An accumulating body of evidence indicates that activation of NMDA receptor complexes modulates a number of morphine-induced responses. Because a single injection of morphine increases extracellular glutamate levels and downregulates NMDA receptors, acute morphine appears to increase glutamatergic transmission. On the basis of those data and the fact that morphine and glutamate induce hyperthermia, we investigated whether NMDA receptors modulate the hyperthermic effects of acute morphine in male Sprague-Dawley rats. Subcutaneous injection of morphine (0.1-15 mg/kg) evoked dose-dependent hyperthermia, which was rapid in onset and peaked 45-60 min post-injection. Pretreatment with LY 235959 (0.1-1 mg/kg, s.c.), a highly selective and competitive NMDA antagonist, or dextromethorphan (5-15 mg/kg, s.c.), a noncompetitive NMDA antagonist, attenuated the hyperthermic effect of morphine (4 mg/kg). In contrast, administration of LY 235959 (1 mg/kg) 15 min after morphine (4 mg/kg) did not reverse the hyperthermia. LY 235959 (1 mg/kg) depressed the hyperthermia caused by DAMGO (1 micro g/rat, i.c.v.), a selective mu agonist, confirming that NMDA receptor activation maximizes mu receptor-induced hyperthermia. Neither LY 2359595 nor dextromethorphan by itself significantly altered body temperature. These data indicate that NMDA receptors modulate morphine-induced hyperthermia and suggest that increases in glutamatergic transmission maximize the hyperthermia evoked by morphine.