Acetaminophen alters endogenous lipid signaling and attenuates pathological pain through a mechanism requiring diacylglycerol lipase, monoacylglycerol lipase and cannabinoid CB1 receptors in mice

This dataset contains behavioral, physiological, and lipidomic data generated to investigate the role of the endocannabinoid system in acetaminophen (APAP)-induced analgesia. Although acetaminophen has been widely used as an analgesic and antipyretic for decades, its mechanisms of action remain incompletely understood. The study evaluated the hypothesis that APAP-induced analgesia requires central cannabinoid CB1 receptors and enzymes involved in 2-arachidonoylglycerol (2-AG) metabolism, including diacylglycerol lipase (DAGL) and monoacylglycerol lipase (MAGL). Experiments were conducted using two pathological pain models in mice: Complete Freund’s Adjuvant (CFA)-induced inflammatory pain and hind paw incisional injury. The dataset includes measures of pain-related behaviors, paw edema, body temperature, locomotor activity, pharmacological manipulations targeting DAGL, MAGL, and CB1 receptors, and lipidomic profiling of brain, spinal cord, and paw skin tissues. Key findings represented in the dataset include: (1) APAP produced analgesic effects in both pain models without altering CFA-induced paw edema; (2) APAP-induced analgesia was blocked by DAGL and MAGL inhibitors and by brain-permeant CB1 receptor antagonists, but not by a peripherally restricted CB1 receptor antagonist; (3) APAP-induced changes in body temperature and locomotor performance were independent of DAGL and CB1 receptor signaling; and (4) APAP treatment produced substantial alterations in endogenous lipid profiles across multiple tissues, including reductions in prostaglandin levels. The robustness of the behavioral findings was assessed across multiple experimental conditions, including two pathological pain models, both male and female mice, two mouse strains, and different routes of APAP administration (intraperitoneal and oral). This dataset supports investigations into the neurobiological mechanisms underlying acetaminophen analgesia and the contribution of endocannabinoid signaling pathways to pain modulation.