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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 APAP\u2019s analgesic effects. Global (rimonabant, AM251) but not peripherally restricted (AM6545) cannabinoid receptor antagonists prevented APAP-induced analgesia. APAP increased corticosterone levels &gt;2-fold and reduced prostaglandins &gt;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.<\/jats:p>","DOI":"10.1101\/2025.05.08.652937","type":"posted-content","created":{"date-parts":[[2025,5,14]],"date-time":"2025-05-14T02:10:15Z","timestamp":1747188615000},"source":"Crossref","is-referenced-by-count":1,"title":["Acetaminophen alters endogenous lipid signaling and attenuates pathological pain through a mechanism requiring diacylglycerol lipase, monoacylglycerol lipase and cannabinoid CB1 receptors in mice"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3308-0022","authenticated-orcid":false,"given":"Carlos Henrique Alves","family":"Jesus","sequence":"first","affiliation":[{"name":"Psychological and Brain Sciences, Indiana University, Bloomington, IN, United States"},{"name":"Gill Institute of Neuroscience, Indiana University, Bloomington, IN, United 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