Effect of dextromethorphan, amantadine, and ketamine on morphine withdrawal syndrome in mice

Recent studies have shown that NMDA receptors are involved in the tolerance and dependence to opioids. In addition, it has been reported that ketamine, dextromethorphan and amantadine have antagonistic activity at NMDA receptors. Therefore, this study was conducted to clarify the effect of these drugs on morphine withdrawal syndrome. Morphine dependence was induced by increasing doses of morphine (30, 45, 60, and 90 mg/kg, s.c.) administered at 2 h intervals. Dextromethorphan (12.5, 25, and 50 mg/kg), amantadine (50, 100, and 150 mg/kg), ketamine (50 mg/kg), and clonidine (0.2 mg/kg) were injected (i.p.) 90 minutes after the last injection of morphine. Furthermore, these drugs were administered orally 60 minutes after the last morphine injection. All animals received naloxone (5 mg/kg, i.p.) 2 h after the last morphine injection. Withdrawal syndrome (number of jumping, standing on feet. and diarrhea) was recorded during a 30-min period. Dextromethorphan and amantadine inhibited jumping, standing on feet and diarrhea in a dose-dependent manner. Ketamine (50 mg/kg) had a similar effect and clonidine produced an almost complete inhibition of withdrawal syndrome. Although these test drugs belong to different pharmacological classes, but they share NMDA receptor antagonistic effect and it may be the probable cause for inhibition of withdrawal syndrome.