Effect of selective inhibition of monoacylglycerol lipase (MAGL) on acute nausea, anticipatory nausea, and vomiting in rats and Suncus murinus

• Published in: Psychopharmacology 2015-02, Vol.232 (3), p.583-593
• Main Authors: Parker, Linda A., Niphakis, Micah J., Downey, Rachel, Limebeer, Cheryl L., Rock, Erin M., Sticht, Martin A., Morris, Heather, Abdullah, Rehab A., Lichtman, Aron H., Cravatt, Benjamin F.
• Format: Article
• Language: English
• Subjects: Animals; Biomedical and Life Sciences; Biomedicine; Carbamates - administration & dosage; Carbamates - pharmacology; Care and treatment; Disease Models, Animal; Female; Health aspects; Inhibitor drugs; Lipase; Male; Monoacylglycerol Lipases - antagonists & inhibitors; Nausea; Nausea - drug therapy; Neurosciences; Original Investigation; Pharmacology/Toxicology; Psychiatry; Psychopharmacology; Rats; Rats, Sprague-Dawley; Shrews; Small mammals; Succinimides - administration & dosage; Succinimides - pharmacology; Suncus murinus; Vomiting; Vomiting - drug therapy
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s00213-014-3696-x

Rationale To determine the role of the endocannabinoid, 2-arachodonyl glycerol (2-AG), in the regulation of nausea and vomiting. Objective We evaluated the effectiveness of the potent selective monoacylglycerol lipase (MAGL) inhibitor, MJN110, which selectively elevates the endocannabinoid 2-AG, to suppress acute nausea and vomiting, as well as anticipatory nausea in rat and shrew models. Methods The rat gaping models were used to evaluate the potential of MJN110 (5, 10, and 20 mg/kg, intraperitoneally [IP]) to suppress acute nausea produced by LiCl and of MJN110 (10 and 20 mg/kg, IP) to suppress anticipatory nausea elicited by a LiCl-paired context. The potential as well of MJN110 (10 and 20 mg/kg, IP) to suppress vomiting and contextually elicited gaping in the Suncus murinus was evaluated. Results MJN110 suppressed acute nausea in rats, LiCl-induced vomiting in shrews and contextually-elicited anticipatory nausea in both rats (accompanied by elevation of 2-AG in the visceral insular cortex) and shrews. These effects were reversed by the CB 1 antagonist/inverse agonist, SR141716. The MAGL inhibitor did not modify locomotion at any dose. An activity-based protein profiling analysis of samples of tissue collected from the visceral insular cortex in rats and whole brain tissues in shrews revealed that MJN110 selectively inhibited MAGL and the alternative 2-AG hydrolase, ABHD6. Conclusions MAGL inhibition by MJN110 which selectively elevates endogenous 2-AG has therapeutic potential in the treatment of acute nausea and vomiting as well as anticipatory nausea, a distressful symptom that is resistant to currently available treatments.