Interference with GABA transmission in the rostral ventromedial medulla: disinhibition of off-cells as a central mechanism in nociceptive modulation.

Blockade of GABA-mediated synaptic transmission in the rostral ventromedial medulla by local application of GABAA receptor antagonists produces antinociception, indicating that a GABA-mediated inhibition of some population of neurons in this region is normally required if nociceptive information is to be transmitted. The aim of the present study was to elucidate the medullary circuitry mediating this antinociception by recording the activity of putative nociceptive modulating neurons in the rostral ventromedial medulla before and after local infusion of the GABAA receptor antagonist bicuculline methiodide. It was thus possible to correlate changes in the activity of cells of different classes with the ability of the infusion to produce a behaviorally measurable antinociception. One class of medullary neurons, "off-cells," is identified by a pause in firing associated with the occurrence of nocifensor reflexes such as the tail flick evoked by noxious heat. These neurons are uniformly activated following systemic administration of morphine, and are thought to have a net inhibitory effect on nociception. Following local bicuculline administration, off-cells enter a prolonged period of continuous firing that is temporally linked with the period of tail flick inhibition. A second class of neurons, "on-cells," is identified by a burst of activity beginning just before the tail flick, and is directly inhibited by opioids. Unlike off-cells, cells of this class do not show a consistent change in activity associated with inhibition of the tail flick following bicuculline. These data indicate that alterations in the discharges of on-cells would not be able to explain the antinociceptive effect of bicuculline, and therefore point to disinhibition of off-cells as a sufficient basis for antinociception originating within the rostral ventromedial medulla.