gw9662 and Pain

Notwithstanding the experimental evidence indicating Withania somnifera Dunal roots extract (WSE) ability to prolong morphine-elicited analgesia, the mechanisms underlying this effect are largely unknown. With the aim of evaluating a PPARγ-mediated mechanism in such WSE effects, we verified the ability of the PPARγ antagonist GW-9662 to modulate WSE actions. Further, we evaluated the influence of GW-9662 upon WSE / morphine interaction in SH-SY5Y cells since we previously reported that WSE hampers the morphine-induced μ-opioid receptor (MOP) receptor down-regulation. Nociceptive thresholds / tolerance development were assessed in different groups of rats receiving vehicles (control), morphine (10 mg/kg; i.p.), WSE (100 mg/kg, i.p.) and PPARγ antagonist GW-9662 (1 mg/kg; s.c.) in acute and chronic schedules of administration. Moreover, the effects of GW-9662 (5 and 10 μM) applied alone and in combination with morphine (10 μM) and/or WSE (0.25 and 1.00 mg/mL) on the MOP gene expression were investigated in cell cultures. Data analysis revealed a functional effect of the PPARγ antagonist in attenuating the ability of WSE to prolong morphine analgesic effect and to reduce tolerance development after repeated administration. In addition, molecular experiments demonstrated that the blockade of PPARγ by GW-9662 promotes MOP mRNA down-regulation and counteracts the ability of 1.00 mg/mL of WSE to keep an adequate MOP receptor availability. In conclusion, our results support the involvement of a PPARγ-mediated mechanism in the WSE effects on morphine-mediated nociception and the likely usefulness of WSE in lengthening the analgesic efficacy of opioids in chronic therapy.

Topics: Analgesics, Opioid; Anilides; Animals; Cell Line, Tumor; Drug Tolerance; Humans; Male; Morphine; Pain; Plant Extracts; PPAR gamma; Rats, Sprague-Dawley; Withania

In the present study we investigated the role of sodium butyrate (butyrate), and its more palatable derivative, the N-(1-carbamoyl-2-phenyl-ethyl) butyramide (FBA), in animal models of acute and chronic pain. We found that oral administrations of butyrate (10-200mg/Kg) or equimolecular FBA (21.2-424mg/Kg) reduced visceral pain in a dose- and time-dependent manner. Both drugs were also effective in the formalin test, showing an antinociceptive effect. This analgesic effect was blocked by glibenclamide, suggesting the involvement of ATP-dependent K(+) channels. Moreover, following repeated administration butyrate (100-200mg/Kg) and FBA (212-424mg/Kg) retained their analgesic properties in a model of neuropathic pain, reducing mechanical and thermal hyperalgesia in the chronic constriction injury (CCI) model. The involvement of peroxisome proliferator-activated receptor (PPAR) -α and -γ for the analgesic effect of butyrate was also investigated by using PPAR-α null mice or the PPAR-γ antagonist GW9662. Western blot analysis, confirmed the role of peroxisome receptors in butyrate effects, evidencing the increase of PPAR-α and -γ expression, associated to the reduction of inflammatory markers (COX-2, iNOS, TNF-α and cFOS). In conclusion, we describe the role of butyrate-based drugs in pain, identifying different and converging non-genomic and genomic mechanisms of action, which cooperate in nociception maintenance.

Topics: Acetic Acid; Amides; Analgesics; Anilides; Animals; Butyric Acid; Formaldehyde; Hot Temperature; Hyperalgesia; Kaolin; Magnesium Sulfate; Male; Mice; Mice, Knockout; Pain; Physical Stimulation; PPAR alpha; PPAR gamma; Sciatic Nerve; Spinal Cord

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

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

Opioid drugs are potent analgesics. However, their chronic use leads to the rapid development of tolerance to their analgesic effects and subsequent increase of significant side effects, including drug dependence and addiction. Here, we investigated the role of PPARγ in the development of analgesic tolerance to morphine in mice.. We monitored analgesia on alternate days using the tail immersion test.. Daily administration of morphine (30 mg·kg(-1) , bid) resulted in the rapid development of tolerance to thermal analgesia. Co-administration of pioglitazone (10 and 30 mg·kg(-1) , bid) significantly attenuated the development and expression of tolerance. However, pretreatment with GW-9662 (5 mg·kg(-1) , bid), a selective PPARγ antagonist, completely abolished this effect. Injection of GW-9662 and a lower dose of morphine (15 mg·kg(-1) , bid) accelerated the development of tolerance to its antinociceptive effect. Subsequently, we found that conditional neuronal PPARγ knockout (KO) mice develop a more rapid and pronounced tolerance to morphine antinociception compared with wild-type (WT) controls. Moreover, in PPARγ KO mice, pioglitazone was no longer able to prevent the development of morphine tolerance.. Overall, our results demonstrate that PPARγ plays a tonic role in the modulation of morphine tolerance, and its pharmacological activation may help to reduce its development. These findings provide new information about the role of neuronal PPARγ and suggest that combining PPARγ agonists with opioid analgesics may reduce the development of tolerance and possibly attenuate the potential for opioid abuse.

Topics: Analgesics, Opioid; Anilides; Animals; Body Temperature; Drug Tolerance; Hot Temperature; Male; Mice, Inbred C57BL; Mice, Knockout; Morphine; Motor Activity; Pain; Pioglitazone; PPAR gamma; Thiazolidinediones

Systemic administration of thiazolidinediones reduces peripheral inflammation in vivo, presumably by acting at peroxisome proliferator-activated receptor gamma (PPARgamma) in peripheral tissues. Based on a rapidly growing body of literature indicating the CNS as a functional target of PPARgamma actions, we postulated that brain PPARgamma modulates peripheral edema and the processing of inflammatory pain signals in the dorsal horn of the spinal cord. To test this in the plantar carrageenan model of inflammatory pain, we measured paw edema, heat hyperalgesia, and dorsal horn expression of the immediate-early gene c-fos after intracerebroventricular (ICV) administration of PPARgamma ligands or vehicle. We found that ICV rosiglitazone (0.5-50 microg) or 15d-PGJ(2) (50-200 microg), but not vehicle, dose-dependently reduced paw thickness, paw volume and behavioral withdrawal responses to noxious heat. These anti-inflammatory and anti-hyperalgesia effects result from direct actions in the brain and not diffusion to other sites, because intraperitoneal and intrathecal administration of rosiglitazone (50 microg) and 15d-PGJ(2) (200 microg) had no effect. PPARgamma agonists changed neither overt behavior nor motor coordination, indicating that non-specific behavioral effects do not contribute to PPAR ligand-induced anti-hyperalgesia. ICV administration of structurally dissimilar PPARgamma antagonists (either GW9662 or BADGE) reversed the anti-inflammatory and anti-hyperalgesic actions of both rosiglitazone and 15d-PGJ(2). To evaluate the effects of PPARgamma agonists on a classic marker of noxious stimulus-evoked gene expression, we quantified Fos protein expression in the dorsal horn. The number of carrageenan-induced Fos-like immunoreactive profiles was less in rosiglitazone-treated rats as compared to vehicle controls. We conclude that pharmacological activation of PPARgamma in the brain rapidly inhibits local edema and the spinal transmission of noxious inflammatory signals.

Topics: Anilides; Animals; Benzhydryl Compounds; Brain; Central Nervous System Agents; Disease Models, Animal; Edema; Epoxy Compounds; Gene Expression; Inflammation; Male; Pain; PPAR gamma; Prostaglandin D2; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Rosiglitazone; Spinal Cord; Thiazolidinediones