAK-637, which has more potent tachykinin NK1 receptor antagonistic activity but permeates the central nervous system less well than TAK-637, produced less inhibition of the viscerosensory response. When given intrathecally, TAK-637 and (+/-)-CP-99,994 markedly reduced the number of abdominal contractions. These results suggest that tachykinin NK1 receptors play an important role in mediating visceral pain and that TAK-637 inhibits the viscerosensory response to colorectal distention by antagonizing tachykinin NK1 receptors, mainly in the spinal cord. They also suggest that TAK-637 may be useful in treating functional bowel disorders such as IBS.

Topics: Acetates; Animals; Catheterization; Central Nervous System; Colon; Irritants; Male; Naphthyridines; Neurokinin-1 Receptor Antagonists; Pain; Peripheral Nervous System; Physical Stimulation; Piperidines; Rabbits; Rectum; Sensation

Activation of cannabinoid receptors causes inhibition of spasticity, in a mouse model of multiple sclerosis, and of persistent pain, in the rat formalin test. The endocannabinoid anandamide inhibits spasticity and persistent pain. It not only binds to cannabinoid receptors but is also a full agonist at vanilloid receptors of type 1 (VR1). We found here that vanilloid VR1 receptor agonists (capsaicin and N-N'-(3-methoxy-4-aminoethoxy-benzyl)-(4-tert-butyl-benzyl)-urea [SDZ-249-665]) exhibit a small, albeit significant, inhibition of spasticity that can be attenuated by the vanilloid VR1 receptor antagonist, capsazepine. Arvanil, a structural "hybrid" between capsaicin and anandamide, was a potent inhibitor of spasticity at doses (e.g. 0.01 mg/kg i.v.) where capsaicin and cannabinoid CB(1) receptor agonists were ineffective. The anti-spastic effect of arvanil was unchanged in cannabinoid CB(1) receptor gene-deficient mice or in wildtype mice in the presence of both cannabinoid and vanilloid receptor antagonists. Likewise, arvanil (0.1-0.25 mg/kg) exhibited a potent analgesic effect in the formalin test, which was not reversed by cannabinoid and vanilloid receptor antagonists. These findings suggest that activation by arvanil of sites of action different from cannabinoid CB(1)/CB(2) receptors and vanilloid VR1 receptors leads to anti-spastic/analgesic effects that might be exploited therapeutically.

Topics: Animals; Arachidonic Acids; Benzoxazines; Camphanes; Cannabinoid Receptor Modulators; Capsaicin; Disease Models, Animal; Dose-Response Relationship, Drug; Genotype; Mice; Mice, Inbred Strains; Mice, Knockout; Morpholines; Multiple Sclerosis; Muscle Spasticity; Naphthalenes; Pain; Pain Measurement; Piperidines; Pyrazoles; Receptors, Cannabinoid; Receptors, Drug; Rimonabant

This study investigates the effect of microinjections of capsaicin in the periaqueductal grey matter of rats on nociceptive behaviour and the possible interactions with NMDA and mGlu receptors. Intra-periaqueductal grey microinjection of capsaicin (1-3-6 nmol/rat) increased the latency of the nociceptive reaction in the plantar test. This effect was prevented by pretreatment with capsazepine (6 nmol/rat), which had no effect per se on the latency of the nociceptive reaction. 7-(Hydroxyimino)cyclopropa[b]chromen-1alpha-carboxylate ethyl ester (CPCCOEt, 50 nmol/rat) and 2-Methyl-6-(phenylethynyl)pyridine (MPEP, 50 nmol/rat), antagonists of mGlu(1) and mGlu(5) receptors, respectively, completely blocked the effect of capsaicin. Similarly, pretreatment with DL-2-Amino-5-phosphonovaleric acid (DL-AP5, 5 nmol/rat) and riluzole (4 nmol/rat), an NMDA receptor antagonist and a voltage-dependent Na(+) channels blocker which inhibits glutamate release, respectively, completely antagonized the effect of capsaicin. However, pretreatment with (2S)-alpha-Ethylglutamic acid (30 nmol/rat) and (RS)-alpha-Methylserine-O-phosphate (MSOP, 30 nmol/rat), antagonists of group II and group III mGlu receptors, respectively, had no effects on capsaicin-induced analgesia. Similarly, pretreatment with N-(piperidin-1-yl)-5-(4-chlophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR 141716A, 5 pmol/rat), a selective cannabinoid CB(1) receptor antagonist, did not affect the capsaicin-induced antinociception. In conclusion, this study shows that capsaicin might produce antinociception at the periaqueductal grey level by increasing glutamate release, which activates postsynaptic group I mGlu and NMDA receptors.

Topics: 2-Amino-5-phosphonovalerate; Animals; Capsaicin; Chromones; Excitatory Amino Acid Antagonists; Male; Pain; Periaqueductal Gray; Phosphoserine; Piperidines; Protein Binding; Pyrazoles; Pyridines; Rats; Rats, Wistar; Receptors, Drug; Receptors, Glutamate; Riluzole; Rimonabant; Time Factors

The role of duration of action on the relative reinforcing effects of three opioid drugs (fentanyl, alfentanil, and remifentanil) was evaluated. Duration and onset of action were determined using measures of respiratory depression and antinociception after i.v. administration. Effects on minute volume of respiration indicated that each of the three opioids had immediate onsets of action after i.v. administration. Fentanyl's duration of suppression of respiration and antinociception was longer than that of alfentanil, which was longer than that of remifentanil. Reinforcing strength was measured in i.v. self-administration studies in which the fixed ratio resulting in drug administration was increased from one session to the next. Comparisons were made of the behavioral economic variables P(max) and area under the demand curve (O(max)). Remifentanil maintained higher rates of responding than did alfentanil, and alfentanil maintained higher rates of responding than did fentanyl. When normalized demand functions were compared, however, the drugs did not differ significantly from each other in terms of P(max) or O(max). These data agree with those of others who have suggested that duration of action is not an important contributor to drugs' reinforcing strength.

Topics: Alfentanil; Analgesics, Opioid; Animals; Female; Fentanyl; Injections, Intravenous; Macaca mulatta; Male; Pain; Pain Measurement; Piperidines; Remifentanil; Respiration; Self Administration

The acute administration of the neurosteroid precursor, progesterone (10 mg/kg, s.c.) produced significant hyperphagia in female mice as observed at 0.5-, 1-, 2- and 3-h time intervals. At this dose progesterone also produced significant increase in immobility period duration in Porsolt's forced swim test and nociceptive response in hot-plate and tail-flick tests. Treatment with direct (quipazine, 5 mg/kg, i.p.) and indirect (fluoxetine, 10 mg/kg, i.p.) acting serotonergic agents per se produced significant hypophagia, decrease in immobility period and induced analgesic effect in hot-plate and tail-flick test. Further, treatment with both fluoxetine (10 mg/kg, i.p.) and quipazine (5 mg/kg, i.p.) significantly reversed progesterone-induced hyperphagia, depression and algesia in the female mice. Pretreatment with seganserin, a 5-HT(2) receptor antagonist (2 mg/kg, i.p.) significantly reversed fluoxetine and quipazine-induced antidepressant and analgesic effects. Seganserin reversed quipazine-induced hypophagia but in a replicate study it failed to reverse fluoxetine-induced hypophagia. Further, seganserin, 2 mg/kg, i.p., significantly reversed the suppressive effect of fluoxetine and quipazine on progesterone-induced hyperphagia, depression and algesia in hot-plate test. Seganserin also reversed the suppressive effect of fluoxetine and quipazine on progesterone-induced algesia in hot-plate test. These data suggest that the modulation of progesterone-induced effects by these serotonergic agents possibly involve 5-HT(2) receptor mechanisms. Further, the study underscores the use of serotonergic agents for the treatment of eating and affective disorders caused by the regular changes or disturbances of ovarian steroid levels in females.

Topics: Analgesics; Animals; Antidepressive Agents, Second-Generation; Brain; Depression; Disease Models, Animal; Drug Interactions; Female; Fluoxetine; Hyperphagia; Menstrual Cycle; Mice; Mice, Inbred Strains; Motor Activity; Pain; Pain Measurement; Piperidines; Progesterone; Quipazine; Receptors, Serotonin; Serotonin; Serotonin Antagonists

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

Dietary factors can modulate visceral sensitivity and are suggested to interact with neuroimmune pathways. To determine whether daily low-level exposure to a food contaminant (diquat) alters sensitivity to gastric distension (GD) and the role of mast cells and tachykinin receptors activation, two series of experiments were conducted in eight groups of eight male Wistar rats (200-250 g) receiving daily doses of either diquat (0.1 mg/kg per day orally) or water for 21 days. In the first series, rats were sacrificed at the end of treatments and the gastric mucosal mast cell (MMC) number was histologically quantified. In the second series, after 21 days of treatment the cardiovascular depressor (CVD) response and corresponding gastric volumes were recorded under GD (from 10 to 40 mmHg). Doxantrazole (5 mg/kg intraperitoneally (i.p.)), a mast cell stabilizer, and SR 140333 (1 mg/kg i.p.) and MEN 11420 (0.1 mg/kg intravenously), respectively NK1 and NK2 receptor antagonists, were administered before GD. Before and after GD, blood samples were taken to measure blood histamine and the gastric MMC number was determined after sacrifice. Diquat treatment increased the MMC number. In diquat-treated rats, GD increased the CVD response and blood histamine level and induced MMC degranulation. Doxantrazole did not modify the hypersensitivity to GD but prevented mast cell degranulation. Both NK1 and NK2 receptor antagonists blocked the enhanced CVD response induced by diquat and prevented mast cell degranulation. None of the drugs had any effect in control animals. Prolonged exposure to a food contaminant at doses possibly found in food increases gastric sensitivity to distension, activates tachykinin receptors and results in MMC degranulation after GD.

Topics: Animals; Blood Pressure; Bronchodilator Agents; Diquat; Food Contamination; Gastric Dilatation; Herbicides; Histamine; Male; Mast Cells; Nociceptors; Pain; Peptides, Cyclic; Phosphodiesterase Inhibitors; Piperidines; Quinuclidines; Rats; Rats, Wistar; Receptors, Neurokinin-1; Receptors, Neurokinin-2; Stomach; Thioxanthenes; Xanthones

Donepezil, an oral acetylcholinesterase inhibitor approved for the treatment of Alzheimer's disease, was given to 6 cancer pain patients having sedation related to the analgesic use of opioids. Each patient was taking more than 200 mg of oral morphine equivalents per day, and several were receiving complex analgesic regimens consisting of multiple adjuvant medications. Sedation improved at least moderately in 5 of the patients and mildly in 1 after they began taking donepezil. Patients reported a decrease in episodes of spontaneous sleeping during the day, fewer myoclonic twitches, improved daily function and greater social interaction. Several also reported improved sleep at night. Analgesia was not compromised by the use of donepezil, and in some cases it appeared improved. Donepezil may be a valuable alternative to psychostimulants in the treatment of opioid-induced sedation. A prospective controlled trial comparing the treatment effects of psychostimulants and donepezil on patients having opioid-induced sedation is underway.

Topics: Adult; Aged; Analgesics, Opioid; Cholinesterase Inhibitors; Donepezil; Female; Humans; Indans; Male; Middle Aged; Pain; Piperidines; Sleep Stages

The authors investigated the role of endogenously released nociceptin (also known as orphanin FQ) spinal and supraspinal nociceptive transmission during the rat formalin test by examining the effect of intrathecal and intracerebroventricular injection of J-113397, a non-peptidyl ORL1 receptor selective antagonist. When J-113397 was injected intrathecally or intracerebroventricularly 10 min before the formalin injection, it enhanced the agitation behavior induced by paw formalin injection. This suggested that paw formalin injection induced nociceptin release in the spinal cord and the supraspinal brain sites, that this endogenously released nociceptin produced an analgesic effect and that J-113397 antagonized this analgesic effect of nociceptin and produced an algesic effect in the rat formalin test.

Topics: Animals; Benzimidazoles; Brain; Dose-Response Relationship, Drug; Efferent Pathways; Injections, Intraventricular; Injections, Spinal; Male; Motor Activity; Narcotic Antagonists; Neurons; Nociceptin; Nociceptin Receptor; Nociceptors; Opioid Peptides; Pain; Pain Measurement; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Opioid; Spinal Cord

The analgesic properties of the synthetic cannabinoid WIN55,212-2 were investigated in a model of neuropathic pain. In male Wistar rats, bilateral hind limb withdrawal thresholds to cold, mechanical and noxious thermal stimuli were measured. Following this, unilateral L5 spinal nerve ligation was performed. Seven days later, sensory thresholds were reassessed and the development of allodynia to cold and mechanical stimuli and hyperalgesia to a noxious thermal stimulus confirmed. The effect of WIN55,212-2 (0.1 - 5.0 mg kg(-1), i.p.) on the signs of neuropathy was then determined; there was a dose related reversal of all three signs of painful neuropathy at doses which did not generally alter sensory thresholds in the contralateral unligated limb. This effect was prevented by co-administration of the CB(1) receptor antagonist SR141716a, but not by co-administration of the CB(2) receptor antagonist SR144528, suggesting this action of WIN55,212-2 is mediated via the CB(1) receptor. Administration of SR141716a alone had no affect on the observed allodynia and hyperalgesia, which does not support the concept of an endogenous analgesic tone. These data indicate that cannabinoids may have therapeutic potential in neuropathic pain, and that this effect is mediated through the CB(1) receptor.

