Modification of naloxone-induced withdrawal signs by dextromethorphan in morphine-dependent mice

In the present study the effect of dextromethorphan on naloxone-induced withdrawal signs in morphine-dependent mice was examined. In addition, the modulatory role of dopaminergic mechanisms upon the effect of dextromethorphan was investigated. Mice were rendered dependent on morphine by subcutaneous (s.c.) injections of morphine sulfate three times a day for 3 days, and withdrawal signs were induced by intraperitoneal (i.p.) administration of naloxone 2 h after the 10th injection of morphine sulfate on day 4. Dextromethorphan (20-50 mg/kg, i.p.) caused a significant decrease in withdrawal jumping, paw-shakes, grooming, burrows, writhing and diarrhea in morphine-dependent mice. The mixed dopamine D1/D2 receptor agonist apomorphine (0.5 and 1 mg/kg, s.c.) reduced the response induced by dextromethorphan. The effect of apomorphine was blocked by the dopamine D1 receptor antagonist SCH 23390 (R-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepine-7- ol maleate) (0.5 and 1 mg/kg, i.p.) but not by the dopamine D2 receptor antagonist sulpiride (25 and 50 mg/kg, s.c.) nor the peripheral dopamine receptor antagonist domperidone (5 and 10 mg/kg, s.c.). These results suggest that the dopaminergic system(s) may in part mediate the suppressive action of the NMDA receptor antagonist dextromethorphan on naloxone-induced withdrawal signs in morphine-dependent mice.