MAGL inhibition modulates gastric secretion and motility following NSAID exposure in mice

Non-steroidal anti-inflammatory drugs (NSAIDs) are common analgesic drugs that also cause well-known, negative gastrointestinal (GI) side effects. The physiological mechanism(s) of NSAID-induced GI damage are unclear and are likely due to multiple causes. The most studied contributing mechanisms are increased gastric acid secretion and increased gastric motility. The present study was designed to determine which ulcerogenic effects of the NSAID diclofenac sodium are reversed by blocking the endocannabinoid catabolic enzyme monoacylglycerol lipase (MAGL). Both male and female mice were used to identify possible sex differences. We hypothesized that the MAGL inhibitor JZL184 would attenuate diclofenac-induced increases in both gastric acid secretion and gastric motility. Diclofenac dose-dependently induced gastric hemorrhages to a similar extent in both male and female mice. Gastric hemorrhage severity significantly correlated with gastric levels of myeloperoxidase, an objective measure of neutrophil infiltration. Similarly, JZL184 reduced gastric acidity, in controls as well as mice treated with pentagastrin, which stimulates gastric acid release. As hypothesized, JZL184 decreased gastric motility. Surprisingly, diclofenac also slowed gastric emptying, indicating that diclofenac-induced ulcers most likely occur through increased gastric acid secretion, and not increased gastric motility, as measured in the present study. Thus, MAGL inhibition may proffer gastroprotection through modulating the secretory pathway of gastric hemorrhage. These data underscore the importance of sampling multiple time points and using both sexes in research, in addition to multiple mechanistic targets, and contribute to the basic understanding of NSAID-induced gastric inflammation.