To assess the contribution of the active metabolite of morphine, morphine-6-glucuronide (M6G), to the analgesic effect of systemically administered morphine, experiments were carried out on rats under urethane anesthesia in which nociceptive activity was evoked by electrical stimulation of afferent C fibers in the sural nerve and recorded from single neurons in the ventrobasal complex of the thalamus. Intravenous (i.v.) injections of morphine completely blocked the activity at doses of 500 and 1000 micrograms/kg, the ED50 being 44 micrograms/kg. M6G administered by i.v. injection reduced the evoked nociceptive activity only by about 40% at 80 and 160 micrograms/kg, the ED50 being 6 micrograms/kg. After intrathecal (i.t.) injection, morphine produced maximum depression of 55% of the control activity at 20 micrograms; the ED50 is 18 micrograms. M6G injected i.t. produced maximum depression of 40% at doses ranging from 0.2 to 10 micrograms. The ED50 of M6G i.t. is below 0.2 micrograms. The effects of morphine and M6G were reversed by naloxone (200 micrograms/kg i.v.). The results show that M6G is more potent than morphine, regardless of the route of administration, while morphine is more effective when injected i.v. Due to the low efficacy of M6G, it seems unlikely that this glucuronide contributes substantially to the analgesic effect of morphine when renal function is normal. The results also make evident that the maximum effect of morphine results from an action at spinal and supraspinal sites.