On- and off-cells of the rostral ventromedial medulla are thought to be involved in bulbospinal inhibition of ascending nociceptive information. Experiments were carried out in lightly anaesthetized rats to assess the effects of prefrontal cortex stimulation on the responses of neurons in the rostral ventromedial medulla. For comparison purposes, effects of periaqueductal gray stimulation were also investigated. Single unit activity was recorded in the rostral ventromedial medulla and on-, off- and neutral-cells were identified based on the tail nocifensor reflex to noxious heat. Short (0.1-1 s) and long (10-15 s) trains of bipolar electrical stimulation (100-300 Hz) were delivered to the ventrolateral orbital cortex of the rat forebrain and the periaqueductal gray. Short-train stimulation of the periaqueductal gray (including dorsolateral, ventrolateral and the dorsal raphé regions) excited 58% (25 of 43) of on-cells and 44% (seven of 16) of off-cells in the rostral ventromedial medulla. Long trains blocked the noxious stimulus-evoked pause of all seven off-cells tested and blocked the excitatory response of two, and enhanced one of three on-cells. Such stimulation also inhibited or abolished the tail-flick reflex at currents below 100 microA. Glutamate microinjections into the periaqueductal gray inhibited the noxious-evoked response of two off- and two on-cells and increased the tail-flick latency. Short-train stimulation of the ventrolateral orbital cortex (100-400 microA) excited eight of 25 on-cells and inhibited the ongoing activity of 10 of 14 off-cells. Long-train ventrolateral orbital cortex stimulation (5-15 s, 100-200 microA, 200-300 Hz) enhanced the noxious evoked responses of 10 of 11 on-cells, prolonged the noxious heat-evoked pause of all of four off-cells and decreased the tail-flick latency (pronociception). The results of this study support the proposed role of on- and off-cells in descending inhibition of nociception from the periaqueductal gray and implicate the ventrolateral orbital cortex in the control of this pathway.