Evaluation of the effects of selegiline and amantadine on morphine induced tolerance and dependence in mice

Several studies have indicated that co-administration of N-methyl-D-aspartate (NMDA) receptor antagonists could attenuate the development of morphine induced tolerance and dependence in mice. The aim of this study was to investigate the effects of selegiline (MAO-B inhibitor and NMDA receptor inhibitor) and amantadine (NMDA receptor antagonist and Dopaminergic system activator) or their co administration on tolerance (to analgesic effect) and withdrawal syndrome in mice. In different groups of mice morphine (50 mg/kg, ip) or morphine (50 mg/kg, ip) + selegiline (10, 20, 40 mg/kg, ip) or morphine (50 mg/kg, ip) + amantadine (20, 40, 80 mg/kg, ip) or morphine (50 mg/kg, ip) + amantadine (20 mg/kg, ip) + selegiline (10 mg/kg, ip) was administrated once a day for four days. The drugs (selegiline or amantadine) administered 30 minutes before daily administration of morphine (50 mg/kg, ip). Tolerance was assessed by administration of morphine (9 mg/kg, ip) and using hot plate test on fifth day. To investigate the withdrawal symptoms (jumping and standing on feet) in different groups morphine (50 mg/kg, ip) injected for 4 days. In the forth day half hour after the last injection, different doses of selegiline, amantadine or their co-administration were injected and after 1.5 hour later naloxone (5 mg/kg, ip) was injected and immediatly the withdrawal symptoms were detected during 30 minutes. The results showed that different doses of amantadine, increased the tolerance to analgesic effects of morphine significantly (P 0.001), withdrawal syndroms in the doses of 40 & 80 decreased significantly (P<0.01). But selegiline (10, 20, 40 mg/kg, ip) did not have a siginificant effect on the inhibition of tolerance and withdrawal syndromes. Co administration of selegiline and amantadine didn’t decrease the tolerance to morphine in hot plate test significantly. Conclution: It is concluded that, Probably amantadine in this study has a mechanism of activation of dopaminergic system in the administered doses. On the other hand selegiline potentiated adrenergic system with these doses.