| 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 themorphine tolerance and attenuating the dependence. |