Topics: Analgesics; Animals; Benzoxazines; Cannabinoids; Disease Models, Animal; Drug Interactions; Hyperalgesia; Male; Morpholines; Naphthalenes; Pain; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB2; Receptors, Cannabinoid; Receptors, Drug; Rimonabant

We investigated the effect of topical application of capsaicin cream on withdrawal latency in the hind foot of rat in response to radiant heat in an experimental model of neuropathic pain. A neuropathic state was induced by loose ligation of the sciatic nerve with chromic gut suture. A marked thermal hyperalgesia was observed in response to heat stimulus applied to the operated side from 3 days through 2 weeks, followed by a gradual return to the control level by 35 days after surgery. Capsaicin cream applied to both the bilateral hind instep and sole once a day for a continuous period of 2 weeks or 4 weeks alleviated thermal hyperalgesia in a dose-dependent manner. A remarkable effect was observed 2 weeks after the start of the application and this effect proved to be reversible. On the other hand, in sham-operated animals when capsaicin cream was applied once daily from day 7 after the sham operation, from 1 day through 3 weeks following capsaicin application, withdrawal latency of the sham-operated paws of the capsaicin-treated group was significantly increased as compared to that of the vehicle cream-treated group. The effects of antagonists of glutamate receptor and tachykinin receptors were investigated 7 days post surgery. Pretreatment with MK-801 (0.5 mg kg(-1), i.p.), but not with CNQX (0.5 mg kg(-1), i.p.), reversed the thermal hyperalgesia following nerve injury. Neither of RP67580 (1--10 mg kg(-1), i.p.) nor SR48968 (1--10 mg kg(-1), i.p.) had any effect on the withdrawal latency in the injured and non-injured hind paw. These results suggest that although the manifestation of effectiveness may be delayed by changes in networks of neurotransmitters related to the nociceptive pathways following nerve injury, longer-term repetitive application of capsaicin cream has a significant therapeutic effect on subjects with painful peripheral neuropathy.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Analgesics; Animals; Benzamides; Capsaicin; Carrageenan; Disease Models, Animal; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Hyperalgesia; Indoles; Isoindoles; Male; Neuroprotective Agents; Pain; Peripheral Nervous System Diseases; Piperidines; Postoperative Period; Rats; Rats, Sprague-Dawley; Sciatic Nerve; Substance Withdrawal Syndrome; Time Factors

Endothelin-1 (ET-1) induces endothelin-A (ETA) receptor-mediated pain and selective excitation of nociceptors. Here we studied ET-1-induced changes in intracellular calcium (Ca2+in) in Fura-2 loaded mouse neuroblastoma-rat dorsal root ganglion hybrid cells (ND7/104). ET-1 (1-400 nM) induced concentration-dependent, transient increases in Ca2+in, probably of intracellular source. Responses to repeated application declined with increasing ET-1 concentration, implying receptor desensitization. Treatment of cells with the selective ETA receptor antagonist, BQ-123, produced a dose-dependent inhibition of the response that was 20% of ET-1 alone (IC50 = 20 nM, KI = 7 nM). No inhibition of the calcium response was observed with the selective ETB antagonist, BQ-788 (10-1000 nM). These results demonstrate that ET-1 induces dose- and ETA receptor-dependent release of Ca2+in in nociceptor-like neurons, and permit further examination of the pathways that underlie ET-1-induced pain signaling.

Topics: Animals; Antihypertensive Agents; Calcium; Calcium Channels; Calcium Signaling; Cell Line, Transformed; Dose-Response Relationship, Drug; Endothelin Receptor Antagonists; Endothelin-1; Fluorescent Dyes; Fluorometry; Fura-2; Ganglia, Spinal; Intracellular Fluid; Mice; Models, Biological; Neuroblastoma; Neurons, Afferent; Nociceptors; Oligopeptides; Pain; Peptides, Cyclic; Piperidines; Rats; Receptor, Endothelin A; Receptors, Endothelin

Cannabinoid1 (CB1) receptors are located at CNS sites, including the spinal cord, involved in somatosensory processing. Analgesia is one of the tetrad of behaviors associated with cannabinoid agonists. Here, effects of a potent cannabinoid CB1 receptor agonist arachidonyl-2-chloroethylamide (ACEA) on evoked responses of dorsal horn neurons in anesthetized rats were investigated. Extracellular recordings of convergent dorsal horn neurons were made in halothane anesthetized Sprague-Dawley rats (n = 16). Effects of spinal application of ACEA on electrically evoked responses of dorsal horn neurons were studied. Mean maximal effects of 0.5, 5, 50, and 500 ng/50 microl ACEA on the C-fiber-mediated postdischarge response were 79 +/- 6, 62 +/- 10, and 54 +/- 7% (P < 0.01), 45 +/- 6% (P < 0.01), of control, respectively. ACEA (500 ng/50 microl) also reduced the C-fiber-evoked nonpotentiated responses of neurons (59 +/- 9% of control, P < 0.05) and Adelta-fiber-evoked responses of neurons (68 +/- 10% of control, P < 0.01). Minor effects of ACEA on Abeta-fiber-evoked responses were observed. Spinal pre-administration of the selective CB1 receptor antagonist SR141716A (0.01 microg/50 microl) significantly reduced effects of ACEA (500 ng/50 microl) on postdischarge responses of dorsal horn neurons. This study demonstrates that spinal CB1 receptors modulate the transmission of C- and Adelta-fiber-evoked responses in anesthetized rats; this may reflect pre- and/or postsynaptic effects of cannabinoids on nociceptive transmission. CB1 receptors inhibit synaptic release of glutamate in rat dorsolateral striatum, a similar mechanism of action may underlie the effects of ACEA on noxious evoked responses of spinal neurons reported here.

Topics: Action Potentials; Animals; Arachidonic Acids; Male; Nerve Fibers; Nerve Fibers, Myelinated; Nociceptors; Pain; Piperidines; Posterior Horn Cells; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptors, Cannabinoid; Receptors, Drug; Rimonabant; Spinal Cord; Synaptic Transmission

The single-channel properties of native NMDA receptors in laminae I and II of the dorsal horn of the neonatal rat spinal cord were studied using outside-out patch-clamp techniques. These receptors were found to have several features that distinguish them from native NMDA receptors elsewhere in the CNS. Single-channel currents activated by NMDA (100 nm) and glycine (10 microm) exhibited five distinct amplitude components with slope-conductance values of 19.9 +/- 0.8, 32.9 +/- 0.6, 42.2 +/- 1.1, 53.0 +/- 1.0 and 68.7 +/- 1.5 pS. Direct transitions were observed between all conductance levels but transitions between 69-pS openings and 20-, 33- and 42-pS openings were rare. There was no significant difference in the frequency of direct transitions from 42- to 20-pS compared to 20- to 42-pS transitions. The Kb (0 mV) for Mg2+ was 89 microm. The Mg2+ unblocking rate constant was similar to other reported values. However, the Mg2+ blocking rate constant was larger than other reported values, suggesting an unusually high sensitivity to Mg2+. The NR2B subunit-selective antagonist, ifenprodil, had no significant effect on overall channel activity but significantly decreased the mean open time of 53-pS openings. These results suggest neonatal laminae I and II NMDA receptors are not simply composed of NR1 and NR2B subunits or NR1 and NR2D subunits. It is possible that these properties are due to an as yet uninvestigated combination of two NR2 subunits with the NR1 subunit or a combination of NR3A, NR2 and NR1 subunits.

Topics: Aging; Animals; Excitatory Amino Acid Antagonists; Ion Channels; Magnesium; Membrane Potentials; N-Methylaspartate; Nociceptors; Pain; Patch-Clamp Techniques; Piperidines; Posterior Horn Cells; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Synaptic Transmission

Recent pharmacological evidence has implicated substance P and neurokinin A, natural ligands for neurokinin-1 and neurokinin-2 receptors, respectively, as neurotransmitters in brain neuronal circuits activated upon noxious stimulation. The expression of the inducible transcription factor, c-Fos, was used to identify areas in the brain activated by a noxious stimulus (the subcutaneous injection of formalin), and to investigate the effects of intracerebroventricular administration of selective, nonpeptide antagonists for neurokinin-1 and neurokinin-2 tachykinin receptors on the neural activity in these areas and on the behavioural response to formalin-induced pain. Formalin (5%, 50 microl), injected subcutaneously through a chronically implanted catheter in the region of the lower hindlimb, increased c-Fos expression in a number of brain areas related to nociceptive transmission or the integration of stress responses. Grooming behaviour, licking and biting directed to the injected site, was the most frequent behavioural response. Intracerebroventricular pretreatment of rats with either RP 67580 (500 pmol), the active enantiomer of a neurokinin-1 receptor antagonist, or with SR 48968 (500 pmol), the active enantiomer of a neurokinin-2 receptor antagonist, reduced the formalin-induced c-Fos staining in the prefrontal cortex, dorsomedial and ventromedial nuclei of the hypothalamus, the locus coeruleus and the periaqueductal gray. The neurokinin-1, but not the neurokinin-2, receptor antagonist attenuated the formalin-induced activation of c-Fos in the paraventricular nucleus of the hypothalamus. Simultaneous intracerebroventricular pretreatment with both neurokinin-1 and neurokinin-2 receptor antagonists did not produce any additional inhibitory effect on the post-formalin c-Fos expression. None of the tachykinin receptor antagonists had an effect on the formalin-induced c-Fos expression in the septohypothalamic nucleus, medial thalamus, parabrachial nucleus and central amygdaloid nucleus, indicating that neurotransmitters other than neurokinins are most probably responsible for the activation of these areas in response to noxious stimulation. While both tachykinin receptor antagonists reduced the grooming behaviour to formalin, the neurokinin-1 receptor antagonist was clearly more effective than the neurokinin-2 receptor antagonist. Intracerebroventricular pretreatment of rats with the inactive enantiomers of the tachykinin receptor antagonists, RP 68651 and S

Topics: Analgesics; Animals; Behavior, Animal; Benzamides; Brain; Formaldehyde; Grooming; Indoles; Injections, Intraventricular; Isoindoles; Male; Pain; Piperidines; Proto-Oncogene Proteins c-fos; Rats; Rats, Wistar; Receptors, Tachykinin

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

Topics: Humans; Muscle Relaxants, Central; Musculoskeletal Diseases; Pain; Parasympatholytics; Piperidines; Sodium Channel Blockers; Tolperisone

New strategies have recently been developed where infusion of neurotrophic factors into the brain can rescue different neuronal populations. However, negative side effects have been observed in clinical trials infusing nerve growth factor (NGF) into the lateral ventricle in man, namely pain. Little is known about pain behavior in animals after intracerebroventricular (i.c.v.) neurotrophic injections. Thus, we have examined the effects of i.c.v. infusion of NGF for 2 weeks on the behavioral response of rats to mechanical, cold and heat stimulation. Seven micrograms/day of NGF elicited a significant decrease in vocalization threshold to mechanical stimulation and a significantly increased response to cold and heat stimuli as compared with control. The concentration of NGF in cerebrospinal fluid (CSF) was significantly increased as compared with non-allodynic rats. The enhanced responses to mechanical and heat, but not to cold, stimulation were significantly reduced by CP-99994, a selective antagonist to tachykinin NK-1 receptors. When NGF was infused into the brain parenchyma (striatum, cortex and septum) no allodynic nor hyperalgesic responses could be detected. These results indicate that in rats i.c.v. but not intraparenchymal infusion of NGF induce mechanical and cold allodynia as well as heat hyperalgesia, which is mediated, at least in part, by activation of NK-1 receptors.

Topics: Animals; Behavior, Animal; Brain; Cold Temperature; Hot Temperature; Hyperesthesia; Injections, Intraventricular; Male; Nerve Growth Factor; Neurokinin-1 Receptor Antagonists; Pain; Pain Threshold; Physical Stimulation; Piperidines; Rats; Rats, Sprague-Dawley; Reference Values; Vocalization, Animal

The reemergence on the debate of the use of marijuana for medicinal purposes has been the impetus for developing an acceptable delivery form of aerosolized cannabinoids. The goals of the present study were to: (1) develop and characterize the physical properties of an aerosolized form of Delta(9)-tetrahydrocannabinol (Delta(9)-THC), the major psychoactive constituent present in marijuana; and (2) assess the pharmacological effects of cannabinoid inhalation in mice. A Small Particle Aerosol Generator (SPAG) nebulizer, used to generate the aerosol, had an output of approximately 0.154 mg/l of aerosolized Delta(9)-THC with a 2.0 microm mass median aerodynamic diameter and a 2.2 geometric standard deviation (GSD). Virtually all the particles were less than 5.0 microm in diameter suggesting that they were sufficiently small to penetrate deeply into the lungs. Inhalation exposure to aerosolized Delta(9)-THC in mice elicited antinociceptive effects that were dependent on concentration and exposure time with an estimated Delta(9)-THC dose of 1.8 mg/kg. On the other hand, inhalation exposure to Delta(9)-THC failed to produce two other indices indicative of cannabinoid activity, hypothermia and decreases in spontaneous locomotor activity. The antinociceptive effects occurred within 5 min of exposure and lasted approximately 40 min in duration. The cannabinoid receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2, 4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide HCl (SR 141716A), but not naloxone, blocked these antinociceptive effects (AD(50)=0.09 mg/kg) indicating a cannabinoid receptor mechanism of action. Similarly, inhalation exposure to a water soluble cannabinoid analog, 3-(5'-cyano-1', 1'dimethylheptyl)-1-(4-N-morpholinobutyrloxy)-Delta(8)-te trahydrocann abinol (O-1057), produced antinociception that was blocked by SR 141716A. These results demonstrate that the development of an aerosolized form of cannabinoids for human medicinal use is feasible.

