piperidines and Chronic-Pain

To summarize and evaluate the existing literature regarding medications to treat opioid-induced constipation (OIC) in patients with chronic noncancer pain (CNCP).. PubMed, EMBASE, and Web of Science were searched using the following terms: constipation, opioid, chronic, pain, noncancer, nonmalignant, methylnaltrexone, alvimopan, lubiprostone, naloxegol, and naldemedine.. The search was limited to randomized controlled trials reporting human outcomes. Data extracted included the following: study design, population, intervention, control, outcomes related to OIC and safety, and potential biases assessed using Cochrane Collaboration's Risk of Bias Assessment Tool.. After assessment, 16 of the 190 studies were included: methylnaltrexone (n = 4), naloxegol (n = 3), naldemedine (n = 2), lubiprostone (n = 3), and alvimopan (n = 4). Lubiprostone was the only nonperipherally acting µ-opioid receptor antagonist included. Only 1 study (naloxegol) used "usual care" (nonstudy laxative) rather than placebo as a comparator. Placebo-controlled trials demonstrated benefit for methylnaltrexone, naloxegol, naldemedine, and lubiprostone, with conflicting evidence for alvimopan. No data suggest that one agent is better than another. Overall risk of bias across all studies was low to moderate.. With risk of bias determined to be low to moderate, published data to date suggest that methylnaltrexone, naloxegol, and naldemedine may be appropriate to treat OIC in patients with CNCP.

Topics: Analgesics, Opioid; Chronic Pain; Constipation; Evidence-Based Practice; Humans; Laxatives; Lubiprostone; Morphinans; Naltrexone; Narcotic Antagonists; Piperidines; Polyethylene Glycols; Quaternary Ammonium Compounds; Randomized Controlled Trials as Topic

Remifentanil is an ultra-short-acting opioid that is used commonly during both short-term and prolonged surgery. This review investigated associations of intraoperative remifentanil administration with acute postoperative pain, hyperalgesia, and chronic postoperative pain, with emphasis on the perioperative coanesthetic drug regimen used.. Medline and Embase databases were searched for randomized studies, evaluating the intraoperative use of remifentanil (>2 h) versus another analgesic or a different dosage of remifentanil, and reporting acute postoperative pain parameters such as postoperative pain scores, hyperalgesia, acute opioid tolerance, or analgesics requirements. Furthermore, all studies in which remifentanil was used intraoperatively and parameters for chronic postoperative pain were measured were included (pain levels after a prolonged period of time after surgery).. From the 21 studies that were identified, less than half of the studies found higher acute postoperative pain, higher postoperative analgesic requirements after intraoperative remifentanil use, or both. Coanesthetics to some extent determined this incidence, with mainly studies using volatile agents reporting increased pain levels. There was less evidence when remifentanil was combined with total intravenous anesthesia or a combination of anesthetics. The limited number of studies (n=4) evaluating chronic pain suggested a potential association with the intraoperative use of remifentanil.. Although studies are diverse and sample sizes small, coanesthetics used in combination with remifentanil may influence the occurrence of postoperative hyperalgesia. No firm conclusions could be made regarding acute and chronic pain, indicating that further research with the goal to investigate the effect of volatile or intravenous anesthetics along with simultaneous remifentanil infusion on acute and chronic postoperative pain is needed.

Topics: Analgesics, Opioid; Chronic Pain; Humans; Intraoperative Care; Pain, Postoperative; Piperidines; Remifentanil

