Endogenous opioid-mediated inhibition of putative pain-modulating neurons in rat rostral ventromedial medulla

The rostral ventromedial medulla is a critical relay for midbrain regions, including the periaqueductal gray and nucleus cuneiformis, that control nociception at the spinal cord. Opioid-containing neurons and terminals are concentrated in both the periaqueductal gray and the rostral ventromedial medulla in the rat. However, the function of endogenous opioid peptides within the medulla in pain modulation is unclear. In this study, bicuculline (30-50 ng) or morphine (5 μg) microinjected into the periaqueductal gray inhibited the tail-flick reflex and the firing of on-cells (cells that increase firing just before tail flick) in the medulla. Iontophoretically applied naloxone (20 or 30 nA), which blocked the inhibition of on-cell firing induced by iontophoresis of morphine (20 or 30 nA), consistently reduced the on-cell inhibition produced by bicuculline or morphine microinjected into the periaqueductal gray. Naloxone did not reduce the inhibition of on-cell firing induced by iontophoretically applied clonidine (10 or 20 nA), an α₂ adrenoceptor agonist. The firing of off-cells (cells that pause in firing just prior to tail-flick) in the medulla was increased by bicuculline applied in the periaqueductal gray and was not affected by naloxone. The present results suggest that when activation of neurons in the periaqueductal gray produces antinociception, endogenous opioid peptides are released in the rostral ventromedial medulla and selectively inhibit on-cells, which presumably have a facilitating action on spinal nociceptive transmission. This action is proposed to be critical for the behavioral antinociception induced by bicuculline or morphine in the periaqueductal gray.