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Inhibition of cannabinoid metabolic enzymes reduces NSAID-induced gastric pathology

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Chronic use of non-steroidal anti-inflammatory drugs (NSAIDs) causes gastric hemorrhages, erosion, and ulceration. The endocannabinoid (eCB) system, comprised of cannabinoid receptors (CB1 and CB2), endocannabinoid ligands, and eCB regulatory enzymes, offers several targets to treat inflammatory disorders. We hypothesized that elevating the eCB 2-arachidonoylglycerol (2-AG) via JZL184, a selective inhibitor of its main catabolic enzyme monoacylglycerol lipase (MAGL), protects against NSAID-induced gastropathy. Mice administered the NSAID diclofenac sodium displayed gastric hemorrhages. JZL184, the proton pump inhibitor Omeprazole, or the primary constituent of marijuana, 9-tetrahydrocannbinol (THC), significantly blocked hemorrhage development and increased stomach levels of 2-AG, but had no effect on the eCB anandamide or prostaglandins PGE2 or PGD2. Pharmacological inhibition or genetic deletion of CB1 or CB2 receptors revealed that the gastroprotective effects of JZL184 and THC were mediated via CB1. The anti-hemorrhagic effects of JZL184 persisted with repeated administration, indicating a lack of tolerance at low doses (e.g. 4 mg/kg). These data indicate that 2-AG protects against NSAID-induced gastropathy. Further, the eCB catabolic enzymes MAGL and FAAH offer promising targets for development of analgesic, gastroprotective therapeutics. Research supported by NIDA.

Source: fasebj.org
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