Acetaminophen attenuates pathological pain through a mechanism that requires CB1 cannabinoid receptors and the enzyme diacylglycerol lipase in mice

Jesus, C. A.; Wirt, J. L.; Ferreira, L. A.; Hainline, J.; Huizenga, M.; Rems, L.; Makriyannis, A.; van der Stelt, M.; Hohmann, A. G.

doi:10.1101/2025.05.08.652937

bioRxiv · 10.1101/2025.05.08.652937

Acetaminophen attenuates pathological pain through a mechanism that requires CB1 cannabinoid receptors and the enzyme diacylglycerol lipase in mice

Jesus, C. A.·Wirt, J. L.·Ferreira, L. A.·Hainline, J.·Huizenga, M.·Rems, L.·Makriyannis, A.·van der Stelt, M.·Hohmann, A. G.

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Abstract

Acetaminophen (APAP) produces analgesia through mechanisms that remain poorly understood. Here, we tested the hypothesis that APAP-induced suppression of pathological pain is associated with cannabinoid receptors and activity of enzymes regulating endogenous lipids (diacylglycerol lipase, DAGL; monoacylglycerol lipase, MAGL) including endocannabinoids. APAP suppressed mechanical hypersensitivity in mouse models of post-surgical and inflammatory pain and the DAGL inhibitors (RHC-80267, DO34) and MAGL inhibitor JZL184 blocked APAPs analgesic effects. Global (rimonabant, AM251) but not peripherally restricted (AM6545) cannabinoid receptor antagonists prevented APAP-induced analgesia. APAP increased corticosterone levels >2-fold and reduced prostaglandins >5-fold across the brain and in the paw skin. In addition, APAP reduced up to 39% of signaling lipids detected in the targeted screen in CFA-treated subjects in a tissue-dependent manner. These observations suggest that APAP plays a wider role in endogenous lipid signaling than previously hypothesized and provides novel insight into mechanisms of action.

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Jesus, C. A., Wirt, J. L., Ferreira, L. A., Hainline, J., Huizenga, M., Rems, L., Makriyannis, A., van der Stelt, M., Hohmann, A. G.. 2025-05-13. Acetaminophen attenuates pathological pain through a mechanism that requires CB1 cannabinoid receptors and the enzyme diacylglycerol lipase in mice. https://doi.org/10.1101/2025.05.08.652937

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