It is generally believed that morphine activates a descending system(s) of inhibition, an effect contributing significantly to the analgesia produced. There has arisen, however, considerable controversy on this point. To address whether morphine inhibits spinal nociceptive transmission when given into the brainstem, the effects of focal electrical stimulation and monosodium S-glutamate (Glu) given in the periaqueductal gray (PAG), the locus coeruleus/subcoeruleus (LC/SC) and/or the nucleus raphe magnus (NRM) on spinal unit responses to noxious heating (50 degrees C) of the skin were examined and compared with effects produced by morphine (Mor). Focal electrical stimulation in 46 sites in the midbrain, dorsolateral pons and ventromedial medulla reliably inhibited unit responses to noxious heating of the skin (mean 34% of control). Microinjections of Glu (50 nmol, 0.5 microliter) were made into 17 sites in the midbrain, 10 sites in the LC/SC and 11 sites in the NRM, inhibiting unit responses to a mean 57% at 22 of the 38 sites of microinjection. Mor (10-20 micrograms, 0.5 microliter) was microinjected into 15 sites in the midbrain, 13 sites in the LC/SC and 11 sites in the NRM, inhibiting unit responses to heat to 63% of control at 24 sites of microinjection. The effects of morphine were shown to be receptor specific by antagonism with naloxone administered either intravenously or into the brainstem at the same site of microinjection as morphine. In 31 sites in the midbrain, dorsolateral pons and ventromedial medulla, microinjections of both Mor and Glu into the same sites attenuated unit responses to heating of the skin to a mean 77% and 71% of control, respectively. The results support the hypothesis that Mor acts supraspinally to modulate spinal nociceptive transmission by activating an endogenous descending inhibitory system(s). Focal electrical stimulation, glutamate and morphine modulated spinal nociceptive transmission by activation of descending inhibitory systems whose cell bodies of origin are in the PAG, the LC/SC or the NRM.