Chronic thoracic pain after cardiac surgery is prevalent (11 to 56%) and may affect patients' physical and mental health status. Despite its favorable pharmacokinetic and pharmacodynamic properties, high doses of remifentanil administered during surgery are reported to cause acute postoperative pain and increased requirements for analgesics. Recently, an association between remifentanil use and the incidence of chronic thoracic pain in the long term was also reported. Our objective is to investigate the influence of the intraoperative remifentanil on chronic postoperative pain in a prospective randomized controlled trial.. In this prospective, randomized, single-blind clinical trial, all patients (N = 126) between 18 and 85 years undergoing cardiac surgery via sternotomy receive a continuous infusion of propofol together with intermittent intravenous fentanyl at predetermined times perioperatively. Patients are randomized to receive either an additional continuous infusion of remifentanil (0.15 μg(-1)kgIBW(-1) min(-1)) or additional fentanyl (200 to 500 μg) as needed during surgery.The primary end point is the prevalence of chronic thoracic pain 12 months after surgery. Secondary end points include acute postoperative pain; postoperative analgesic use; chronic thoracic pain 3 and 6 months after surgery; quality of life (SF-12) at 3, 6 and 12 months after surgery; work productivity; and use of health care. In addition, thermal detection and pain thresholds are measured preoperatively, 3 days after surgery and 12 months after surgery using quantitative sensory testing (QST). Finally, the influence of several genetic variances on the different outcomes will be measured.. Chronic thoracic pain is prevalent after cardiac surgery, and research is needed to minimize the risk of chronic persistent postoperative pain, which is an invalidating, long-term complication of surgery. The objective of this trial is to determine the influence of perioperative remifentanil on long-term pain outcomes for cardiac patients in a prospective randomized trial. The results may be used to optimize perioperative analgesia techniques and, thereby, improve quality of life after cardiac surgery.. Clinicaltrials.gov NCT02031016 on 13 December 2013.

Topics: Analgesics, Opioid; Cardiac Surgical Procedures; Chest Pain; Chronic Pain; Clinical Protocols; Drug Administration Schedule; Employment; Fentanyl; Humans; Infusions, Intravenous; Netherlands; Pain Measurement; Pain Threshold; Pain, Postoperative; Piperidines; Prospective Studies; Quality of Life; Remifentanil; Research Design; Single-Blind Method; Surveys and Questionnaires; Thermosensing; Time Factors; Treatment Outcome

Chronic thoracic pain after cardiac surgery is a serious condition affecting many patients. The aim of this study was to identify predictors for chronic thoracic pain after sternotomy in cardiac surgery patients by analysing patient and perioperative characteristics.. A follow-up study was performed in 120 patients who participated in a clinical trial on pain levels in the early postoperative period after cardiac surgery. The presence of chronic thoracic pain was evaluated by a questionnaire 1 yr after surgery. Patients with and without chronic thoracic pain were compared. Associations were studied using multivariable logistic regression analysis.. Questionnaires of 90 patients were analysed. Chronic thoracic pain was reported by 18 patients (20%). In the multivariable regression model, remifentanil during cardiac surgery, age below 69 yr, and a body mass index above 28 kg m(-2) were independent predictors for chronic thoracic pain {odds ratios 8.9 [95% confidence interval (CI) 1.6-49.0], 7.0 (95% CI 1.6-31.7), 9.1 (95% CI 2.1-39.1), respectively}. No differences were observed in patient and perioperative characteristics between patients receiving remifentanil (58%, n=52) compared with patients not receiving remifentanil (42%, n=38). The association between remifentanil and chronic thoracic pain appeared dose-dependent, both for total dose and for dose corrected for kilogram lean body mass and duration of surgery (P-value for trend: <0.01 and <0.005, respectively).. In this follow-up study in cardiac surgery patients, intraoperative remifentanil was predictive for chronic thoracic pain in a dose-dependent manner. Randomized studies designed to evaluate the influence of intraoperative remifentanil on chronic thoracic pain are needed to confirm these results.

Topics: Adult; Aged; Aged, 80 and over; Anesthesia, Intravenous; Anesthesiology; Anesthetics, Intravenous; Cardiac Surgical Procedures; Chronic Pain; Critical Care; Dose-Response Relationship, Drug; Double-Blind Method; Female; Follow-Up Studies; Humans; Intraoperative Period; Male; Middle Aged; Multivariate Analysis; Pain Measurement; Pain, Postoperative; Piperidines; Prospective Studies; Remifentanil; Risk Factors; ROC Curve; Sternotomy; Surveys and Questionnaires

Effectively treating chronic pain remains a therapeutic challenge in the clinic. Recent evidence has shown the inhibition of the soluble epoxide hydrolase (sEH) to be an effective strategy to limit chronic pain in preclinical models, horses and companion animals. Determining the safety of sEH inhibition in addition to this demonstrated efficacy is a critical step to the further development of sEH inhibitors (sEHI) as analgesics. Here we describe a comparison of the sEHI TPPU with other first in class analgesics for human chronic pain. We assess the development of tolerance to the analgesia mediated by TPPU with extended use. We also assess for CNS effects by measuring changes in motor control and functioning. The sEHI are multimodal analgesics that have demonstrated potent efficacy against chronic pain. They have previously been tested and show no reward potential using operant methods. The results of the current experiments show that they lack motor function effects and also lack the development of tolerance with extended dosing.

