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An analgesia circuit activated by cannabinoids

Abstract

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 results3,4,5,6. In animal studies, the apparent pain-suppressing effects of delta-9-THC and other cannabinoid drugs7,8,9,10,11,12 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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Figure 1: Inactivation of the RVM with microinjection of muscimol prevents the antinociception produced by the cannabinoid agonist WIN55,212-2.
Figure 2: Cannabinoid-induced motor impairments are not affected by inactivation of the RVM with muscimol.
Figure 3: Systemic cannabinoids reduce the ‘off’ cell pause and ‘on’ cell burst of RVM neurons, and eliminate the tail-flick reflex in a manner similar to morphine.
Figure 4: The cannabinoid receptor antagonist SR141716A decreases ‘off’ cell activity, increases ‘on’ cell activity and produces hyperalgesia.

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Acknowledgements

This work was supported by the National Institute of Drug Abuse, the UCSF Center for the Neurobiology of Addiction and the Canadian MRC.

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Correspondence to Ian D. Meng.

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Meng, I., Manning, B., Martin, W. et al. An analgesia circuit activated by cannabinoids. Nature 395, 381–383 (1998). https://doi.org/10.1038/26481

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