Dual effect of topiramate on the expression of tolerance to analgesic effects of morphine in mice

Introduction: Topiramate is an anti-convulsant drug, which produces its effects via glutamate metabotropic receptors inhibition and/or GABA receptor excitation. In the present study, attempts were made to investigate the effects of topiramate on the tolerance to morphine-induced analgesia activity in male NMRI mice (20-30 g). Methods: Hot plate method was chosen for the study. First of all the analgesic effects of morphine and topiramate on mice were investigated. Then, the animals became tolerant to morphine (50 mg/kg twice daily for three consecutive days). Different doses of topiramate were administered to the animals 30 min before each morphine (50 mg/kg) injections (acquisition) during tolerance development or on the test day, 30 min before the experiment. Results: Subcutaneous morphine injection (10 mg/kg) induced analgesia. However, intraperitoneal administration of topiramate (0.5, 2.5 and 5 mg/kg) had no effect. In addition, topiramate (0.5, 2.5 and 5 mg/kg) did not affect morphine-induced analgesia. Administration of a single daily dose of morphine (50 mg/kg twice daily) for 3 days, induced tolerance. Injections of topiramate (0.5 and 2.5 mg/kg) had no effects on the acquisition of morphine tolerance. However, topiramate (0.5 and 2.5 mg/kg) enhanced the expression of morphine tolerance. The drug reduced the expression of morphine tolerance at the dose of 5 mg/kg. Conclusion: Topirmate showed a biphasic effect on the expression of tolerance to morphine-induced analgesia in lower and higher doses which may be due to glutamate and/or GABAergic mechanisms.