Topics: Administration, Inhalation; Aerosols; Animals; Cannabinoids; Dose-Response Relationship, Drug; Dronabinol; Hallucinogens; Injections, Intravenous; Male; Mice; Mice, Inbred ICR; Pain; Piperidines; Pyrazoles; Rimonabant

Remifentanil, a recently introduced ultra-short acting opioid, was used as a component of a conscious sedation technique in 30 patients for 40 painful medical procedures. In 31 of these procedures, remifentanil provided sufficient analgesia. However, 25 of those 31 patients developed apnea that required constant verbal stimulation at doses equal to or less than the dose required for analgesia. Ten of these apneic patients developed hypoxemia (oxyhemoglobin saturation less than 90%). Nine patients required abandonment of remifentanil and addition of either ketamine or propofol to achieve an analgesic state without respiratory depression. Although discharge times with remifentanil were considerably shorter, most patients, parents, and practitioners were not satisfied with the technique because of the prolonged time to reach an analgesic state, and their fear of persistent apnea. Therefore, remifentanil is generally not a useful agent as part of a conscious sedation technique during brief painful procedures. Although discharge times are rapid, it is accompanied by a high incidence of life-threatening respiratory depression at subtherapeutic levels.

Topics: Adolescent; Adult; Apnea; Child; Child, Preschool; Clinical Medicine; Conscious Sedation; Female; Humans; Hypnotics and Sedatives; Infant; Male; Pain; Piperidines; Remifentanil; Retrospective Studies

A better knowledge of the pathophysiology of chronic pain could help to improve the treatment of patients with such syndrome. The aim of the present work was to elucidate the possible involvement of spinal substance P and neurokinin A in the mechanical and thermal allodynia observed in streptozocin-induced diabetic rats. A tachykinin NK(1) receptor antagonist, RP-67,580 ((3aR,7aR) -7, 7-diphenyl-2-(1-imino-2(2-methoxy phenyl)-ethyl) perhydroisoindol-4-one hydrochloride), a tachykinin NK(2) receptor antagonist, SR-48,968 ((S)-N-methyl (4-(acetylamino-4phenylpiperidino)-2-(3, 4-dichlorophenyl) butyl) benzamide) and their respective enantiomers were intrathecally administered 4 weeks after the induction of diabetes. Mechanical and thermal allodynia were evaluated before and up to 60 min after injection. The tachykinin receptor antagonists at the highest doses (10 and 25 microgram) significantly reduced allodynia, their enantiomers being inactive. Both of these data suggest the involvement of substance P and neurokinin A in the neuropathy-induced allodynia and offer a novel hypothesis to treat chronic pain due to diabetes.

Topics: Analgesics; Animals; Benzamides; Diabetes Mellitus, Experimental; Dose-Response Relationship, Drug; Indoles; Isoindoles; Male; Neurokinin-1 Receptor Antagonists; Pain; Pain Threshold; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Neurokinin-2; Tachykinins; Temperature; Time Factors

We found that spinorphin, a novel neuropeptide showed analgesia in a different manner compared with morphine. By measuring flexor responses induced by the intraplanter injection of substances, the presence of three different types of sensory neurons were demonstrated. Although spinorphin completely blocked 2-metylthioadenosine (2-MeS ATP, a P2X(3) agonist)-induced responses, morphine did not. On the other hand, morphine-induced blockade of bradykinin (BK, a B(2)-receptor agonist)-responses was attenuated by pertussis toxin (PTX) treatment, whereas that of spinorphin was not. Thus it is suggested that spinorphin has a spectrum of analgesia which covers the blockade of nociception insensitive to morphine.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Adenosine; Analgesics, Opioid; Animals; Animals, Newborn; Bradykinin; Capsaicin; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Male; Mice; Morphine; Neurons, Afferent; Neuroprotective Agents; Oligopeptides; Pain; Pertussis Toxin; Piperidines; Protease Inhibitors; Purinergic Agonists; Thionucleosides; Time Factors; Virulence Factors, Bordetella

New condensed derivatives of anpirtoline, in which the pyridine ring is replaced with quinoline, quinazoline, 7-chloroquinoline, and 7-chloroquinazoline nuclei, have been synthesized. Their receptor binding profiles (5-HT1A, 5-HT1B) and analgesic activity (hot plate, acetic acid induced writhing) have been studied. The analgesic activity of compounds 4e-4g, and 4l are at least comparable to that of clinically used drugs flupirtine and tramadol under the same conditions.

Topics: Aminopyridines; Analgesics; Animals; Hot Temperature; Male; Mice; Mice, Inbred Strains; Molecular Structure; Pain; Piperidines; Pyridines; Quinazolines; Reaction Time; Receptor, Serotonin, 5-HT1B; Receptors, Serotonin; Receptors, Serotonin, 5-HT1; Structure-Activity Relationship; Tramadol

Topics: Animals; Aprepitant; Clinical Trials as Topic; Disease Models, Animal; Humans; Morpholines; Neurokinin-1 Receptor Antagonists; Pain; Piperidines; Stereoisomerism

We studied the effects of sevoflurane and remifentanil, alone and in combination, on phrenic nerve activity (PNA), resting heart rate (HR), arterial pressure (MAP), and changes in HR (delta HR) and MAP (delta MAP) evoked by electrical stimulation of tibial nerves in anesthetized rabbits. The 50% effective dose (95% confidence intervals) for the depressant effects of sevoflurane on delta HR, delta MAP, and PNA were 2.3 (1.8%-2.6%), 2.7 (2.3%-2.9%), and 3.4 (3.1%-3.7%), respectively, and for remifentanil were 0.100 (0.050-0.132), 0.850 (0.720-1.450), and 0.090 (0.080-0.145) microgram.kg-1.min-1, which were reduced to 0.046 (0.021-0.065), 0.110 (0.080-0.200), and 0.030 (0.020-0.040) microgram.kg-1.min-1, respectively, by 1% sevoflurane. Depression of evoked cardiovascular responses relative to PNA was greater for sevoflurane and less for remifentanil both alone and in combination with sevoflurane. Sevoflurane acted synergistically with remifentanil on PNA and delta MAP, but not delta HR, for which their combined effect was additive. Coadministration of 1% sevoflurane with the highest infusion rate of remifentanil (1.6 micrograms.kg-1.min-1) used during combined administration reduced resting HR and MAP by 25% (P < 0.05) and 41% (P < 0.05), respectively, which was greater than the predicted reductions of only 14% and 15% if their combined effects had been additive. We conclude that sevoflurane caused a relatively greater depression of nociceptive cardioaccelerator and pressor responses compared with PNA and vice versa for remifentanil. When coadministered, their combined effects on PNA, resting HR, MAP, and delta MAP were synergistic, whereas they were merely additive for delta HR.. Although sevoflurane caused relatively greater depression of nociceptive cardiovascular responses compared with phrenic nerve activity, remifentanil either alone or combined with sevoflurane caused a much greater depression of phrenic nerve activity than cardio-accelerator and pressor responses. This could imply that, during major surgery using anesthesia combining sevoflurane and remifentanil, spontaneous ventilation is not acceptable, and depression of the resting circulation may be much greater than anticipated.

Topics: Action Potentials; Anesthesia; Anesthetics, Inhalation; Anesthetics, Intravenous; Animals; Blood Pressure; Depression, Chemical; Drug Interactions; Electric Stimulation; Evoked Potentials; Heart Rate; Hemodynamics; Methyl Ethers; Pain; Phrenic Nerve; Piperidines; Rabbits; Remifentanil; Respiration; Sevoflurane

The intraplantar injection of lysophosphatidic acid (LPA) at doses of 0.1-100 pmol into the hind limb of mice showed dose-dependent nociceptive flexor responses. Repeated challenges of LPA at 100 pmol every 5 min showed constant responses at least for 30 min. The prior application of pertussis toxin (PTX) at a dose of 10 ng markedly reduced the following LPA (100 pmol) actions. In addition, the intraplantar application of CP-99994 (1 pmol), a substance P (NK1) receptor antagonist, but not CP-100263 (1 pmol), an inactive derivative, also markedly reduced the LPA responses. These findings suggest that LPA has a nociception-producing activity on sensory neurons through G(i/o) activation and substance P release from nociceptor endings.

Topics: Animals; Hindlimb; Lysophospholipids; Male; Mice; Mice, Inbred Strains; Nerve Endings; Neurokinin-1 Receptor Antagonists; Pain; Peripheral Nerves; Pertussis Toxin; Piperidines; Stereoisomerism; Substance P; Time Factors; Virulence Factors, Bordetella

Acute levels of distension were applied by balloon to the colo-rectal region in conscious rats and visceromotor responses observed as abdominal muscle contraction; the threshold was typically between 10-40 mmHg. In saline-pretreated rats, the selective 5-HT3 (granisetron) and 5-HT4 (SB-207266) receptor antagonists had no effects on the visceromotor thresholds. 5-Hydroxytryptophan 10 mg/kg, subcutaneously (s.c.) decreased the distension threshold, indicating mechanical allodynia. This increased sensitivity was dose-dependently inhibited by granisetron but was unaffected by SB-207266 100 microg/kg, s.c., a dose which maximally and selectively antagonizes at 5-HT4 receptors. However, this dose of SB-207266 potentiated the inhibitory activity of submaximally-effective doses of granisetron, reducing the ED50 from 0.83 to 0.02 microg/kg, s.c., but without changing the maximum response or the bell-shaped nature of the dose-response curve for granisetron. These data suggest that 5-HT4 receptor activation enhances the ability of 5-HT3 receptor activation to induce intestinal allodynia.

Topics: Animals; Colon; Dose-Response Relationship, Drug; Granisetron; Indoles; Male; Pain; Piperidines; Rats; Rats, Wistar; Receptors, Serotonin; Receptors, Serotonin, 5-HT3; Receptors, Serotonin, 5-HT4; Rectum; Serotonin Antagonists

Intrathecal administration of anandamide, delta9-tetrahydrocannabinol (THC) and (-)-3-[2-hydroxy-4-(1,1-dimethyheptyl)ptyl)phenyl]-4-(3-hydr oxypropyl)-cicloexan-1-ol (CP55,940) induced spinal antinociception accompanied by differential kappa-opioid receptor involvement and dynorphin A peptide release. Antinociception using the tail-flick test was induced by the classical cannabinoid THC and was blocked totally by 17,17'-bis(cyclopropylmethyl)-6',6,7,7'-tetrahydro-4,5,4'5'-diepoxy++ +-6,6'-(imino)[7,7'-bimorphinan]-3,3',14,14'-tetrol (norbinaltorphimine) indicating a significant and critical kappa-opioid receptor component. The endogenous cannabinoid, anandamide and the non-classical bicyclic cannabinoid, CP55,940, induced non-nor-BNI-sensitive effects. The N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyrazo le-carboxamide (SR141716A)-mediated attenuation of spinal antinociception imparted by the various cannabinoids indicates cannabinoid CB1 receptor involvement. THC-induced an enhancement of immunoreactive dynorphin A release which coincided with the onset, but not duration antinociception. The release of dynorphin A was also attenuated by SR141716A suggesting it is cannabinoid CB1 receptor-mediated. These data indicate a critical role for dynorphin A release in the initiation of the antinociceptive effects of the cannabinoids at the spinal level.

Topics: Analgesics; Animals; Cannabinoids; Cyclohexanols; Dimethyl Sulfoxide; Dronabinol; Dynorphins; Injections, Spinal; Male; Naltrexone; Narcotic Antagonists; Nociceptors; Pain; Pain Measurement; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Rimonabant

Synthetic cannabinoids produce behavioral analgesia and suppress pain neurotransmission, raising the possibility that endogenous cannabinoids serve naturally to modulate pain. Here, the development of a sensitive method for measuring cannabinoids by atmospheric pressure-chemical ionization mass spectrometry permitted measurement of the release of the endogenous cannabinoid anandamide in the periaqueductal gray (PAG) by in vivo microdialysis in the rat. Electrical stimulation of the dorsal and lateral PAG produced CB1 cannabinoid receptor-mediated analgesia accompanied by a marked increase in the release of anandamide in the PAG, suggesting that endogenous anandamide mediates the behavioral analgesia. Furthermore, pain triggered by subcutaneous injections of the chemical irritant formalin substantially increased the release of anandamide in the PAG. These findings indicate that the endogenous cannabinoid anandamide plays an important role in a cannabinergic pain-suppression system existing within the dorsal and lateral PAG. The existence of a cannabinergic pain-modulatory system may have relevance for the treatment of pain, particularly in instances where opiates are ineffective.

