| J Neurosci. 2017 Nov 22. pii: 1945-17. doi: 10.1523/JNEUROSCI.1945-17.2017. [Epub ahead of print]|
Acetaminophen Relieves Inflammatory Pain Through CB1 Cannabinoid Receptors in the Rostral Ventromedial Medulla.
Klinger-Gratz PP1, Ralvenius WT1, Neumann E1, Kato A2, Nyilas R2, Lele Z2, Katona I2, Zeilhofer HU3,4.
1Institute of Pharmacology and Toxicology, University of Zurich, Winterthurerstrasse 190, CH-8057, Switzerland.2Institute of Experimental Medicine, Hungarian Academy of Sciences, 43 Szigony Street, H-1083 Budapest, Hungary.3Institute of Pharmacology and Toxicology, University of Zurich, Winterthurerstrasse 190, CH-8057, Switzerland email@example.comInstitute of Pharmaceutical Sciences, Swiss Federal Institute of Technology (ETH) Zurich, Vladimir-Prelog-Weg 1-5/10, CH-8093 Zürich, Switzerland.
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 CB1receptors 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 CB1receptors 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.SIGNIFICANCE STATEMENT Acetaminophen is a widely used analgesic drug with multiple but only incompletely understood mechanisms of action including a facilitation of endogenous cannabinoid signaling via one of its metabolites. Our present data indicate that enhanced cannabinoid signaling is also responsible for the analgesic effects of acetaminophen against inflammatory pain. Local injections of the acetaminophen metabolite AM 404 and of cannabinoid receptor antagonists as well as data from tissue specific CB1 receptor deficient mice suggest the rostral ventromedial medulla as an important site of the cannabinoid-mediated analgesia by acetaminophen.