Topics: Analgesics; Animals; Chronic Pain; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetic Neuropathies; Drug Tolerance; Enzyme Inhibitors; Epoxide Hydrolases; Gait Analysis; Male; Morphine; Phenylurea Compounds; Piperidines; Pregabalin; Rats; Rats, Sprague-Dawley; Streptozocin

Exogenous cannabinoid receptor agonists are clinically effective for treating chronic pain but frequently cause side effects in the central nervous system. Fatty acid amide hydrolase (FAAH) is a primary catabolic enzyme for anandamide, an endogenous cannabinoid agonist. 3-Pyridyl 4-(phenylcarbamoyl)piperidine-1-carboxylate (ASP8477) is a potent and selective FAAH inhibitor that is orally active and able to increase the brain anandamide level and is effective in rat models of neuropathic and osteoarthritis pain without causing motor coordination deficits. In the present study, we examined the pharmacokinetics and pharmacodynamics, analgesic spectrum in pain models, and the anti-nociceptive mechanism of ASP8477. Single and four-week repeated oral administration of ASP8477 ameliorated mechanical allodynia in spinal nerve ligation rats with similar improvement rates. Further, single oral administration of ASP8477 improved thermal hyperalgesia and cold allodynia in chronic constriction nerve injury rats. ASP8477 also restored muscle pressure thresholds in reserpine-induced myalgia rats. This analgesic effect of ASP8477 persisted for at least 4 h, consistent with the inhibitory effect observed in an ex vivo study using rat brain as well as the increasing effect on oleoylethanolamide and palmitoylethanolamide levels but not the ASP8477 concentration in rat brain. ASP8477 also improved α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-, N-methyl-D-aspartic acid (NMDA)-, prostaglandin E

Topics: Amides; Amidohydrolases; Analgesics; Animals; Behavior, Animal; Brain; Chronic Pain; Disease Models, Animal; Enzyme Inhibitors; Ethanolamines; Male; Neuralgia; Oleic Acids; Pain Threshold; Palmitic Acids; Piperidines; Pyridines; Rats, Sprague-Dawley

Chronic pain and sleep have a bidirectional relationship that promotes a vicious circle making chronic pain more difficult to treat. Therefore, pain and sleep should be treated simultaneously. In our previous study, we suggested that hyperactivation of ascending serotonergic neurons could cause secondary sleep disturbance in chronic pain. This study aimed to demonstrate the effects of a tricyclic antidepressant (amitriptyline) and a selective 5-hydroxy-tryptamine 2A (5-HT2A) antagonist (MDL 100907) that adjust serotonergic transmission, on secondary sleep disturbance induced in a preclinical chronic pain model. We produced a chronic neuropathic pain model by partial sciatic nerve ligation in mice, analyzed their electroencephalogram (EEG) and electromyogram (EMG) using the SleepSign software, and evaluated the sleep condition of the pain model mice after administration of amitriptyline or MDL 100907. Amitriptyline improved thermal hyperalgesia and the amount of sleep, especially non-REM sleep. Time change of normalized power density of δ wave in the nerve ligation group with amitriptyline administration showed a normal pattern that was similar to sham mice. In addition, MDL 100907 normalized sleep condition similar to amitriptyline, without improvement in pain threshold. In conclusion, amitriptyline could improve sleep quantity and quality impaired by chronic pain. 5-HT2A receptor antagonism could partially contribute to this sleep improvement, but is not associated with pain relief.

Topics: Amitriptyline; Animals; Antidepressive Agents, Tricyclic; Chronic Pain; Disease Models, Animal; Fluorobenzenes; Male; Mice; Neuralgia; Piperidines; Receptor, Serotonin, 5-HT2A; Serotonin 5-HT2 Receptor Antagonists; Sleep Wake Disorders

Topics: Adenosine; Animals; Anti-Inflammatory Agents; Chronic Pain; Male; Piperidines; Rats; Sciatic Nerve

From the Aristotelian ancient Greece, pain has been associated with appetites or emotions and is opposite to pleasure. Reward and addiction is also linked to pleasure and compulsive drug seeking reinstates pleasure. Alleviation of chronic pain can induce a euphoric phase similar to what is found in addiction. Both chronic pain and addiction are recognized as a disease of the central nervous system. They share many characteristics and brain regions/mechanisms. Evidence points to the usefulness of cannabinoids as a new class of agents to add to the pharmaceutical toolbox in the management of chronic pain. Wilkerson and colleagues, in this issue, examine SA-57, an inhibitor of two different endocannabinoid catabolic enzymes FAAH and MAGL, demonstrating its analgesic effectiveness and morphine-sparing properties in a chronic pain model, as well as its ability to reduce heroin seeking behavior in a self-administration paradigm in mice. This timely study emphasizes the need for development of more efficacious chronic pain therapeutics with minimized abuse potential and/or reinforcing properties. It also highlights the need for better understanding of the overlapping circuitry of chronic pain, reward, and addiction.

