title: Inhibition of monoacylglycerol lipase attenuates nonsteroidal anti-inflammatory drug-induced gastric hemorrhages in mice.
abstract: Nonsteroidal 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 cannabinoid receptor type 1 (CB(1)), cannabinoid receptor type 2 (CB(2)), and enzymes that regulate the eCB ligands 2-arachidonoylglycerol (2-AG) and N-arachidonoyl ethanolamine (anandamide; AEA). In the presented study, we tested whether 4-nitrophenyl 4-(dibenzo[d][1,3]dioxol-5-yl(hydroxy)methyl)piperidine-1-carboxylate (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, Δ(9)-tetrahydrocannabinol (THC), significantly prevented diclofenac-induced gastric hemorrhages. JZL184 also increased stomach levels of 2-AG, but had no effect on AEA, arachidonic acid, or the prostaglandins E(2) and D(2). MAGL inhibition fully blocked diclofenac-induced increases in gastric levels of proinflammatory cytokines interleukin (IL)-1β, IL-6, tumor necrosis factor α, and granulocyte colony-stimulating factor, as well as IL-10. Pharmacological inhibition or genetic deletion of CB(1) or CB(2) revealed that the gastroprotective effects of JZL184 and THC were mediated via CB(1). The antihemorrhagic 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 analgesic therapeutics possessing gastroprotective properties.
authors.affiliation: Department of Psychology, West Virginia University, Morgantown, West Virginia, USA. steven.kinsey@mail.wvu.edu.
authors.forename: Steven G
authors.initials: SG
authors.lastname: Kinsey
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Nomura
authors.forename: Scott T
authors.initials: ST
authors.lastname: O'Neal
authors.forename: Jonathan Z
authors.initials: JZ
authors.lastname: Long
authors.forename: Anu
authors.initials: A
authors.lastname: Mahadevan
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Cravatt
authors.forename: John R
authors.initials: JR
authors.lastname: Grider
authors.forename: Aron H
authors.initials: AH
authors.lastname: Lichtman
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal; D052117:Benzodioxoles / Q000494:pharmacology; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004008:Diclofenac; D013759:Dronabinol / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D004797:Enzyme-Linked Immunosorbent Assay; D005508:Food Deprivation; D005753:Gastric Mucosa / Q000378:metabolism; D006471:Gastrointestinal Hemorrhage / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors*; D009853:Omeprazole / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011453:Prostaglandins / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000187:drug effects; D043885:Receptor, Cannabinoid, CB2 / Q000187:drug effects; D013270:Stomach / Q000187:drug effects / Q000473:pathology; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D000894:Anti-Inflammatory Agents, Non-Steroidal; D052117:Benzodioxoles; D063385:Cannabinoid Receptor Modulators; D016207:Cytokines; D004008:Diclofenac; D013759:Dronabinol; D004791:Enzyme Inhibitors; D008994:Monoacylglycerol Lipases; D009853:Omeprazole; D010880:Piperidines; D011453:Prostaglandins; D011725:Pyridines; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D000099252:Fatty Acid Amide Hydrolases; C534333:JZL 184; C557973:PF 3845