USF-LVHN SELECT
Acetaminophen inhibits diacylglycerol lipase synthesis of 2-arachidonoyl glycerol: Implications for nociception.
Publication/Presentation Date
5-12-2025
Abstract
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 α (DAGLα), but not DAGLβ, decreasing the production of the endocannabinoid 2-arachidonoyl glycerol. This gives rise to the counterintuitive hypothesis that decreasing endocannabinoid production by DAGLα 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 DAGLα may exacerbate some forms of nociception and (2) a mechanism for the antinociceptive actions of acetaminophen, whereby acetaminophen inhibits a DAGLα/CB1-based circuit that plays a permissive role in at least one form of nociception.
First Page
102139
Last Page
102139
ISSN
2666-3791
Published In/Presented At
Dvorakova, M., Bosquez-Berger, T., Billingsley, J., Murataeva, N., Woodward, T., Leishman, E., Zimmowitch, A., Gibson, A., Wager-Miller, J., Cai, R., Cai, S., Ware, T., Hsu, K. L., Li, Y., Bradshaw, H., Mackie, K., & Straiker, A. (2025). Acetaminophen inhibits diacylglycerol lipase synthesis of 2-arachidonoyl glycerol: Implications for nociception. Cell reports. Medicine, 102139. Advance online publication. https://doi.org/10.1016/j.xcrm.2025.102139
Disciplines
Medical Education | Medicine and Health Sciences
PubMedID
40381619
Department(s)
USF-LVHN SELECT Program, USF-LVHN SELECT Program Students
Document Type
Article