Topics: Amidohydrolases; Analgesics; Animals; Chronic Pain; Endocannabinoids; Heroin Dependence; Mice; Monoacylglycerol Lipases; Piperidines

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

The occurrence of chronic stress, depression, and anxiety can increase nociception in humans and may facilitate the transition from localized to chronic widespread pain. The mechanisms underlying chronic widespread pain are still unknown, hindering the development of effective pharmacological therapies. Here, we exposed C57BL/6J mice to chronic unpredictable stress (CUS) to investigate how persistent stress affects nociception. Next, mice were treated with multiple intramuscular nerve growth factor (NGF) injections, which induced chronic widespread nociception. Thus, combination of CUS and NGF served as a model where psychophysiological impairment coexists with long-lasting hyperalgesia. We found that CUS increased anxiety- and depression-like behavior and enhanced basal nociception in mice. When co-applied with repeated NGF injections, CUS elicited a sustained long-lasting widespread hyperalgesia. In order to evaluate a potential therapeutic strategy for the treatment of chronic pain associated with stress, we hypothesized that the endocannabinoid system (ECS) may represent a target signaling system. We found that URB597, an inhibitor of the anandamide-degrading enzyme fatty acid amide hydrolase (FAAH), and JZL184, an inhibitor of the 2-arachidonoyl glycerol-degrading enzyme monoacylglycerol lipase (MAGL), increased eCB levels in the brain and periphery and were both effective in reducing CUS-induced anxiety measured by the light-dark test and CUS-induced thermal hyperalgesia. Remarkably, the long-lasting widespread hyperalgesia induced by combining CUS and NGF was effectively reduced by URB597, but not by JZL184. Simultaneous inhibition of FAAH and MAGL did not improve the overall therapeutic response. Therefore, our findings indicate that enhancement of anandamide signaling with URB597 is a promising pharmacological approach for the alleviation of chronic widespread nociception in stress-exposed mice, and thus, it could represent a potential treatment strategy for chronic pain associated with neuropsychiatric disorders in humans.

Topics: Amidohydrolases; Analgesics, Non-Narcotic; Animals; Anxiety; Benzamides; Benzodioxoles; Brain; Carbamates; Chronic Pain; Depression; Disease Models, Animal; Endocannabinoids; Enzyme Inhibitors; Hyperalgesia; Male; Mice, Inbred C57BL; Monoacylglycerol Lipases; Nerve Growth Factor; Piperidines; Stress, Psychological; Uncertainty

Treatment of fibromyalgia is an unmet medical need. To develop novel therapies for the treatment of fibromyalgia, we explored pain therapeutic actions of existing pharmaceuticals, which inhibit the somatic symptoms frequently observed in fibromyalgia patients. This study first examined the therapeutic actions of pilocarpine, which inhibits dry-eye and dry-mouth symptoms, using an experimental fibromyalgia-like chronic pain model produced by intermittent cold stress (ICS) in mice. A single intraperitoneal and intracerebroventricular, but not intrathecal, pilocarpine administration attenuated ICS-induced thermal hyperalgesia and mechanical allodynia, and this action was abolished by muscarinic antagonist pirenzepine (i.c.v.). Treatment with 1-10 μg/kg donepezil (i.p.), which can easily penetrate into the brain, also showed similar therapeutic effects. Importantly, we found that both pilocarpine and donepezil produced antihyperalgesic effects via supraspinal action. Furthermore, repeated donepezil treatments completely cured the ICS-induced hyperalgesia and allodynia even after the cessation of drug treatments. Acute and chronic treatments of these cholinomimetics had no effects on the nociceptive threshold in control animals. By contrast, the lack of morphine (i.c.v.) analgesia initially observed in the ICS model remained in ICS model mice treated with long-term donepezil. Collectively, these findings suggest that stimulation of the muscarinic cholinergic system effectively inhibits some mechanisms underlying chronic pain in the ICS model, but does not inhibit the lack of descending pain-inhibitory mechanisms, which are driven by central morphine.

