Although many anecdotal reports indicate that marijuana and its active constituent, delta-9-tetrahydrocannabinol (delta-9-THC), may reduce pain sensation¹,², studies of humans have produced inconsistent results^3,4,5,6. In animal studies, the apparent pain-suppressing effects of delta-9-THC and other cannabinoid drugs^{7,8,9,10,11,12} are confounded by motor deficits¹³,¹⁴. Here we show that a brainstem circuit that contributes to the pain-suppressing effects of morphine¹⁵ is also required for the analgesic effects of cannabinoids. Inactivation of the rostral ventromedial medulla (RVM) prevents the analgesia but not the motor deficits produced by systemically administered cannabinoids. Furthermore, cannabinoids produce analgesia by modulating RVM neuronal activity in a manner similar to, but pharmacologically dissociable from, that of morphine. We also show that endogenous cannabinoids tonically regulate pain thresholds in part through the modulation of RVM neuronal activity. These results show that analgesia produced by cannabinoids and opioids involves similar brainstem circuitry and that cannabinoids are indeed centrally acting analgesics with a new mechanism of action.

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