The rostral ventromedial medulla is part of a neural network through which systemically administered morphine produces antinociception. Two physiologically characterized classes of presumed nociceptive modulating neurons that respond differentially to systemically administered morphine have been identified in this region: the firing of "on-cells" is depressed, whereas "off-cells" become continuously active. On-cells have been proposed to permit or facilitate, and off-cells to inhibit, nociceptive transmission. Because local application of morphine in the rostral ventromedial medulla itself is sufficient to produce antinociception, it is important to determine whether systemically administered morphine exerts its effects on neurons in this region by a direct action. Thus, activity of physiologically characterized neurons was studied before, during and after ionotophoretic administration of morphine. As with systemic administration, iontophoretic application of morphine depresses the activity of on-cells, an effect that is reversed by iontophoretic as well as by systemic administration of naloxone. In contrast, no reliable changes in the firing of off-cells are produced by iontophoretic administration of morphine. Cells of a third class, "neutral cells", are not affected by systemic morphine administration, nor do they respond to iontophoretic application of the drug. The present experiments demonstrate that direct opioid responsiveness in the rostral ventromedial medulla is limited to a single physiologically characterized class of presumed nociceptive modulatory neuron, the on-cell. This implies that the antinociceptive effect exerted by systemically administered morphine involves at least two components within the rostral ventromedial medulla: a direct inhibition of on-cells, and an indirect activation of off-cells. Each of these actions is likely to have a net hypoalgesic effect.