The relationships between mean arterial blood pressure (MAP) and the activity of putative pain modulatory neurons of the rostroventral medulla (ON and OFF cells) were determined in intact and cardiopulmunary deafferented rats. A total of 173 neurons were recorded from 97 rats as follows: 32 ON cells and 25 OFF cells from 39 intact rats; 32 ON cells and 20 OFF cells from 24 rats with bilateral sino-aortic deafferentation (SAD); 12 ON cells and 20 OFF cells from 19 rats with bilateral cervical vagotomy (CVAG); and 20 ON cells and 12 OFF cells from 15 rats with both SAD and CVAG. ON and OFF cells showed spontaneous fluctuations in activity such that ON cell activity was negatively correlated with MAP whereas OFF cell activity was positively correlated with MAP under conditions of no applied stimuli. These correlations were present in both intact and cardiopulmonary deafferented rats. Further, experimentally induced increases in MAP decreased ON cell activity and increased OFF cell activity in intact rats, but not in rats with SAD, CVAG, or the combination of SAD and CVAG. Experimentally induced decreases in MAP decreased OFF cell activity in intact rats and rats with CVAG, but not in rats with SAD or the combination of SAD and CVAG. These findings indicate that ON and OFF cells are modulated by baroreceptor activity, but baroreceptor input is not necessary for the spontaneous fluctuations in ON and OFF cell activity. Electrical stimulation of vagal afferents (VAS) inhibited 60% of the OFF cells studied, excited 4%, and produced biphasic effects consisting of excitation at low intensities and inhibition at greater intensities in 28% of all OFF cells. In general, VAS excited the majority of the ON cells studied, although there were significant differences between effects in intact and cardiopulmonary deafferented rats. Greater intensities of VAS that inhibited OFF cells and excited ON cells also inhibited the tail flick. Thus, inhibition of OFF cells and excitation of ON cells was correlated with antinociception. The effects of intravenous (i.v.) administration of 1.0 mg/kg morphine on neuronal activity did not differ between intact and cardiopulmonary deafferented rats. Intravenous administration of morphine produced a sustained inhibition of 20.7% of all ON cells studied, produced a biphasic effect consisting of a brief excitation followed by a sustained inhibition in 62.1% of the ON cells, and had no effect on the activity of 17.2% of the ON cells. Morphine-produced inhibition of ON cell activity was reversed by i.v. administration of naloxone HCl, but was not affected by i.v. administration of naloxone methobromide (NMB). However, pre-treatment with NMB attenuated the initial morphine-produced excitation of ON cells. In studies of OFF cells, i.v. administration of morphine excited 40.0% of the OFF cells, produced a biphasic effect consisting of an initial inhibition followed by excitation in 33.3% of the OFF cells, and had no effect on the activity of 26.7% of the OFF cells. Naloxone HCl reversed the effects of morphine within 1 min after administration, whereas NMB had no effect on the morphine-produced excitation of OFF cells. Intravenous administration of morphine following pre-treatment with NMB excited the 2 OFF cells studied. These data suggest that ON and OFF cells in the rostroventral medulla not only receive converging input from cardiopulmonary and somatic afferents, but may also function in the regulation of both systems. Specifically, the excitation of ON cells and inhibition of OFF cells may decrease MAP and nociception, whereas the inhibition of ON cells and excitation of OFF cells may increase MAP and nociception. This hypothesis contradicts previous hypotheses suggesting that inhibition of ON cells and excitation of OFF cells attenuates nociception indicating that current hypotheses on the function of ON and OFF cells require further analyses. © 1995.