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 40mg/kg) daily. Thirty minutes before pioglitazone (40mg/kg), GW-9662, a selective PPAR-γ antagonist, (2mg/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 9days, rats received additive doses of morphine to induce dependence. Naloxone was administrated 2h after the morphine last dose, and withdrawal symptoms were recorded for 45min. Morphine administration to rats over a duration of 17days resulted in the development of tolerance, whereas pioglitazone (40mg/kg) delayed the day of the established tolerance for 15days. 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.
Published Version
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