Acetaminophen Relieves Inflammatory Pain Through CB1 Cannabinoid Receptors in the Rostral Ventromedial Medulla

2017. december 8.

Acetaminophen (paracetamol) is a widely used analgesic and antipyretic drug with only incompletely understood mechanisms of action. Previous work, using models of acute nociceptive pain, indicated that analgesia by acetaminophen involves an indirect activation of CB1 receptors by the acetaminophen metabolite and endocannabinoid re-uptake inhibitor AM 404. However, the contribution of the cannabinoid system to anti-hyperalgesia against inflammatory pain, the main indication of acetaminophen, and the precise site of the relevant CB1 receptors have remained elusive. Here, we analyzed acetaminophen analgesia in mice of either sex with inflammatory pain and found that acetaminophen exerted a dose-dependent anti-hyperalgesic action, which was mimicked by intrathecally injected AM 404. Both compounds lost their anti-hyperalgesic activity in CB1-/- mice confirming the involvement of the cannabinoid system. Consistent with a mechanism down-stream of pro-inflammatory prostaglandin formation, acetaminophen also reversed hyperalgesia induced by intrathecal prostaglandin E2 (PGE2). To distinguish between a peripheral/spinal and a supraspinal action, we administered acetaminophen and AM 404 to hoxB8-CB1-/- mice, which lack CB1 receptors from the peripheral nervous system and the spinal cord. These mice exhibited unchanged anti-hyperalgesia indicating a supraspinal site of action. Accordingly, local injection of the CB1 receptor antagonist rimonabant into the rostral ventromedial medulla (RVM) blocked acetaminophen-induced anti-hyperalgesia, while local RVM injection of AM 404 reduced hyperalgesia in wild-type mice but not in CB1-/- mice. Our results indicate that the cannabinoid system contributes not only to acetaminophen analgesia against acute pain but also against inflammatory pain, and suggest that the relevant CB1 receptors reside in the RVM.

Reference
Klinger-Gratz PP, Ralvenius WT, Neumann E, Kato A, Nyilas R, Lele Z, Katona I, Zeilhofer HU: Acetaminophen Relieves Inflammatory Pain Through CB1 Cannabinoid Receptors in the Rostral Ventromedial Medulla
Journal of Neuroscience 22 November 2017, 1945-17;
DOI: https://doi.org/10.1523/JNEUROSCI.1945-17.2017