title: Pioglitazone prevents morphine antinociception tolerance and withdrawal symptoms in rats.
abstract: 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.
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran.
authors.forename: Hamed
authors.initials: H
authors.lastname: Ghavimi
authors.forename: Kambiz
authors.initials: K
authors.lastname: Hassanzadeh
authors.forename: Nasrin
authors.initials: N
authors.lastname: Maleki-Dizaji
authors.forename: Alireza
authors.initials: A
authors.lastname: Azarfardian
authors.forename: Saeed
authors.initials: S
authors.lastname: Ghasami
authors.forename: Elmira
authors.initials: E
authors.lastname: Zolali
authors.forename: Mohammad
authors.initials: M
authors.lastname: Charkhpour
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D004361:Drug Tolerance; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D009043:Motor Activity / Q000187:drug effects; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D047495:PPAR gamma / Q000819:agonists* / Q000037:antagonists & inhibitors; D010146:Pain / Q000188:drug therapy; D000077205:Pioglitazone; D017208:Rats, Wistar; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy*; D045162:Thiazolidinediones / Q000627:therapeutic use*
chemical_list: C457499:2-chloro-5-nitrobenzanilide; D000701:Analgesics, Opioid; D000813:Anilides; D009292:Narcotic Antagonists; D047495:PPAR gamma; D045162:Thiazolidinediones; D009270:Naloxone; D009020:Morphine; D000077205:Pioglitazone