Topics: Analgesics, Opioid; Animals; Chronic Pain; Donepezil; Fibromyalgia; Hyperalgesia; Indans; Injections, Intraventricular; Male; Mice; Mice, Inbred C57BL; Morphine; Muscarinic Agonists; Nootropic Agents; Pain Measurement; Pilocarpine; Piperidines; Stress, Psychological

The sigma 1 (σ1) receptor, which is widely distributed in the CNS in areas that are known to be important for pain control, may play a role in persistent pain characterized by the hypersensitivity of nociceptive transmission. Here, we investigated the effect of σ1 blockade in an inflammatory pain model.. An intraplantar injection of carrageenan (2 %) was used to induce paw inflammation. The effects of the σ1 antagonist (+)-MR200, given subcutaneously at a dose of 0.1, 0.25, 0.5,1, 1.5, and 2 mg/kg prior to injection of carrageenan, on inflammatory pain and inflammation were assessed. Mechanical allodynia with von Frey filaments, thermal hyperalgesia with the plantar test and edema evaluation with a plethysmometer were measured. Intergroup comparisons were assessed by one- or two-way analysis of variance when appropriate, followed by post-hoc tests (Dunnett's test for one-way or Bonferroni for two-way ANOVA).. (+)-MR200 dose-dependently prevented allodynia and hyperalgesia induced by carrageenan. Furthermore, it reduced paw edema with a significant inhibition percentage of 37.82 % at 3 h after carrageenan treatment.. The blockade of the σ1 receptor with the selective antagonist (+)-MR200 may contribute to the suppression of the typical symptoms of inflammatory pain.

Topics: Animals; Carrageenan; Chronic Pain; Cyclopropanes; Dose-Response Relationship, Drug; Edema; Foot; Hot Temperature; Hyperalgesia; Inflammation; Male; Physical Stimulation; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, sigma; Sigma-1 Receptor

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

Pain and learning memory have striking similarities in synaptic plasticity. Activation of the N-methyl-D-aspartic acid receptors 2B subunits (NR2B-NMDAs) is responsible for the hippocampal LTP in memory formation. In our previous studies, we found the significant enhancement of CA1 hippocampal long-term potentiation (LTP) induced by high-frequency stimulation (HFS) in rats with chronic visceral pain. However, it is unclear whether the NR2B-NMDAs are required for the LTP in chronic visceral pain. In this study, a rat model with irritable bowel syndrome (IBS) was established by colorectal distention (CRD). The sensitivity of visceral pain and HFS-induced LTP at SC-CA1 synapses were significantly enhanced in IBS-like rats (p<0.05). In addition, hippocampal NR2B protein levels significantly increased in IBS-like rats (p<0.05). To test whether NR2B-NMDAs are responsible for the LTP, effects of Ro 25-6981, a selective antagonist of NR2B-NMDAs, on field potential in CA1 region were investigated in vitro. Our results demonstrated that Ro 25-6981 dose-dependently inhibited the facilitation of CA1 LTP in IBS-like rats. The plausible activation mechanism of hippocampal NR2B-NMDAs in the LTP enhancement was further explored. Western blot data indicated that expression of tyrosine phosphorylated NR2B protein in hippocampus significantly enhanced in IBS-like rats. Accordingly, genistein, a specific inhibitor of tyrosine kinases, dose-dependently blocked the facilitation of hippocampal LTP in IBS-like rats. Furthermore, EMG data revealed that intra-hippocampal injection of Ro 25-6981 dose-dependently attenuated the visceral hypersensitivity. In conclusion, hippocampal NR2B-NMDAs are responsible for the facilitation of CA1 LTP via tyrosine phosphorylation, which leads to visceral hypersensitivity.

