Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used analgesics, but can cause gastric and esophageal hemorrhages, erosion, and ulceration. The endogenous cannabinoid (endocannabinoid; eCB) system possesses several potential targets to reduce gastric inflammatory states, including CB1 and CB2 receptors and enzymes that regulate the eCB ligands 2-arachidonoylglycerol (2-AG)and N-arachidonoyl ethanolamine (anandamide; AEA). In the presented study, we tested whether JZL184, a selective inhibitor of the primary catabolic enzyme of 2-AG, monoacylglycerol lipase (MAGL), would protect against NSAID-induced gastric damage. Food deprived mice administered the nonselective cyclooxygenase inhibitor, diclofenac sodium, displayed gastric hemorrhages and increases in proinflammatory cytokines. JZL184, the proton pump inhibitor omeprazole (positive control), or the primary constituent of marijuana, Δ9-tetrahydrocannbinol (THC), significantly prevented diclofenac-induced gastric hemorrhages. JZL184 also increased stomach levels of 2-AG, but had no effect on AEA, as well as arachidonic acid or the prostaglandins PGE2 and PGD2. MAGL inhibition fully blocked diclofenac-induced increases in gastric levels of proinflammatory cytokines IL-1β, IL-6, TNF-α, and G-CSF, as well as IL-10. Pharmacological inhibition or genetic deletion of CB1 or CB2 receptors revealed that the gastroprotective effects of JZL184 and THC were mediated via the CB1 receptor. The anti-hemorrhagic effects of JZL184 persisted with repeated administration, indicating a lack of tolerance. These data indicate that increasing 2-AG protects against gastric damage induced by NSAIDs, and its primary catabolic enzyme MAGL offers a promising target for the development of an analgesic therapeutic possessing gastroprotective properties.
- 2-ararchidonylglycerol (2-AG)
- endogenous cannabinoid
- fatty acid amide hydrolase (FAAH)
- gastric inflammation
- monoacylglycerol lipase (MAGL)
- Received September 30, 2010.
- Revision received June 8, 2011.
- Accepted June 8, 2011.
- The American Society for Pharmacology and Experimental Therapeutics