Topics: Analgesia; Animals; Arachidonic Acids; Calcium Channel Blockers; Cannabinoids; Electrophysiology; Endocannabinoids; Formaldehyde; Gas Chromatography-Mass Spectrometry; Humans; Male; Microdialysis; Models, Biological; Pain; Periaqueductal Gray; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Rats; Rats, Sprague-Dawley; Rimonabant; Time Factors

The antihistaminic drug levocabastine is a ligand for the low affinity neurotensin receptor (NTS2). Its intracerebroventricular administration to mice induced a significant analgesia in the writhing test but not in the hot plate test. In the writhing test, levocabastine decreased neurotensin-induced analgesia to a level not significantly different from the effects of levocabastine alone. In the hot plate test, levocabastine had no analgesic effect but completely reversed the neurotensin-induced analgesia. Mepyramine, another antihistaminic drug, did not share these levocabastine effects. Neither levocabastine nor mepyramine modified the colonic temperature or reversed the neurotensin-induced hypothermia. Thus, levocabastine behaves as a partial agonist at neurotensin NTS2 receptors, which are involved in visceral nociception, but not at yet unidentified neurotensin receptors involved in hypothermia.

Topics: Analgesia; Analgesics; Animals; Dose-Response Relationship, Drug; Histamine H1 Antagonists; Male; Mice; Neurotensin; Pain; Pain Threshold; Piperidines; Pyrilamine; Receptors, Neurotensin

Although opioids can reduce stimulus-evoked efflux of Substance P (SP) from nociceptive primary afferents, the consequences of this reduction on spinal cord nociceptive processing has not been studied. Rather than assaying SP release, in the present study we examined the effect of opioids on two postsynaptic measures of SP release, Fos expression and neurokinin-1 (NK-1) receptor internalization, in the rat. The functional significance of the latter was first established in in vitro studies that showed that SP-induced Ca(2+) mobilization is highly correlated with the magnitude of SP-induced NK-1 receptor internalization in dorsal horn neurons. Using an in vivo analysis, we found that morphine had little effect on noxious stimulus-evoked internalization of the NK-1 receptor in lamina I neurons. However, internalization was reduced when we coadministered morphine with a dose of an NK-1 receptor antagonist that by itself was without effect. Thus, although opioids may modulate SP release, the residual release is sufficient to exert maximal effects on the target NK-1 receptors. Morphine significantly reduced noxious stimulus-induced Fos expression in lamina I, but the Fos inhibition was less pronounced in neurons that expressed the NK-1 receptor. Taken together, these results suggest that opioid analgesia predominantly involves postsynaptic inhibitory mechanisms and/or presynaptic control of non-SP-containing primary afferent nociceptors.

Topics: Analgesia, Epidural; Analgesics, Opioid; Animals; Cells, Cultured; Embryo, Mammalian; Male; Morphine; Neurokinin-1 Receptor Antagonists; Pain; Piperidines; Posterior Horn Cells; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Receptors, Neurokinin-1; Signal Transduction; Spinal Cord; Substance P; Tetrazoles

The effects of propofol, remifentanil, and their combination on phrenic nerve activity (PNA), resting heart rate (HR), mean arterial pressure (MAP), and nociceptive cardiovascular responses were studied in rabbits.. Basal anesthesia and constant blood gas tensions were maintained with alpha-chloralose and mechanical ventilation. PNA, HR, MAP, and maximum changes in HR and MAP (deltaHR, deltaMAP) evoked by electrical nerve stimulation of tibial nerves were recorded. The comparative effects were observed for propofol at infusion rates from 0.05 to 3.2 mg x kg(-1) x min(-1) (group I) and remifentanil from 0.0125 to 12.8 microg x kg(-1) x min(-1) alone (group II), and during constant infusions of propofol at rates of 0.1 and 0.8 mg x kg(-1) x min(-1) (groups III and IV, respectively). Finally, the effect of remifentanil on propofol blood levels was observed (group V).. The infusion rates for 50% depression (ED50) of PNA, deltaHR, and deltaMAP were 0.41, 1.32, and 1.58 mg x kg-(1) x min(-1) for propofol, and 0.115, 0.125, and 1.090 microg x kg(-1) x min(-1) for remifentanil, respectively. The ratios for the ED50 values of deltaHR and deltaMAP to PNA were 3.2 and 3.9 for propofol, and 1.1 and 9.5 for remifentanil, respectively. Analysis of the expected and observed responses and isobologrms showed that although their combined effects on PNA, resting HR, and MAP, and deltaMAP were synergistic for deltaHR, they were merely additive. Remifentanil had no effect on propofol blood levels.. PNA was abolished by propofol and remifentanil, alone and in combination, before significant depression of nociceptive pressor responses occurred. Their combined effects on PNA, HR, MAP, and deltaMAP are greater than additive, ie., synergistic. Unlike propofol, remifentanil obtunded pressor responses more than the resting circulation.

Topics: Anesthetics, Intravenous; Animals; Blood Pressure; Carbon Dioxide; Drug Interactions; Electrophysiology; Female; Heart Rate; Hemodynamics; Infusions, Intravenous; Male; Pain; Phrenic Nerve; Piperidines; Propofol; Rabbits; Remifentanil; Respiratory Mechanics

Delta(9)-Tetrahydrocannabinol (1 and 5 mg/kg, i.p.) produced, dose-dependently, antinociceptive effects using hot plate and tail flick tests in rats. These effects were suppressed not only by the cannabinoid CB(1) receptor antagonist SR 141716A (0.5 mg/kg; i.p.) but also by the dopamine D(2) receptor antagonists S(-)-sulpiride (5 and 10 mg/kg; i.p.) and S(-)-raclopride (1.5 and 3 mg/kg; i.p.). Conversely, Delta(9)-tetrahydrocannabinol antinociceptive effects were potentiated by the dopamine D(2) receptor agonists (-)-quinpirole (0.025 mg/kg, s.c.) and (+)-bromocriptine (0.5 and 1 mg/kg; i.p.). Our results indicate that the antinociceptive effects of Delta(9)-tetrahydrocannabinol are mediated by the concomitant activation of cannabinoid CB(1) and dopamine D(2) receptors and that dopamine D(2) receptor agonists may be useful in improving the analgesic effects of cannabinoids.

Topics: Analgesics, Non-Narcotic; Animals; Bromocriptine; Dopamine Agonists; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Dronabinol; Male; Nociceptors; Pain; Piperidines; Pyrazoles; Quinpirole; Raclopride; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2; Rimonabant; Sulpiride

The present study was designed to investigate the modulatory effects of blockade of spinal histamine receptors on antinociception induced by supraspinally administered mu-epsilon-, delta-, and kappa-opioid receptor agonists. The effects of intrathecal (i.t.) injections with cyproheptadine [a histamine-1 (H1) receptor antagonist], ranitidine (a H2 receptor antagonist), or thioperamide (a H3 receptor antagonist) injected i.t., on the antinociception induced by morphine (a mu-receptor antagonist), beta-endorphin (an epsilon-receptor agonist), D-Pen(2,5)-enkephalin (DPDPE, a delta-receptor agonist) or trans-3, 4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl) cyclohxyl] benzeocetamide (U50,488H, a kappa-receptor agonist) injected intracerebroventricularly (i.c.v.) were studied. The antinociception was assayed using the tail-flick test. The i.t. injection of cyproheptadine (from 0.31 to 62 nmole), ranitidine (from 0.28 to 56 nmole), or thioperamide (from 0.24 to 48 nmole) alone did not show any antinociceptive effect. The i.t. pretreatment with cyproheptadine or thioperamide dose-dependently attenuated the inhibition of the tail-flick response induced by i.c.v. administered morphine (0.6 nmole), b-endorphin (0.03 nmole), DPDPE (1.5 nmole), and U50,488H (130 nmole). In addition, the i.t. pretreatment with ranitidine dose-dependently attenuated the inhibition of the tail-flick response induced by morphine, b-endorphin and U50,488H without affecting DPDPE-induced response. Our results suggest that spinal histamine H1 and H3 receptors may involved in the production of antinociception induced by supraspinally applied morphine, b-endorphin, DPDPE and U50,488H. Spinal H2 receptors appear to be involved in supraspinally administered morphine, b-endorphin- and U50,488H-induced antinociception but not DPDPE-induced antinociception.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Animals; beta-Endorphin; Cerebral Ventricles; Cyproheptadine; Enkephalin, D-Penicillamine (2,5)-; Histamine Antagonists; Injections, Intraventricular; Injections, Spinal; Male; Mice; Mice, Inbred ICR; Morphine; Pain; Piperidines; Ranitidine; Receptors, Histamine H1; Receptors, Histamine H2; Receptors, Histamine H3; Receptors, Opioid; Spinal Cord

To define the effects of antisense oligonucleotides on spinal neurokinin 1 (NK1) receptor function in nociceptive processing, several antisense oligonucleotides directed against the NK1 receptor mRNA were intrathecally injected into rats via an implanted catheter, and their effect on the behavioural response to formalin injected into the paw was assessed. We observed that there was no significant reduction of pain behaviour or immunostaining of spinal NK1 receptors after repeated daily intrathecal treatment with an antisense oligonucleotide. However, spinal application of substance P (SP) in the antisense oligonucleotide-treated animals resulted in a profound and long-lasting reduction in the behavioural response to formalin injection, and a parallel reduction in the NK1 receptor immunoreactivity normally observed in spinal dorsal horn. Intrathecal SP in the control groups, i.e., rats treated with an oligonucleotide containing four mismatched bases, the corresponding sense oligonucleotide, a mixture of the sense and the antisense oligonucleotides, in each case had no effect. The effects of SP were blocked by NK1 receptor antagonists and were not mimicked by NMDA. The mechanism underlying these effects is not clear. It may be due to partial degradation of the internalised receptors, which cannot be replaced by newly synthesised receptors because of the action of the NK1 antisense oligonucleotide.

Topics: Animals; Down-Regulation; Formaldehyde; Indoles; Injections, Spinal; Isoindoles; Male; N-Methylaspartate; Oligonucleotides, Antisense; Pain; Pain Threshold; Piperidines; Quinuclidines; Rats; Rats, Sprague-Dawley; Receptors, Neurokinin-1; Spinal Cord; Substance P

The effects of novel substance P (NK-1) receptor antagonists LY303870 and LY306740, as well as LY306155, the enantiomer of LY303870, were tested on the responses of nociceptive spinal dorsal horn neurons to iontophoretically applied substance P and to peripheral noxious stimuli. The peripheral stimuli included noxious thermal and pinch stimuli applied to the cutaneous receptive field in the hind paw and stimulation of the superficial peroneal nerve with a train of high-intensity electrical stimuli. Extracellular recordings were obtained using multi-barrel electrodes from L4-L7 segments of the spinal cord in cats anaesthetized with alpha-chloralose and spinalized at the L1 level. The antagonists were given i.v. (0.5-4.0 mg/kg). Responses to substance P were inhibited by LY303870 and by LY306740 in a dose-related manner, but were not affected by LY306155. Responses to peripheral noxious thermal stimulation were inhibited in a dose-related manner by LY303870 and LY306740, and only at higher doses (2 mg/kg or more) by LY306155. Responses to pinch stimuli were inhibited by LY303870 and LY306740. LY306155 lacked consistent effects on pinch responses. LY303870 selectively inhibited the late component of the response to electrical stimulation of the superficial peroneal nerve. When these three drugs were tested against the responses of dorsal horn neurons to the excitatory amino acid, N-methyl-D-aspartate, the responses were unaffected. These data suggest that LY303870 and LY306740 pass from the circulation into the spinal cord where they antagonize dorsal horn neuronal responses to substance P and nociceptive inputs.

Topics: Acetamides; Animals; Cats; Electric Stimulation; Indoles; Iontophoresis; Neurokinin-1 Receptor Antagonists; Neurons; Pain; Piperidines; Receptors, Neurokinin-1; Spinal Cord; Stereoisomerism; Substance P

The present study describes in vivo experiments in the rat addressing the role of levocabastine, and two other specific histamine H1 antagonists, diphenhydramine and pyrilamine, at neurotensin (NT)-mediated hypothermia and antinociception (hotplate). Levocabastine given i.p. or microinjected directly into the periaqueductal gray (PAG) did not cause antinociception or hypothermia. This indicates that despite the results with the recently-cloned levocabastine-sensitive NT receptors (NTR) in the rat (NTR-2) and mouse (NTRL), levocabastine by itself does not mediate either hypothermia or antinociception at NT receptors. However, pretreatment with 5 or 50 microg/kg of levocabastine or 5 microg/kg diphenhydramine all caused over a three-fold reduction in NT-mediated antinociception. Higher doses (500 or 5000 microg/kg) of levocabastine did not cause any antagonism of NT-mediated antinociception. All three antihistamines did not affect NT-mediated hypothermia. In addition, histamine H1 pathways are not involved in NT-mediated antinociception, as pretreatment with the much more potent histamine H1 antagonist pyrilamine did not affect antinociception mediated by NT. Therefore, these data may suggest the presence of yet unidentified NTR subtypes responsible for NT-mediated hypothermia and antinociception.

