Evaluating the effects of clomipramine on morphine induced dependence and tolerance in male mice

Abstract

Introduction: The main problem that follows the chronic use of opioids is the occurrence of dependence and tolerance. Morphine is a p-gp substrate. Clomipramine is a TCA that has inhibitory effects on p-gp. Aim: Evaluate the effects of clomipramine on the dependence and tolerance of morphine in male mice.Method: Adult male mice with a weight range of 20-30 grams were studied in 5 groups of 10, including a saline control group, a morphine control group and 3 groups receiving clomipramine (12.5-25-50mg/kg,ip).First, animals in control groups received saline (10ml/kg,ip) and morphine (25mg/kg,ip) for 14 days.Then, clomipramine from the 15th day was injected half an hour before the injection of morphine for one weak. On the 21th day, two hours after the morphine injection, naloxone (4 mg/kg,ip) was injected, and withdrawal symptoms were measured within half an hour. On the 21nd day, the analgesic effects caused by the morphine dose test (9mg/kg,ip) were measured in all groups by the hot plate method. Finally, the animals were anesthetized by injecting ketamine and xylazine, and blood was drawn from the heart to measure the serum levels of MDA and TAC.Result: The results showed that clomipramine injection (25-50mg/kg,ip) has a significant effect on reducing tolerance and dependence caused by morphine consumption.Conclusion: Clomipramine reversed some of the symptoms of dependence and tolerance to the analgesic effects of morphine in mice, which do not occur in the amount used in this study, through inhibition of oxidative stress. In order to obtain the exact mechanisms, we need additional studies.