Dvorakova_2025_Cell.Rep.Med__102139

Acetaminophen (paracetamol) is a common analgesic, but its mechanism of action remains unknown. Despite causing around 500 deaths annually in the US, safer alternatives have not been developed. Because endocannabinoids may have a role in acetaminophen action, we examine interactions between the two. We report that acetaminophen inhibits the activity of diacylglycerol lipase alpha (DAGLalpha), but not DAGLbeta, decreasing the production of the endocannabinoid 2-arachidonoyl glycerol. This gives rise to the counterintuitive hypothesis that decreasing endocannabinoid production by DAGLalpha inhibition may be antinociceptive in certain settings. Supporting this hypothesis, we find that diacylglycerol lipase (DAGL) inhibition by RHC80267 is antinociceptive in wild-type but not CB1 knockout mice in the hot-plate test. We propose (1) that activation of DAGLalpha may exacerbate some forms of nociception and (2) a mechanism for the antinociceptive actions of acetaminophen, whereby acetaminophen inhibits a DAGLalpha/CB1-based circuit that plays a permissive role in at least one form of nociception.