Topics: Animals; Body Temperature Regulation; Diphenhydramine; Drug Evaluation, Preclinical; Histamine H1 Antagonists; Male; Mice; Neurotensin; Pain; Piperidines; Pyrilamine; Rats; Rats, Sprague-Dawley

Trigeminal stimulation of C-fibers increased c-fos expression within the trigeminal nucleus caudalis (NtV) and thalamic neuronal activity which both reflect the transmission of a nociceptive message. We examined the effects on both these phenomena of the selective NK1 and NK2 receptor antagonists, SR140333 and SR48968. SR140333 (0.3, 1 and 3 micrograms/kg intravenously [i.v.]) dose-dependently, reversibly and stereoselectively antagonized the increase of contralateral thalamic activity. This compound, when given i.v. (30 micrograms/kg) or orally (10 mg/kg), also reduced the number of Fos-like immunoreactive cells particularly at the medial and caudal level of the NtV. In contrast, SR48968 did not exert any antagonistic effect either on thalamic activity or on Fos-like immunoreactivity. The data strongly suggest a preferential involvement of NK1 vs NK2 receptors in nociceptive transmission following trigeminal ganglion stimulation. Taken together, our results indicate that SR140333 could provide a potent drug for the relief of pain occurring under excessive activity of sensory trigeminal fibers.

Topics: Administration, Oral; Animals; Benzamides; Electric Stimulation; Immunohistochemistry; Injections, Intravenous; Male; Neural Pathways; Neurokinin-1 Receptor Antagonists; Neurons; Pain; Piperidines; Proto-Oncogene Proteins c-fos; Quinuclidines; Rats; Rats, Sprague-Dawley; Receptors, Neurokinin-2; Thalamus; Trigeminal Nuclei

Distension of the rat intestine causes a cardiovascular response which is indicative of nociception. Since tachykinins are involved in nociception, we tested the effect of neurokinin receptor antagonists against the distension-induced response. The jejunal distension-induced depressor responses were inhibited in a dose-dependent fashion by CP 99,994 (+)-(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine, tachykinin NK1 receptor antagonist, ED50 = 0.8 mg/kg) and SR 48968 (S)-N-methyl-N[4-(4-acetylamino-4-phenylpiperidino)-2-(3,4-dichloropheny l)butyl]benzamide, tachykinin NK2 receptor antagonist, ED50 = 0.7 mg/kg). SR 142801 (S)-(N)-(1-(3-(1-benzoyl-3-(3,4-dichlorophenyl)piperidin-3-yl)prop yl)-4-phenylpiperidin-4-yl)-N-methylacetamide, tachykinin NK3 receptor antagonist, 0.3-10 mg/kg) did not significantly affect the depressor responses to jejunal distension. In addition, CP 99,994 (3 mg/kg) and SR 48968 (3 and 10 mg/kg) reduced sensitivity to distension as revealed by a 2.7-fold (CP 99.994, 3 mg/kg), 2.6-fold (SR 48968, 3 mg/kg) and 4.7-fold (SR 48968, 10 mg/kg) increase in the threshold pressure. Intestinal compliance was not affected by the antagonists. In conclusion, these results suggest that tachykinin NK1 and NK2 but not NK3 receptors are possibly involved in the rat jejunal distension pain response.

Topics: Analgesics, Non-Narcotic; Animals; Benzamides; Blood Pressure; Jejunum; Male; Neurokinin-1 Receptor Antagonists; Pain; Piperidines; Pressure; Rats; Rats, Wistar; Receptors, Neurokinin-2; Receptors, Neurokinin-3; Receptors, Tachykinin; Regression Analysis

Studies in experimental animals have demonstrated a rapidly developing acute tolerance to the analgesic effect of opioids administered by continuous i.v. infusion. The aim of the present study was to determine whether acute tolerance plays an important role in the analgesic effect of remifentanil provided by i.v. infusion to humans. The analgesic effect of remifentanil, infused at a constant rate of 0.1 microg x kg(-1) x min(-1) for 4 h, was evaluated by measuring pain tolerance with thermal (2 degrees C water) and mechanical (pressure) noxious stimulations in 13 paid volunteers. The constant-rate infusion of remifentanil resulted in a threefold increase in pain tolerance with both tests. After reaching its maximum in 60-90 min, the analgesic effect of remifentanil began to decline despite the constant-rate infusion, and after 3 h of infusion, it was only one fourth of the peak value. A comparative rate in the development of acute tolerance measured in terms of time to 50% recovery during infusion was 129 +/- 27 min (mean +/- SD) with the cold water test and 138 +/- 39 min with the pressure test. We conclude that the development of tolerance should be included in the calculations for target-controlled infusions.. Our study shows that tolerance to analgesia during remifentanil infusion is profound and develops very rapidly. The administration of opioids during anesthesia based on target-controlled infusions should include corrections for the development of tolerance.

Topics: Adult; Analgesia; Analgesics, Opioid; Analysis of Variance; Cold Temperature; Drug Tolerance; Female; Humans; Infusions, Intravenous; Least-Squares Analysis; Male; Pain; Pain Threshold; Piperidines; Placebos; Pressure; Remifentanil; Single-Blind Method; Time Factors

Injection of formalin into the hind paw of the rat evokes a biphasic nociceptive behavioural response, which is considered to be an animal model of postoperative pain in humans. The initial response (phase 1) is caused by activation of peripheral nociceptors and is followed by a second phase attributed to ongoing activity in primary afferents and increased sensitivity of dorsal horn neurones. The latter effect is thought to result from glutamate-mediated N-methyl-D-aspartate receptor activation. In studies to date it has been difficult to discriminate mechanisms underlying phase 1 and phase 2 events because of the long-lasting half-times of intrathecally administered opioids. To further understanding of the opioid pharmacology of the two different phases of the formalin test, we have studied behavioural activity and spinal glutamate release after intrathecal administration of remifentanil, a new short-lasting mu opioid. Intrathecal remifentanil 3 micrograms microliter-1 min-1 delivered during phase 1 inhibited behavioural response during phase 1 (100%), but did not abolish subsequent phase 2 behavioural activity completely (67 (12) %). Intrathecal remifentanil administered separately in phase 1 and phase 2 revealed a similar ED50 (0.2 microgram microliter-1 min-1) for inhibition of the behavioural responses. In vivo, spinal microdialysis showed incomplete reduction in glutamate concentrations in response to intrathecal remifentanil administration; this in turn inhibited phase 1 behavioural responses. Therefore we contend that supramaximal doses of intrathecal remifentanil sufficient to inhibit phase 1 activity still permitted sufficient glutamate release to allow spinal facilitation. Incomplete suppression of spinal excitatory neurotransmitter release by intrathecal opioids is consistent with spinal wind-up that is triggered during phase 1 and results in phase 2 afferent drive. This might reflect one of the mechanisms underlying post-operative pain.

Topics: Analgesics, Opioid; Animals; Behavior, Animal; Dose-Response Relationship, Drug; Glutamic Acid; Infusions, Parenteral; Male; Pain; Pain Measurement; Piperidines; Rats; Rats, Sprague-Dawley; Remifentanil; Spinal Cord

The development and use of serotonin-1B/1D agonists to treat the acute attack of migraine has been a significant advance, but their vasoconstrictor effects have lead to a search for non-vasoconstrictor approaches to the management of the acute attack of migraine. One such suggested approach has been substance P (neurokinin-1) antagonists, since substance P is involved in mediating neurogenic plasma protein extravasation and has long been held to have a role in pain transmission. In this study, one such candidate compound, GR205171, a highly lipophilic potent neurokinin-1 antagonist, has been tested in a model of trigeminovascular nociception with considerable predictive value for anti-migraine activity. The superior sagittal sinus was isolated in the alpha-chloralose (60 mg/kg, i.p., and 20 mg/kg, i.v., supplemented every 2 h)-anaesthetized cat. The sinus was stimulated electrically (100 V, 250 micros duration, 0.3 Hz) and neurons in the dorsal C2 spinal cord monitored using electrophysiological methods. In separate experiments, the animals were prepared for stimulation and then maintained for 24 h before stimulation and perfusion for Fos immunohistochemistry. Stimulation of the superior sagittal sinus resulted in activation of cells in the dorsal horn of C2. Cells fired with a probability of 0.7 +/- 0.1 at a latency of 10.7 +/- 0.2 ms. Administration of GR205171 (100 microg/kg, i.v.) had no effect on probability of firing or latency. Stimulation of the sinus in separate cats resulted in increased expression over control levels in the superficial laminae of the trigeminal nucleus caudalis and C1/2 dorsal horns. GR205171 in the same dose had no effect upon Fos expression. Inhibition of substance P by the potent, selective and brain penetrant neurokinin-1 antagonist GR205171 had no effect upon either cell firing or Fos expression in the central trigeminal cells activated by stimulation of the superior sagittal sinus. These data and the published clinical data for other compounds suggest that neurokinin-1 blockade alone will not be an effective anti-migraine strategy. Further data will be required to assess whether neurokinin-1 antagonists will have any more general value in pain.

Topics: Afferent Pathways; Animals; Brain Mapping; Cats; Cranial Sinuses; Electric Stimulation; Neurokinin-1 Receptor Antagonists; Neurons; Nociceptors; Pain; Piperidines; Proto-Oncogene Proteins c-fos; Spinal Cord; Substance P; Synaptic Transmission; Tetrazoles; Trigeminal Nuclei

Topics: Analgesics, Opioid; Animals; Nociceptors; Pain; Piperidines; Rats; Receptors, N-Methyl-D-Aspartate; Remifentanil; Spinal Cord

The intrathecal effect of 0.1 to 10 microg of RP-67,580 (3aR,7aR)-7,7-diphenyl-2[1-imino-2(2-methoxyphenyl)-ethyl]++ +perhydroisoindol-4-one hydrochloride, CP-96,345 (2S,3S)-cis-(2(diphenylmethyl)-N-[(2-methoxyphenyl) methyl]-1-azabicyclo[2.2.2]octan-3-amine), SR-140,333 (S)-(1-¿2-[3-(3,4-dichlorophenyl)- 1-(3-isopropoxyphenylacetyl)piperidin-3-yl]ethyl¿-4-phenyl-1 -azonia-bicyclo[2.2.2.]-octane,chloride), all neurokinin (NK)1-receptor antagonists, SR-48,968 (S)-N-methyl-N[4-(4-acetylamino-4-[phenylpiperidino)-2-(3,4-dichlorophen yl)-butyl]benzamide, a tachykinin NK2 receptor antagonist and SR-142,801 (S)-(N)-(1-(3-(1-benzoyl-3-(3,4-dichlorophenyl) piperidin-3-yl)propyl)-4-phenylpiperidin-4-yl)-N-methyl acetamide, a tachykinin NK3 receptor antagonist, and of their respective inactive enantiomers on thresholds of vocalization due to a mechanical stimulus in mononeuropathic (sciatic nerve ligature) and diabetic rats, was examined. The tachykinin NK1 and the NK2 receptor antagonists were antinociceptive in both models, with a higher effect of the former in diabetic rats. The tachykinin NK3 receptor antagonist was weakly effective in diabetic rats only. This indicates a differential involvement of the tachykinins according to the model of neuropathic pain, suggesting a potential role for tachykinin receptor antagonists in the treatment of neuropathic pain.

Topics: Analgesics; Animals; Benzamides; Biphenyl Compounds; Denervation; Diabetes Mellitus, Experimental; Indoles; Isoindoles; Male; Neurokinin-1 Receptor Antagonists; Pain; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Neurokinin-2; Receptors, Neurokinin-3; Receptors, Tachykinin; Sciatic Nerve

In adult rats response latencies to innocuous mechanical stimuli were found to be reduced and, in electrophysiological studies, the receptive fields of dorsal horn neurones were enlarged 7-14 days after chronic constriction injury of the sciatic nerve. The NK1 receptor antagonist GR205171 at 3 mg kg(-1) blocked responses to NK1 agonist evoked activity and reversed the mechanical hypersensitivity following nerve ligation in behavioural assays. GR205171 also reversed the receptive field expansion of spinal dorsal horn neurones caused by loose ligation of the sciatic nerve in an electrophysiological assay in anaesthetised rats. The less active enantiomer L-796,325 did not block NK1 agonist evoked activity at up to 10 mg kg(-1) and had no effect on behavioural or electrophysiological changes following nerve injury, indicating that the effects of GR205171 were attributable to selective NK1 receptor blockade. These data suggest that NK1 receptor antagonists may be useful for the treatment of certain types of neuropathic pain.

Topics: Analysis of Variance; Animals; Functional Laterality; Hyperalgesia; Isomerism; Male; Mice; Neurokinin-1 Receptor Antagonists; Neurons; Pain; Peripheral Nervous System Diseases; Piperidines; Rats; Rats, Sprague-Dawley; Sciatic Nerve; Spinal Cord; Tetrazoles

The selective neurokinin (NK)-1 antagonist LY303870 has high affinity and specificity for human and guinea pig brain NK-1 receptors labeled with 125I-substance P. It has approximately 15- to 30-fold lower affinity for rat and mouse brain NK-1 receptors, consistent with previously reported species differences in the affinities of nonpeptide antagonists for NK-1 receptors. In vivo, LY303870 blocked the characteristic, caudally directed, biting and scratching response elicited by intrathecal administration of the selective NK-1 agonist Ac-[Arg6,Sar9,Met(O2)11]substance P6-11 in conscious mice. The potentiation of the tail-flick response elicited by intrathecal administration of the NK-1 agonist [Sar9,Met(O2)11]substance P in rats was also selectively blocked by LY303870. When tested in a model of persistent nociceptive activation induced by tissue injury (the formalin test), LY303870 blocked licking behavior in the late phase of the formalin test, in a dose-dependent manner. After oral administration of 10 mg/kg, the blockade of the late-phase licking behavior was evident for at least 24 hr. Ex vivo binding studies in guinea pigs showed that orally administered LY303870 potently inhibited binding to central and peripheral NK-1 receptors labeled with 125I-substance P. This inhibition was long-lasting, consistent with other in vivo activities. LY306155, the opposite enantiomer of LY303870, was less active in all of the functional assays. In rodents, LY303870 did not exhibit any neurological, motor, cardiovascular, gastrointestinal or autonomic side effects at doses of < or = 50 mg/kg p.o. Thus, LY303870 is a potent, centrally active, NK-1 antagonist in vivo, with long-lasting oral activity.

