The effect of antinociceptive doses of cocaine (25 mg/kg, i.p.) on unit responses to noxious somatic stimuli and spontaneous activity of antidromically identified projection neurons in the medial medullary reticular formation (MRF) was studied in the rat. Thirty-three antidromically activated neurons were recorded from the medullary raphe, gigantocellular, or paragigantocellular nuclei in an acute anaesthetized preparation; 25 cells projected to the spinal cord and 8 neurons had rostral projections through the medial forebrain bundle (n = 4) or the medial thalamus (n = 4). After cocaine administration, 24 (73%) of these cells showed immediate (less than 5 min) and prolonged (45-70 min) increases in their level of spontaneous activity. Associated with this increased interstimulus activity, 21 of 29 (72%) neurons responsive to noxious somatic stimulation reduced their responsiveness, relative to prestimulus activity, after cocaine administration. In 5 animals tested, the cocaine-induced changes in spontaneous activity and changes in evoked responsiveness were unaffected by naloxone (1 mg/kg, i.p.) but partially reversed within 5 min of the administration of chlorpromazine (3 mg/kg, i.p.). There were no obvious differences in neuronal response characteristics or the effect of cocaine that correlated with anatomical location or direction of axonal projection. Similar results were obtained while recording from 14 somatically responsive units in chronic, unrestrained, lightly anesthetized or awake rats. These findings provide direct evidence that cocaine, in doses that are antinociceptive for the rat, affects both unit responses to noxious stimuli and the spontaneous activity of caudally and rostrally projecting bulboreticular neurons over a time course that parallels the behavioral antinociception. The observation that unit responses to somatic stimuli were reduced while spontaneous activity was unchanged or increased in most cells suggests that cocaine antinociception may be due to the activation of sensory inhibitory mechanisms mediated by the MRF.