Systemic administration of cannabinoids produce profound antinociception in rodents. The purpose of this study was to examine the contribution of the rostral ventromedial medulla (RVM) to cannabinoid-mediated inhibition of the tail-flick reflex. Rats received direct injections of two selective cannabinoid agonists, WIN55,212-2 and HU210, into the RVM. Both compounds significantly elevated tail-flick latencies by over 50%. WIN55,212-3, the inactive enantiomer, was without effect. Furthermore, co-administration of the selective cannabinoid receptor antagonist, SR141716A greatly attenuated the antinociception produced by HU210. Finally, injections of WIN55,212-2 outside the region of the RVM did not affect tail-flick latencies. These results demonstrate that the cannabinoid receptor system participates in the descending control of nociception and raise the possibility that actions of endogenous cannabinoids in the RVM may modulate nociceptive responsiveness.