Topics: Animals; Drug Synergism; Electroshock; Formaldehyde; Guinea Pigs; Humans; Indoles; Injections, Spinal; Male; Mice; Mice, Inbred Strains; Motor Activity; Neurokinin-1 Receptor Antagonists; Pain; Peptide Fragments; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Neurokinin-1; Reflex, Startle; Species Specificity; Spinal Cord; Substance P

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

Injection of formalin in the rat hindpaw produces two phases of nociceptive behavior. Although it is generally agreed that the first phase results from direct chemical activation of nociceptive primary afferent fibers, the factors that contribute to the second phase are not established. In the present study, we monitored the expression of the c-fos protein to evaluate whether the pattern of activity of dorsal horn neurons differs as a result of ongoing afferent activity during the two phases. To selectively block the first or second phase, we respectively used remifentanil, a potent and short acting opiate agonist, and QX-314, a quaternary derivative of lidocaine, which does not cross the blood brain barrier. We also evaluated the effect of eliminating nociceptive behavior in both phases using both remifentanil and lidocaine or a combination of local anesthetics, bupivicaine and quaternary lidocaine. In all groups, formalin (5%, 50 microliters) was injected subcutaneously into the plantar surface of the hindpaw. To assess the nociceptive behavior produced by formalin, we monitored the number of flinches. Injection of remifentanil during the first phase completely blocked the first phase formalin-evoked nociceptive behavior, and had no effect on the second phase. Injection of lidocaine during the interphase completely blocked second phase nociceptive behavior. As expected, when remifentanil was administered during the first phase and lidocaine during the second phase, all formalin-evoked nociceptive behavior was blocked. The same was true for rats that received injections of bupivicaine and lidocaine during phases 1 and 2, respectively. In laminae I-II of the L4-L5 segment, the magnitude of the decrease in Fos expression was comparable for remifentanil (26.5%) and lidocaine (27.3%); the decrease was greater when both remifentanil and lidocaine were administered (50.5%), and even greater when bupivicaine and lidocaine were used (74.2%). In laminae V-VI, remifentanil, by itself, decreased c-fos expression by 39.4%; for lidocaine alone, the decrease was 58.4%. We did not observe further significant decreases when both remifentanil and lidocaine, or bupivacaine and lidocaine were injected (69.7% and 74.6%, respectively). Our results not only provide strong evidence that activity during the second phase is necessary for maintaining the maximal expression of c-fos in the spinal cord, but also reveal significant regional differences in the central patterns of act

Topics: Analgesics, Opioid; Anesthetics, Local; Animals; Bupivacaine; Formaldehyde; Immunohistochemistry; Lidocaine; Male; Pain; Pain Measurement; Piperidines; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Remifentanil; Spinal Cord

The effects of a high affinity cannabinoid receptor agonist were evaluated in rats subjected to chronic constriction injury of the sciatic nerve (CCI) or a sham operation. Intraperitoneal (i.p.) injections of the active, but not the inactive enantiomer, alleviated the pain behavior exhibited by CCI animals in a dose dependent manner. Moreover, at doses ranging from 0.43 to 4.3 mg/kg effects on sensitivity to a heat stimulus were observed neither in the paw contralateral to the sciatic ligation, nor in animals subjected to sham surgery. Animals subjected to CCI and treated with 4.3 mg/kg exhibited hypoalgesia in the paw ipsilateral to the ligated sciatic, i.e. heat hypoalgesia was completely reversed. The hypoalgesia is presumed to be the results of unmasking of a sensory deficit reflecting the known loss of C and A delta with CCI. Although side effects were present in some CCI animals subjected to the high dose (4.3 mg/kg), a moderate dose (2.14 mg/kg) completely alleviated the thermal and mechanical hyperalgesia, and mechanical allodynia without side effects. In addition to identifying a potential drug treatment for painful neuropathy, this study suggests that changes in cannabinoid receptors occurs in nerve injured animals.

Topics: Analgesics, Non-Narcotic; Animals; Benzoxazines; Cannabinoids; Hot Temperature; Hyperalgesia; Injections, Intraperitoneal; Male; Morpholines; Naphthalenes; Pain; Peripheral Nervous System Diseases; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptors, Cannabinoid; Receptors, Drug; Rimonabant

In spinal cord neurons in anesthetized rats, the role on neurokinin A and neurokinin-2 receptors in the processing of nociceptive information from the knee joint was studied. The specific non-peptide antagonist at the neurokinin-2 receptor, SR48968, its inactive R-enantiomer, SR48965, neurokinin A, substance P and (RS)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), were administered ionophoretically close to neurons with input from the knee joint. SR48968 reduced the effects of exogenous neurokinin A, but not those of exogenous substance P and AMPA, indicating selective blockade of neurokinin-2 receptors. In most neurons with input from the normal knee joint, SR48968 reduced dose-dependently the responses to noxious pressure with applied to the knee, and in approximately 50% of the neurons the responses to innocuous pressure. The administration of SR48968 during the induction of an experimental joint inflammation markedly attenuated the development of inflammation-evoked hyperexcitability. In hyperexcitable neurons with input from the inflamed joint, SR48968 reduced the responses to noxious and innocuous pressure. The relative reduction of the responses was more pronounced than in neurons with input from the normal joint. None of the effects of SR48968 was mimicked by SR48965. These data show that neurokinin-2 receptors are involved in the spinal processing of nociceptive information from the normal joint. Furthermore, neurokinin-2 receptors must be coactivated at an early stage of inflammation, to allow the generation of hyperexcitability. Finally, neurokinin-2 receptors are involved in maintenance of hyperexcitability during inflammation. In summary, spinal neurokinin-2 receptors are important in the generation of pain in the normal and inflamed joint.

Topics: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Arthritis; Benzamides; Carrageenan; Hyperalgesia; Iontophoresis; Kaolin; Knee Joint; Male; Neurokinin A; Nociceptors; Pain; Piperidines; Pressure; Rats; Rats, Wistar; Receptors, Neurokinin-2; Spinal Cord; Substance P

The present study was designed to investigate the modulatory effects of blockade of spinal histamine receptors on antinociception induced by spinally administered morphine, beta-endorphin and U50, 488H. The effects of intrathecal (i.t.) injections with cyproheptadine (a histamine-1 (H1) receptor antagonist), ranitidine (an H2 receptor antagonist), or thioperamide (an H3 receptor antagonist) injected i.t., on the antinociception induced by morphine, beta-endorphin or trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl) cyclohexyl] benzeocetamide (U50, 488H) injected intrathecally (i.t.) were studied. The antinociception was assayed using the tail-flick test. The i.t. injection of cyproheptadine (20 micrograms), ranitidine (20 micrograms), or thioperamide (20 micrograms) alone did not produce any antinociceptive effect. i.t. pretreatment with cyproheptadine attenuated the inhibition of the tail-flick response induced by i.t. administered morphine or beta-endorphin, but not U50, 488H. In addition, i.t. pretreatment with ranitidine attenuated the inhibition of the tail-flick response induced by i.t. administered morphine, beta-endorphin, or U50, 488H. Furthermore, the i.t. pretreatment with thioperamide attenuated the inhibition of the tail-flick response induced by beta-endorphin or U50, 488H, but not morphine, administered i.t. Our results indicate that spinal H1 receptors may be involved in the production of antinociception induced by spinally applied morphine or beta-endorphin- but not U50, 488H. Spinal H2 receptors appear to be involved in spinally administered morphine-, beta-endorphin- and U50, 488H-induced antinociception. Supraspinal histamine H3 receptors may be involved in the production of antinociception induced by supraspinally applied beta-endorphin or U50, 488H, but not morphine.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Animals; beta-Endorphin; Cyproheptadine; Histamine H1 Antagonists; Histamine H2 Antagonists; Injections, Spinal; Male; Mice; Mice, Inbred ICR; Morphine; Pain; Pain Measurement; Piperidines; Pyrrolidines; Ranitidine; Receptors, Histamine H1; Receptors, Histamine H2; Receptors, Histamine H3; Spinal Cord

In anaesthetized rats, the neurokinin (NK)1 receptor antagonist SR140333 (10-1000 micrograms/kg) stereo-selectively inhibited mustard oil-induced plasma protein extravasation in the dorsal skin of the hind paw. After s.c. administration of SR140333, inhibition of plasma protein extravasation was maximal 3 h after injection. A dose of 0.1 mg/kg i.v. or 1.0 mg/kg s.c. produced long-lasting inhibition which was still significant 24 h after treatment. Since systemic administration of SR140333 has been shown to inhibit nociceptive responses in anaesthetized rats, we wanted to evaluate a possible effect of SR140333 on chemo- and thermonociception in conscious rats. SR140333 (100 micrograms/kg s.c.) did not reduce the behavioral response of rats to the irritant effect of capsaicin in the wiping test, nor did it affect the thermal nociceptive threshold in the plantar test. Furthermore, the decrease in thermal nociceptive threshold which was produced by intraplanter injection of PGE2, and which has been shown to be entirely dependent on capsaicin-sensitive afferents, was not affected by treatment with this NK1 receptor antagonist. These results show that systemic administration of SR140333, at doses which cause inhibition of neurogenic inflammation, has no detectable effect on acute chemo- or thermonociception in conscious rats.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Blood Proteins; Capillary Permeability; Capsaicin; Dinoprostone; Female; Hot Temperature; Injections, Intravenous; Injections, Subcutaneous; Male; Motor Activity; Nerve Tissue; Neurokinin-1 Receptor Antagonists; Nociceptors; Pain; Pain Measurement; Piperidines; Quinuclidines; Rats; Rats, Sprague-Dawley

Because histamine (HA) in the CNS may be a mediator of antinociception, a detailed investigation of the effects of the brain-penetrating H2 antagonist zolantidine (ZOL) was performed on five nociceptive tests in the presence and absence of morphine (MOR) in rats. ZOL inhibited MOR antinociception on the tail flick test, although a diurnal difference (inhibition in the dark cycle >> light cycle) was found. Similar results were found with the hot plate test, although details of the test procedure were significant. In contrast, ZOL induced opposing effects on MOR antinociception on two nonthermal tests (jump test and tail pinch test); ZOL alone induced moderate antinociception on the former test and mild antinociception on the latter test. Thus, ZOL exerts differential effects on baseline nociception and on MOR antinociception that vary depending on the nociceptive test employed, the light-dark cycle of the subjects, and the degree of stress associated with the nociceptive testing. These complex effects reveal the heterogeneous nature of opiate-induced modulation of nociception, and show that ZOL is a powerful tool for studying the relationships between opiates, HA, and nociceptive mechanisms.

Topics: Animals; Benzothiazoles; Blood-Brain Barrier; Histamine H2 Antagonists; Hot Temperature; Male; Morphine; Pain; Pain Measurement; Phenoxypropanolamines; Piperidines; Rats; Rats, Sprague-Dawley; Reproducibility of Results; Thiazoles

The effects of the brain-penetrating H2 antagonist zolantidine (ZOL, 3 mg/kg, s.c.) were studied on morphine (MOR, 4 mg/kg, s.c.) antinociception (tail flick test) in the presence and absence of previous restraint stress. Animals were handled for 3 days (to reduce handling stress), restrained for 1 hr or handled on day 4, and tested 24 hrs later. As found previously, restraint enhanced the intensity and duration of MOR antinociception. ZOL potentiated MOR antinociception in handled, non-restrained animals, but inhibited MOR action in restrained animals. In contrast, ZOL had no effects on nociceptive responses in either handled or stressed subjects in the absence of MOR. The data suggest that, in the absence of restraint, brain HA acts at the H2 receptor to inhibit MOR antinociception. In contrast, when an animal has been previously restrained, HA enhances MOR antinociception. Thus, brain HA appears to mediate the restraint-induced potentiation of MOR antinociception. Taken with previous results, the present findings suggest that in the presence of MOR, brain HA can provide bidirectional modulation of nociception. The direction of the modulation seems to depend upon the stress experience of the animal.

