Evaluation the effects of Topiramate and Troxerutin on morphine-induced tolerance in male mice

Abstract

Introduction: Previous studies have shown the effect of glutamatergic system and oxidative stress on morphine tolerance. This study investigated the effects of Topiramate (an enhancer of GABAergic system activity and reducer of glutamatergic activity) and Troxerutin (with antioxidant and anti-inflammatory effects) on the development of tolerance to analgesic effects of morphine. Aim: The main goal of this study was to investigate the effects of Topiramate and Troxerutin on reducing the development of morphine antinociceptive tolerance. Methods: Nine groups of male mice (n=8 in each group, weight= 20-30 g) were administrated the following daily regimens for 4 days: 1) Saline (10 ml/kg, i.p.) + Saline (10 ml/kg, i.p.) 2) Saline (10 ml/kg, i.p.) + Morphine (50 mg/kg, i.p.) 3,4,5) Topiramate (6,12,24 mg/kg, b.i.d, i.p.) + Morphine (50 mg/kg, i.p.) 6,7,8) Troxerutin ( 37.5,75,150 mg/kg, b.i.d, i.p.) + Morphine (50 mg/kg, i.p.) 9) Topiramate (12mg/kg, b.i.d, i.p.) + Troxerutin (75 mg/kg, b.i.d, i.p.) + Morphine (50 mg/kg, i.p.) In the treatment groups, the drug was administered to the animals 30 min before each morphine injections during tolerance development. On the fifth day, tolerance was assessed by administration of morphine (9 mg/kg,i.p.) and using the Hot-plate test, conducted within one hour, at different time points (15, 30, 45, 60 min). Results: Significant reduction in morphine tolerance was observed by Topiramate (12, 24 mg/kg, b.i.d, i.p.) and Troxerutin (150 mg/kg, b.i.d, i.p). Co-administration of Topiramate (12 mg / kg, b.i.d, i.p.) and Troxerutin (75 mg / kg, b.i.d, i.p.) also attenuated the degree of tolerance significantly. Conclusion: Based on these results, Topiramate and Troxerutin may be decreased the development of tolerance to analgesic effects of morphine in a dose realated manner.