Neurons in the medullary raphe magnus (RM) that are important in the descending modulation of nociceptive transmission are classified by their response to noxious tail heat as ON, OFF, or NEUTRAL cells. Experiments in anesthetized animals demonstrate that RM ON cells facilitate and OFF cells inhibit nociceptive transmission. Yet little is known of the physiology of these cells in the unanesthetized animal. The first aim of the present experiments was to determine whether cells with ON- and OFF-like responses to noxious heat exist in the unanesthetized rat. Second, to determine if RM cells have state-dependent discharge, the activity of RM neurons was recorded during waking and sleeping states. Noxious heat applied during waking and slow wave sleep excited one group of cells (ON-U) in unanesthetized rats. Other cells were inhibited by noxious heat (OFF-U) applied during waking and slow wave sleep states in unanesthetized rats. NEUTRAL-U cells did not respond to noxious thermal stimulation applied during either slow wave sleep or waking. ON-U and OFF-U cells were more likely to respond to noxious heat during slow wave sleep than during waking and were least likely to respond when the animal was eating or drinking. Although RM cells rarely respond to innocuous stimulation applied during anesthesia, ON-U and OFF-U cells were excited and inhibited, respectively, by innocuous somatosensory stimulation in the unanesthetized rat. The spontaneous activity of >90% of the RM neurons recorded in the unanesthetized rat was influenced by behavioral state. OFF-U cells discharged sporadically during waking but were continuously active during slow wave sleep. By contrast, ON-U and NEUTRAL-U cells discharged in bursts during waking and either ceased to discharge entirely or discharged at a low rate during slow wave sleep. We suggest that OFF cell discharge functions to suppress pain-evoked reactions during sleep, whereas ON cell discharge facilitates pain-evoked responses during waking.