Topics: Analysis of Variance; Animals; Benzothiazoles; Histamine; Histamine H2 Antagonists; Male; Morphine; Pain; Phenoxypropanolamines; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Histamine H2; Restraint, Physical; Thiazoles; Time Factors

Topics: Animals; Benzamides; Biphenyl Compounds; Models, Neurological; Neurokinin A; Neurokinin-1 Receptor Antagonists; Oligopeptides; Pain; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Neurokinin-1; Receptors, Neurokinin-2; Receptors, Neurokinin-3; Receptors, Neurotransmitter; Spinal Cord; Substance P

The acute effect of two different reversible inhibitors of monoamine oxidase-A on nociceptive thresholds was evaluated in the rat by the tail-flick and hot-plate tests. CGP 11305-A, a monoamine oxidase-A inhibitor that also blocks serotonin reuptake, elicited an increase of latency in the tail-flick and the hot-plate test. Ineffective doses of CGP 11305-A increased nociceptive thresholds when administered in combination with other serotoninergic agents, i.e. chlorimipramine or 5-hydroxytryptophan, at doses that were ineffective alone. CGP 22364-A, a pure inhibitor of monoamine oxidase-A, increased latency only in the hot-plate test. Both compounds decreased spontaneous locomotor activity at the doses effective in the hot-plate test, suggesting that the responses observed in this test are not related to a pure effect on nociceptive thresholds. The data suggest that the increase in serotonin availability induced by monoamine oxidase-A inhibition alone is not sufficient to affect nociceptive thresholds.

Topics: Animals; Male; Monoamine Oxidase Inhibitors; Pain; Piperidines; Rats; Rats, Inbred Strains; Sensory Thresholds; Serotonin

Our work has focused on identifying the type of serotonin receptor through which serotonin acts as a developmental signal in the central nervous system. Previously, we have found that the regulation of development of ascending serotonergic neurons is through the balance of two serotonin receptors. One, the 5-HT1a receptor, releases a growth factor from astroglial cells. The other receptor is related to a release-regulating autoreceptor and can be stimulated indirectly by serotonin releasers such as fenfluramine. In the present study, we examined the receptors which regulate development of the descending neurons by treating pregnant rats with selective serotonergic drugs, from gestation day 12 until birth. Pups were subsequently tested for alterations in development by nociceptive testing (tail-flick latency) and by determining the binding of 3H-paroxetine, an indicator of serotonin terminal density, in spinal cord. Our results show that agents stimulating the 5-HT1a receptor (8-OH-DPAT) or the 5-HT1b receptor (TFMPP) or substances which release serotonin (fenfluramine) had no effect on the development of spinal serotonergic pathways. However, agents acting on the 5-HT3 receptor did--the agonist phenylbiguanide (PG) increased latency on tail-flick testing (postnatal days 10 and 30), while the antagonist, MDL 72222, decreased latency (postnatal days 10 and 18). Interestingly, both the agonist and the antagonist significantly increased 3H-paroxetine binding on postnatal day 18. Our results are discussed in terms of a possible mechanism by which 5-HT3 receptors may influence development.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Aging; Animals; Biguanides; Female; Fenfluramine; Hypoglycemic Agents; Maternal-Fetal Exchange; Neurons; Pain; Paroxetine; Piperazines; Piperidines; Pregnancy; Rats; Rats, Inbred Strains; Receptors, Serotonin; Serotonin; Serotonin Antagonists; Spinal Cord; Tetrahydronaphthalenes; Tropanes

Thiofentanil is a synthetic analgesic with pharmacological effects similar to etorphine hydrochloride (M99). The aim of the present study was to assess its analgesic and immobilization effects and to evaluate its dependence potential in comparison with morphine. The median analgesic dose (AD50) was measured by hot plate method in mice. The median paralytic dose (PD50), as an indicator of immobilization, was tested in rats, rabbits, dogs and monkeys. Results showed that the analgesic potency of this drug was 3260 times that of morphine, 22 times that of fentanyl and 1.5 times that of M99 and the immobilization effect was 2-3 times that of M99. Results from jumping test in mice and physical dependence-producing test in rats (the drug was dissolved in drinking water) showed that thiofentanil possessed physical dependence liability weaker than morphine. Physical dependence was not observed in rats with intravenous injection of one dose each h over a period of 72 h, and also in monkey with 20-week drug medication. The LD50 of thiofentanil was also determined in mice, rats, rabbits, dogs and monkeys in comparison with M99. Results suggest that it should be valuable to develop thiofentanil as an analgesic for clinical use.

Topics: Analgesics, Opioid; Animals; Dogs; Female; Immobilization; Macaca mulatta; Male; Mice; Pain; Piperidines; Rabbits; Rats; Sensory Thresholds; Substance Withdrawal Syndrome; Substance-Related Disorders; Thiazoles

Topics: Analgesics; Animals; Clinical Trials as Topic; Humans; Nervous System Diseases; Pain; Pain Measurement; Palliative Care; Paroxetine; Piperidines

The effect of zolantidine dimaleate (ZOL), the first brain-penetrating histamine H2 receptor antagonist, was determined on morphine (MOR) antinociception (ANC) in rhesus monkeys. ZOL (0.75 mg/kg, s.c., given every 30 min), completely attenuated the ANC resulting from the lowest dose of MOR tested (1.0 mg/kg), with no effect on the responses to higher doses (3-10 mg/kg). ZOL had no effect on baseline nociceptive responses in the absence of MOR. Taken with previous studies on the pharmacological specificity of ZOL, the ANC properties of histamine, and more extensive studies in rodents, the present results suggest that opiates like MOR relieve pain in primates by mechanisms that include activation of brain H2 receptors.

Topics: Animals; Benzothiazoles; Dose-Response Relationship, Drug; Double-Blind Method; Female; Histamine H2 Antagonists; Macaca mulatta; Morphine; Pain; Phenoxypropanolamines; Piperidines; Thiazoles

The effects of levocabastine (R 50 547; CAS 79516-68-0) on the central nervous system were studied in comparison with those of diphenhydramine, ketotifen and azelastine. At high doses, levocabastine caused a decrease in locomotor activity, prolongation of thiopental-induced sleep, depression of acetic acid-induced writhing in mice and inhibition of active avoidance response in rats, but these adverse effects were much less potent than those seen in diphenhydramine, ketotifen and azelastine. Oxotremorine-induced tremor and salivation in mice were delayed after extremely high dosage of levocabastine; however, these were much less effective than those seen after diphenhydramine and ketotifen. Levocabastine did not affect the tonic extensor seizure induced by maximal electroshock in mice which is different from that of diphenhydramine. In EEG analysis, levocabastine at a dose of 20 mg/kg caused no significant changes in the EEG recorded from the frontal cortex, occipital cortex, hippocampus and amygdala in rats with chronic electrodes.

Topics: Acetates; Animals; Avoidance Learning; Central Nervous System; Electroencephalography; Histamine H1 Antagonists; Male; Mice; Mice, Inbred Strains; Motor Activity; Oxotremorine; Pain; Piperidines; Rats; Rats, Inbred Strains; Salivation; Sleep; Thiopental; Tremor

The antinociceptive properties of the 5-HT2 antagonist ritanserin have been investigated in the writhing test using rats implanted with chronic lumbar catheters. The antinociceptive action of 15 mg/kg ritanserin applied subcutaneously (s.c.) was powerfully inhibited by the intrathecal (i.t.) application of ritanserin (50 nmol), methysergide (15 nmol), yohimbine (20 nmol), alpha-flupenthixol (20 nmol) or naloxone (15 nmol), but not atropine (30 nmol), at doses which themselves produced no change in nociceptive threshold. It is concluded that ritanserin acts supraspinally to activate pain-modulating descending serotonergic, noradrenergic, dopaminergic and possibly opioidergic pathways, while spinopetal cholinergic pathways do not seem to be involved. Hyperalgesic effects of s.c. ritanserin following the i.t. application of methysergide or yohimbine were interpreted in terms of the co-release of an excitatory transmitter, possibly substance P, from descending serotonergic and noradrenergic nerve fibres. The supraspinal mechanism by which ritanserin activates spinopetal pathways and its dependence on 5-HT2 receptors have not yet been established.

Topics: Animals; Methysergide; Nociceptors; Pain; Piperidines; Rats; Receptors, Serotonin; Ritanserin; Spinal Cord; Yohimbine

A series of novel 1'-methylxanthene-9-spiro-4'-piperidines has been prepared in the search for opiate analgesics with improved pharmacological properties. It has been found that introduction of a hydroxyl group into the 4-position of the xanthenespiropiperidine nucleus produces a potent mu-opiate agonist. The structure-activity relationship of the series has been explored by use of isosteric replacements of the phenolic hydroxyl group. Moreover, the effect of altering the conformation of the piperidine ring has been studied. It was interesting to note that, in compounds lacking the phenolic hydroxyl group, opiate activity could be produced by introduction of the (phenylamino)ethyl group instead of methyl at the 1'-position.

Topics: Analgesics, Opioid; Animals; Guinea Pigs; Ileum; In Vitro Techniques; Mice; Molecular Structure; Muscle Contraction; Muscle, Smooth; Pain; Piperidines; Structure-Activity Relationship; Xanthines

A non-comparative multicentre study of 105 patients with healed duodenal ulcers was conducted to determine the effect on ulcer recurrence of 6 months' maintenance treatment with roxatidine acetate 75 mg daily. All patients had previously received roxatidine acetate treatment. 31 patients out of 89 had 32 relapsed ulcers after 6 months of treatment, which represents an overall relapse rate of around 30%; the relapse rate in smokers was double that of non-smokers. The overall incidence of epigastric pain did not increase significantly over the period of the trial, although some patients complained of mild pain when they entered the study despite having endoscopically confirmed healed ulcers. At the end of the study continuous poor appetite and pyrosis were reported by 17% and 6% of patients, respectively. Side effects, which included constipation and diarrhoea, were reported by 4 patients, 1 of whom withdrew from therapy. There were no clinically significant changes in laboratory values. Thus, maintenance treatment with roxatidine acetate 75 mg daily proved a safe and effective method of preventing symptomatic duodenal ulcer relapse.

Topics: Adult; Aged; Duodenal Ulcer; Female; Histamine H2 Antagonists; Humans; Male; Middle Aged; Pain; Piperidines; Recurrence; Time Factors

Pirenperone, a new serotonin antagonist with a selective affinity for the 5-HT2 receptor, was administered in conjunction with tests for the antinociceptive effects of morphine sulphate and electrical brain-stimulation at sites in the periaqueductal gray (PAG) and nucleus raphe magnus (NRM). Nociception was assessed by tail-flick latencies in a warm water bath and pirenperone (0.04-0.16 mg/kg) had no effect on baseline scores. When administered prior to morphine, pirenperone (0.16 mg/kg) caused significant attenuation of analgesia induced by morphine. Comparable effects of pirenperone were observed when analgesia was produced by electrical stimulation of the NRM. In contrast, pirenperone had no effect on the analgesic effects of PAG stimulation. This pattern of results suggests that a system involving supraspinal 5-HT2 receptors may modulate some of the antinociceptive effects of morphine and stimulation of the NRM. The differential effects of pirenperone on stimulation-produced analgesia at sites in the NRM and PAG is consistent with separate neural substrates for the analgesia observed from stimulation of these two brain regions.

Topics: Animals; Central Nervous System; Electric Stimulation Therapy; Male; Morphine; Neural Pathways; Pain; Pain Management; Periaqueductal Gray; Piperidines; Raphe Nuclei; Rats; Reaction Time; Receptors, Serotonin

A series of 4-(m-OH phenyl)-piperidine analogs with R4 = methyl or t-butyl and NR = methyl, allyl and phenethyl have been synthesized; and their receptor affinities, in vivo analgetic agonism and antagonism, and energy-conformational profiles determined. These analogs bind selectively and with moderate to high affinity to opioid mu-receptors. Binding in their preferred phenyl axial conformation appears to lead to meperidine-like agonism. In addition, for some R4 = methyl but not t-butyl compounds, binding of an energy-accessible phenyl equatorial conformation produces antagonism.

Topics: Analgesics; Molecular Conformation; Pain; Phenol; Phenols; Piperidines; Structure-Activity Relationship

Both thresholds of nociceptive flexion reflex and pain sensation were studied in 6 normal subjects and in 6 patients with typical thalamic pain. In these patients, on the painful side, these thresholds were found increased (98 p. 100; 89 p. 100 respectively) compared to the normal side. Values obtained in this latter did not significantly differ from those observed in normal subjects. After 8 days of indalpine treatment, the nociceptive reflex threshold was furthered increased in the painful side while the pain threshold was not modified by this drug. In the normal side, changes observed after indalpine were similar to that obtained in normal subjects. All the indalpine-induced modifications were reversed by naloxone in both patients and normals. These results are discussed in the context of the possible mechanisms of thalamic hyperpathia.

Topics: Aged; Female; Humans; Male; Middle Aged; Naloxone; Pain; Pain Measurement; Piperidines; Reflex; Sensory Thresholds; Serotonin; Syndrome; Thalamic Diseases

Picenadol is a unique opioid mixed agonist-antagonist analgesic currently under clinical evaluation. Structurally, picenadol is a 4-phenylpiperidine derivative and a racemic mixture whose mixed agonist-antagonist properties are a consequence of the d-isomer being a potent opiate agonist, whereas the l-isomer is an opioid antagonist. In the mouse writhing and rat tail heat tests, the analgesic potency of picenadol is estimated to be 1/3 that of morphine. Picenadol itself has weak antagonist activity, whereas the antagonist potency of the l-isomer is approx. 1/10 that of nalorphine. Evaluation of picenadol's affinity for opioid receptors reveals that picenadol, unlike other mixed agonist-antagonists has high affinity for both the mu and delta receptors but a markedly lower affinity for the kappa receptor. Extensive pharmacological investigations show picenadol to have a low potential to produce opiate-like side effects, including a low liability for abuse and physical dependence.

