Tolerance to the antinociceptive (analgesic) effect of morphine, a mu-opioid agonist, was developed in male CD-1 mice as assessed by a shift to the right of the analgesic (tail-flick) dose-response curves and an increase in the ED50 values. Administration of dextromethorphan at 30 mg/kg s.c., but not saline, 30 min prior to an escalating 3 times per day (t.i.d.) morphine dosing schedule prevented a 5-fold increase in the morphine ED50 value observed on treatment day 4. Concurrent administration of dextromethorphan at 12 mg/kg/24 h by s.c. infusion prevented the 6-fold increase in the morphine ED50 value that was observed in control mice that received morphine at 30 mg/kg/24 h by s.c. infusion. Implantation of two 25 mg morphine pellets resulted in a 10-fold increase in the morphine ED50 value on treatment day 4. Administration of dextromethorphan at 30 mg/kg s.c. t.i.d., but not saline, resulted in a reversal of morphine tolerance with the almost complete return of the morphine ED50 value to the control (opioid naive) value. These results demonstrate that dextromethorphan, an NMDA receptor antagonist can modulate morphine (mu-receptor)-mediated tolerance.