Topics: Animals; CA1 Region, Hippocampal; Chronic Pain; Disease Models, Animal; Excitatory Amino Acid Antagonists; Genistein; Hippocampus; Hyperalgesia; Irritable Bowel Syndrome; Long-Term Potentiation; Male; Phenols; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Synapses; Visceral Pain

Topics: Analgesics, Opioid; Anesthetics; Breast Neoplasms; Chronic Pain; Female; Humans; Hyperalgesia; Methyl Ethers; Pain, Postoperative; Piperidines; Propofol

Topics: Analgesics, Opioid; Anesthetics; Breast Neoplasms; Chronic Pain; Female; Humans; Hyperalgesia; Methyl Ethers; Pain, Postoperative; Piperidines; Propofol

GPR40 has been reported to be activated by long-chain fatty acids, such as docosahexaenoic acid (DHA). However, reports studying functional role of GPR40 in the brain are lacking. The present study focused on the relationship between pain regulation and GPR40, investigating the functional roles of hypothalamic GPR40 during chronic pain caused using a complete Freund's adjuvant (CFA)-induced inflammatory chronic pain mouse model. GPR40 protein expression in the hypothalamus was transiently increased at day 7, but not at days 1, 3 and 14, after CFA injection. GPR40 was co-localized with NeuN, a neuron marker, but not with glial fibrillary acidic protein (GFAP), an astrocyte marker. At day 1 after CFA injection, GFAP protein expression was markedly increased in the hypothalamus. These increases were significantly inhibited by the intracerebroventricular injection of flavopiridol (15 nmol), a cyclin-dependent kinase inhibitor, depending on the decreases in both the increment of GPR40 protein expression and the induction of mechanical allodynia and thermal hyperalgesia at day 7 after CFA injection. Furthermore, the level of DHA in the hypothalamus tissue was significantly increased in a flavopiridol reversible manner at day 1, but not at day 7, after CFA injection. The intracerebroventricular injection of DHA (50 µg) and GW9508 (1.0 µg), a GPR40-selective agonist, significantly reduced mechanical allodynia and thermal hyperalgesia at day 7, but not at day 1, after CFA injection. These effects were inhibited by intracerebroventricular pretreatment with GW1100 (10 µg), a GPR40 antagonist. The protein expression of GPR40 was colocalized with that of β-endorphin and proopiomelanocortin, and a single intracerebroventricular injection of GW9508 (1.0 µg) significantly increased the number of neurons double-stained for c-Fos and proopiomelanocortin in the arcuate nucleus of the hypothalamus. Our findings suggest that hypothalamic GPR40 activated by free long chain fatty acids might have an important role in this pain control system.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Astrocytes; Benzoates; beta-Endorphin; Chronic Pain; Disease Models, Animal; DNA-Binding Proteins; Docosahexaenoic Acids; Flavonoids; Freund's Adjuvant; Gene Expression; Glial Fibrillary Acidic Protein; Hyperalgesia; Injections, Intraventricular; Male; Methylamines; Mice; Nerve Tissue Proteins; Neuroglia; Nuclear Proteins; Pain Management; Piperidines; Pro-Opiomelanocortin; Propionates; Pyrimidines; Receptors, G-Protein-Coupled; Signal Transduction; Time Factors

Selective blockers of the N-type calcium channel have proven to be effective in animal models of chronic pain. However, even though intrathecally delivered synthetic ω-conotoxin MVIIA from Conus magnus (ziconotide [Prialt®]) has been approved for the treatment of chronic pain in humans, its mode of delivery and narrow therapeutic window have limited its usefulness. Therefore, the identification of orally active, small-molecule N-type calcium channel blockers would represent a significant advancement in the treatment of chronic pain. A novel series of pyrazole-based N-type calcium channel blockers was identified by structural modification of a high-throughput screening hit and further optimized to improve potency and metabolic stability. In vivo efficacy in rat models of inflammatory and neuropathic pain was demonstrated by a representative compound from this series.

Topics: Analgesics; Animals; Calcium Channel Blockers; Calcium Channels, N-Type; Cell Line; Chronic Pain; High-Throughput Screening Assays; Humans; Neuralgia; omega-Conotoxins; Patch-Clamp Techniques; Piperidines; Pyrazoles; Rats; Structure-Activity Relationship

