Evaluation of the effect of dextromethorphan and bupropion in reversing morphine-induced tolerance in mice

Abstract

Introduction: Changes in the function of glutamatergic, dopaminergic and adrenergic systems are among the changes that occur in chronic morphine use. Dextromethorphan is an antitussive and has inhibitory effects on NMDA receptors. Bupropion, as an antidepressant, inhibits the metabolism of dextromethorphan and increases its release into the CNS. Aim: The aim of the study was to evaluate the effect of dextromethorphan and bupropion in the treatment of morphine-induced tolerance in mice. Material & Method: several mices (11 groups, 10 in each, 20-30g) were randomly selected for the following regimens for 17 days: 1. Saline (10ml/kg, 1st-17th days, S.C.) + Saline (10ml/kg, 11th-17th days, S.C.) 2. Morphine (10mg/kg, 1st-17th days, S.C.) + Saline (10ml/kg, 11th-17th days, S.C.) 3, 4, 5. Morphine (10mg/kg, 1st-17th days, S.C.) + Dextromethorphan (15,30,60 mg/kg/12h, 11th-17th days, S.C.) 6, 7, 8. Morphine (10mg/kg, 1st-17th days, S.C.) + Bupropion (40,80,110 mg/kg/12h, 11th-17th days, S.C.) 9, 10, 11. Morphine (10mg/kg, 1st-17th days, S.C.) + Dextromethorphan (15,30,60 mg/kg/12h, 11th-17th days, S.C.) + Bupropion (110,80,40 mg/kg/12h, 11th-17th days, S.C.). once on day11 and once on day17, the hotplate test was performed by injecting a test-dose morphine (9mg/kg) to animals. Results: Injection of dextromethorphan (15mg/kg) and bupropion (80mg/kg and 110mg/kg) and co-injection of dextromethorphan (15mg/kg) and bupropion (110mg/kg) accelerated tolerance compared to S+M group. However, in the injection of bupropion (40mg/kg) and co-injection of dextromethorphan (60mg/kg) and bupropion (40mg/kg), we observed a delay in tolerance compared to S+M group. Significant changes were also observed in MDA and TAC levels in bupropion (mg/kg 40) and dextromethorphan (60mg/kg) and bupropion (40mg/kg) groups compared to S+M group. Conclusion: The co-injection of dextromethorphan (60mg/kg) and bupropion (40mg/kg) and use of bupropion (40mg/kg) seem to be suitable for delaying tolerance to morphine; further studies are needed to observe precise mechanisms.