Topics: Animals; Chemical Phenomena; Chemistry; Columbidae; Dogs; Drug Tolerance; Female; Guinea Pigs; Male; Mice; Morphine; Motor Activity; Naloxone; Pain; Piperidines; Rats; Rats, Inbred Strains; Receptors, Muscarinic; Receptors, Neurotransmitter; Receptors, Opioid; Receptors, Phencyclidine

Research was conducted into post-operative pain and possible means for its control. A total of 66 patients subdivided into 3 groups were studied. In order to document analgesic effectiveness, pain was measured by two subjective methods--Huskisson's Visual Analogue and the "SCORE" index. Patients' anxiety was assessed pre-operatively by a suitably modified tourniquet test. The groups of patients were subdivided according to the analgesic agent used: 1st group (herniectomies, appendicectomies) Baralgina f. 1; 2nd group (cholecystectomies, hysterectomies) Talwin f. 1; 3rd group (cholecystectomies, hysterectomies) Baralgina f. 1 + Talwin f. 1. The latter combination proved to be satisfactory and guaranteed a sufficiently calm post-operative period. On the basis of the data obtained, it is recommended that anaesthesiological procedures include analgesic cover that exploits the action of Phentanyl as an analgesic agent and neurovegetative stabilizer and is to be used at the start of the operation. For operations lasting more than 60 minutes, a combination of Baralgina and Talwin or Buprenorfina may be administered during the post-operative period.

Topics: Adolescent; Adult; Aged; Analgesia; Appendectomy; Benzophenones; Child; Cholecystectomy; Dipyrone; Drug Combinations; Female; Herniorrhaphy; Humans; Hysterectomy; Male; Middle Aged; Pain; Pentazocine; Piperidines; Postoperative Complications

Eight 1-(arylaminothiocarbonyl)-4-hydroxy-4-phenyl piperidines were evaluated for their central nervous system depressant, analgesic, and monoamine oxidase inhibitory properties. The central nervous system depressant property of these substituted piperidines was reflected by their ability to potentiate pentobarbital-induced sleep in mice ranging from 18.3 to 58.5 minutes. The analgesic activity possessed by these substituted piperidines, with the exception of one compound, was shown by their ability to provide 16.7 to 50 percent protection against tail pinch response in mice. All substituted piperidines (1 mM) inhibited in vitro activity of rat brain monoamine oxidase with the degree of inhibition ranging from 17.2 to 18.3 percent.

Topics: Analgesics; Animals; Brain; Central Nervous System Depressants; Male; Monoamine Oxidase Inhibitors; Pain; Piperidines; Rats; Sleep; Structure-Activity Relationship

Contraction of the isolated tracheal strip to capsaicin was prevented by chronic denervation of the tissue. Tetrodotoxin, hyoscine and hexamethonium caused no inhibition of the response, suggesting that tetrodotoxin-resistant terminal portions of non-cholinergic nerves were activated in this way. There was a strong correlation between the pain-producing and tracheoconstrictor effects of piperine, pungent and non-pungent capsaicin congeners. Common site of action was evidenced by crossed tachyphylaxis. It is concluded that the capsaicin-sensitive sensory nerve endings have a dual sensory-efferent function. Excitation-secretion coupling in this system could operate without an axon reflex.

Topics: Alkaloids; Animals; Benzodioxoles; Capsaicin; Denervation; Dose-Response Relationship, Drug; Drug Interactions; Guinea Pigs; Muscle, Smooth; Neuromuscular Junction; Pain; Piperidines; Polyunsaturated Alkamides; Tetrodotoxin; Trachea

Topics: Animals; Drug Interactions; Female; Male; Morphine; Pain; Piperidines; Rats; Serotonin

Topics: Analgesics, Opioid; Animals; Arthritis, Experimental; Benzimidazoles; Chronic Disease; Drug Tolerance; Male; Morphine; Mycobacterium; Pain; Piperidines; Rats

Topics: Analgesics, Opioid; Animals; Benzimidazoles; Chronic Disease; Drug Tolerance; Morphine; Naloxone; Pain; Piperidines; Rats; Reaction Time; Time Factors

Topics: Biperiden; Humans; Pain; Piperidines

The effects of various narcotic analgesics on striatal homovanillic acid (HVA) content, hot plate time and rectal temperature in mice were compared in relation to dose and time. The hypothermia induced by narcotic analgesics did not correlate with the striat"al HVA increase. Pentazocine, cyclazocine and thebaine had no effect on the hot plate time. The maximum prolongation of hot plate time induced by morphine, methadone or piminodine occurred before the highest HVA increase. The highest increase induced by narcotic analgesics in striatal HVA content was twice the original concentration. This occurred 2 hr after 40 mg/kg of morphine; 2 hr after 20 mg/kg of methadone; 1/2 hr after 20 mg/kg of piminodine; and 1 hr after 60 mg/kg of pentazocine. Cyclacozine (10 and 20 mg/kg) and thebaine (10 mg/kg) did not alter the HVA content. With the exception of pentazocine, those doses of narcotic analgesics that caused equal increases in striatal HVA content were also equianalgesic. These results suggest that there are similarities in the structural requirements for antinociceptive and striatal HVA-increasing effects of narcotic analgesics. The neuroleptic compound haloperidol (0.5 mg/kg) caused a fourfold increase in striatal HVA content making it twice as efficient as narcotic analgesics. This finding suggests that narcotic analgesics do not act on the same sites as neuroleptics when causing an increase in striatal HVA content.

Topics: Analgesics, Opioid; Animals; Body Temperature; Corpus Striatum; Cyclazocine; Haloperidol; Homovanillic Acid; Male; Methadone; Mice; Morphine; Pain; Pentazocine; Phenylacetates; Piperidines; Thebaine; Time Factors

Topics: Autonomic Nerve Block; Benzimidazoles; Carcinoma; Celiac Plexus; Female; Glycerol; Humans; Liver Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Nitriles; Pain; Palliative Care; Phenols; Piperidines; Sigmoid Neoplasms

Topics: Aminopyrine; Dipyrone; Drug Combinations; Drug Evaluation, Preclinical; Humans; Pain; Piperidines; Piperidones; Placebos; Skin

A quantitative method for measuring the efficiency of pungent agents of capsaicin-type by the pain reaction elicited on the eye of rats is described. About 50 derivatives -- most of them amides or esters of homovanillic acid -- were tested by this method and the share of different chemical groups of the molecule in the pungent action was analyzed. It turned out that the presence of an acylamide linkage or alkyl chain is not essential for pungency, since acylamide linkage can be replaced by an esteric group and the alkyl chain by cycloalkyl rings. The importance of OH group on the aromatic ring is confirmed. On the basis of the findings a hypothetical pharmacological receptor for capsaicin on pain sensory nerve endings is presented.

Topics: Animals; Butanones; Capsaicin; Condiments; Dose-Response Relationship, Drug; Fatty Acids, Unsaturated; Homovanillic Acid; Pain; Piperidines; Rats; Sensory Receptor Cells; Structure-Activity Relationship

Topics: Amides; Analgesics; Animals; Cough; Dose-Response Relationship, Drug; Drug Antagonism; Drug Evaluation, Preclinical; Drug Synergism; Edema; Female; Fumarates; Hindlimb; Humans; Male; Motor Activity; Pain; Piperidines; Propionates; Pyridines; Respiration; Self Medication; Spasm; Substance Withdrawal Syndrome; Tail

Topics: Administration, Oral; Amides; Analgesics; Differential Threshold; Electric Stimulation; Female; Fumarates; Humans; Male; Motor Activity; Pain; Piperidines; Propionates; Pyridines; Reflex, Pupillary; Stereoisomerism

Topics: Acute Disease; Amides; Analgesics; Chronic Disease; Drug Combinations; Drug Evaluation; Female; Fumarates; Humans; Male; Nerve Compression Syndromes; Neuralgia; Pain; Piperidines; Propionates; Pyridines

Topics: Amides; Analgesics; Colic; Drug Evaluation; Female; Fumarates; Headache; Humans; Male; Neuralgia; Pain; Pain, Postoperative; Piperidines; Propionates; Pyridines; Sampling Studies; Suppositories

Topics: Animals; Apomorphine; Avoidance Learning; Behavior, Animal; Butyrophenones; Catalepsy; Cats; Chlorpromazine; Drug Evaluation, Preclinical; Drug Synergism; Electroencephalography; Epinephrine; Haloperidol; Hexobarbital; Humans; Hydrocarbons, Fluorinated; Imipramine; Lethal Dose 50; Male; Methamphetamine; Mice; Motor Activity; Pain; Piperidines; Rats; Trifluperidol

Topics: Analgesia; Analgesics; Animals; Bridged-Ring Compounds; Depression, Chemical; Dextropropoxyphene; Dimethylamines; Electric Stimulation; Ketones; Male; Meperidine; Methadone; Mice; Morphine; Pain; Piperidines; Thiophenes

Topics: Adolescent; Adult; Aged; Analgesics; Benperidol; Benzimidazoles; Child; Chronic Disease; Cough; Drug Synergism; Female; Humans; Male; Middle Aged; Neoplasm Metastasis; Neoplasms; Pain; Palliative Care; Piperidines; Psychology; Substance-Related Disorders

Topics: Benzocycloheptenes; Diagnosis, Differential; Ergotamine; Headache; Humans; Methysergide; Migraine Disorders; Pain; Piperidines; Thiophenes

Topics: Adult; Aged; Analgesics; Benperidol; Drug Tolerance; Female; Humans; Male; Middle Aged; Pain; Piperidines; Substance-Related Disorders; Time Factors

Topics: Adult; Biliary Tract Diseases; Female; Gastrointestinal Diseases; Humans; Kidney Calculi; Male; Middle Aged; Pain; Parasympatholytics; Piperidines

Topics: Analgesics; Antipyrine; Carbachol; Colic; Dioxoles; Humans; Methylamines; Pain; Parasympatholytics; Pentazocine; Piperidines; Sulfonic Acids; Urinary Bladder Diseases

Topics: Analgesics; Benzimidazoles; Humans; Pain; Piperidines

Topics: Abdomen; Adult; Aged; Aminopyrine; Analgesics; Female; Humans; Male; Middle Aged; Pain; Piperidines

Topics: Administration, Oral; Adolescent; Adult; Aged; Analgesics; Dioxoles; Female; Humans; Male; Middle Aged; Pain; Piperidines; Urinary Calculi

Topics: Adult; Alkaloids; Anti-Bacterial Agents; Anti-Infective Agents, Local; Bandages; Burns; Burns, Chemical; Burns, Electric; Child; Electrolytes; Eye Injuries; Facial Injuries; First Aid; Humans; Pain; Piperidines; Plasma Substitutes; Pyrazoles; Respiratory System; Shock; Tetanus; Transportation of Patients; Wounds and Injuries

Topics: Analgesics; Arthritis; Aspirin; Codeine; Dioxoles; Drug Synergism; Humans; Neoplasms; Pain; Palliative Care; Piperidines

Topics: Anesthetics, Local; Anilides; Cardiovascular Diseases; Humans; Neuritis; Pain; Piperidines; Spondylitis; Surgical Procedures, Operative; Xylenes

Topics: Adult; Aminopyrine; Benzilates; Colic; Drug Synergism; Female; Gallbladder Diseases; Gastrointestinal Diseases; Humans; Male; Middle Aged; Muscles; Pain; Piperidines; Spasm; Urologic Diseases

Topics: Adolescent; Adult; Aged; Aminopyrine; Benzilates; Child; Drug Synergism; Female; Humans; Male; Middle Aged; Muscles; Pain; Piperidines; Postoperative Complications

Topics: Aged; Analgesics; Female; Hallucinations; Humans; Male; Middle Aged; Nitriles; Pain; Phenothiazines; Piperidines; Tranquilizing Agents

Topics: Aminopyrine; Analgesics; Humans; Pain; Piperidines; Postoperative Care; Postoperative Complications; Sulfonic Acids

Topics: Analgesics; Analgesics, Non-Narcotic; Antipyretics; Aspirin; Biomedical Research; Dioxolanes; Drug Therapy; Female; Hallucinogens; Humans; Pain; Pharmacology; Piperidines; Placebos; Puerperal Disorders; Toxicology

Topics: Analgesia; Arteriosclerosis; Biomedical Research; Double-Blind Method; Drug Therapy; Geriatrics; Humans; Meperidine; Morphine; Myocardial Infarction; Pain; Pharmacology; Piperidines; Transplantation, Homologous

Topics: Analgesics; Analgesics, Non-Narcotic; Antipyretics; Codeine; Humans; Hydromorphone; Meperidine; Methadone; Morphine; Narcotics; Oxymorphone; Pain; Phenazocine; Piperidines

Topics: Anticonvulsants; Antihypertensive Agents; Glutethimide; Humans; Pain; Peripheral Arterial Disease; Peripheral Vascular Diseases; Piperidines; Postoperative Care; Postoperative Period; Preoperative Care; Reserpine; Secologanin Tryptamine Alkaloids; Vascular Diseases

Topics: Analgesics; Anesthesia; Humans; Pain; Pain, Postoperative; Piperidines

Topics: Analgesia; Morphine; Morphine Derivatives; Pain; Piperidines