The prevalence of moderate-to-severe pain after inguinal hernia repair (IHR) in adults is ≈ 10%. Two studies with very long follow-up periods (16.8 and 49 yr, respectively) have, however, suggested that the risk of developing chronic pain is much lower in children. The purpose of the present study was to examine the prevalence of chronic pain 6-48 months after IHR in children.. Postal questionnaires were sent to 156 children who had undergone IHR between the age of 6 months and 12 yr. The children were asked to recall the duration of postoperative pain, if necessary with help from their parents, and to describe the intensity and character of their pain, if the pain was still present. Children with chronic pain were offered quantitative sensory testing (QST), and a surgical examination, including ultrasound, in order to exclude hernia recurrence.. Ninety-eight children, mean (sd) age 7.8 (2.6) yr, answered the questionnaire. Their age at the time of surgery was mean (sd) 4.6 (2.4) yr, and the follow-up period was mean (sd) 3.2 (1.3) yr. Five children (5.1%, 95% confidence interval: 0.75-9.5) had pain located in the inguinal region, and three of these children underwent further examination. There was no hernia recurrence, but QST revealed pinprick hyperalgesia and decreased pressure pain thresholds on the operated side in all three children.. The prevalence of chronic pain after IHR in children is 5.1%, which is lower than the prevalence reported after adult hernia repair.

Topics: Anesthesia, Intravenous; Anesthetics, Intravenous; Child; Child, Preschool; Chronic Pain; Female; Hernia, Inguinal; Herniorrhaphy; Humans; Infant; Male; Nerve Block; Pain Measurement; Pain, Postoperative; Piperidines; Propofol; Remifentanil; Surveys and Questionnaires

The voltage-gated calcium channel Ca(v)2.2 (N-type calcium channel) is a critical regulator of synaptic transmission and has emerged as an attractive target for the treatment of chronic pain. We report here the discovery of sulfonamide-derived, state-dependent inhibitors of Ca(v)2.2. In particular, 19 is an inhibitor of Ca(v)2.2 that is selective over cardiac ion channels, with a good preclinical PK and biodistribution profile. This compound exhibits dose-dependent efficacy in preclinical models of inflammatory hyperalgesia and neuropathic allodynia and is devoid of ancillary cardiovascular or CNS pharmacology at the doses tested. Importantly, 19 exhibited no efficacy in Ca(v)2.2 gene-deleted mice. The discovery of metabolite 26 confounds further development of members of this aminopiperidine sulfonamide series. This discovery also suggests specific structural liabilities of this class of compounds that must be addressed.

Topics: Animals; Calcium Channel Blockers; Calcium Channels, N-Type; Cells, Cultured; Chronic Pain; Dogs; Humans; Hyperalgesia; Inflammation; Mice; Mice, Knockout; Microsomes, Liver; Neuralgia; Patch-Clamp Techniques; Piperidines; Rats; Rats, Sprague-Dawley; Sulfonamides; Tissue Distribution

1-(1-Cyclooctylpiperidin-4-yl)-indolin-2-one (SR14150) and 1-(1-(2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl)piperidinl-4-yl)-indolin-2-one (SR16835) are moderately selective nociceptin/orphanin FQ (NOP) receptor agonists. In the [(35)S]guanosine 5'-O-(3-thiotriphosphate) assay in vitro, SR14150 is a partial agonist at both the NOP and μ-opioid receptors, whereas SR16835 is a full agonist at the NOP receptor and has low efficacy at μ receptors. These compounds were tested for antinociceptive and antiallodynic activity, using mice in chronic pain, subsequent to spinal nerve ligation (SNL) surgery. When administered subcutaneously to mice after SNL surgery, SR14150 but not SR16835 increased tail-flick latency, which was blocked by the opioid antagonist naloxone, but not by the 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). In contrast, both SR14150 and SR16835 had antiallodynic activity when mechanical allodynia was measured with von Frey monofilaments. This effect was completely blocked by SB-612111 but not by naloxone. On the other hand, morphine antinociception and antiallodynia were both blocked by naloxone and potentiated by SB-612111. These results indicate that, in mice, circuitry mediating antinociceptive activity in acute and chronic pain states is different. It is possible that during a chronic pain state, an up-regulated NOP system in the spinal cord leads to NOP receptor-mediated antiallodynia, which is blocked by NOP antagonists. However, supraspinal up-regulation could lead to an attenuation of morphine antinociception and antiallodynia, which can be alleviated by an NOP receptor antagonist. Thus, although neither NOP agonists nor antagonists are effective as analgesics in acute pain, they may have efficacy as analgesics, either alone or in combination with morphine, for treatment of chronic pain.

Topics: Acute Pain; Animals; Chronic Pain; Cycloheptanes; Hot Temperature; Hyperalgesia; Indoles; Ligation; Male; Mice; Mice, Inbred ICR; Morphine; Naloxone; Narcotic Antagonists; Nociceptin Receptor; Piperidines; Receptors, Opioid; Sciatic Nerve