Elevation of 2-AG by monoacylglycerol lipase inhibition in the visceral insular cortex interferes with anticipatory nausea in a rat model.

Abstract

Anticipatory nausea (AN) is a conditioned nausea reaction experienced by chemotherapy patients upon returning to the clinic. Currently, there are no specific treatments for this phenomenon, with the classic anti-emetic treatments (e.g., ondansetron) providing no relief. The rat model of AN, contextually elicited conditioned gaping reactions in rats, provides a tool for assessing potential treatments for this difficult to treat disorder. Systemically administered drugs which elevate the endocannabinoids, anandamide (AEA) and 2-arachodonyl glycerol (2-AG), by interfering with their respective degrading enzymes, fatty acid amide hydrolase (FAAH) and monoacyl glycerol lipase (MAGL) interfere with AN in the rat model. We have shown that MAGL inhibition within the visceral insular cortex (VIC) interferes with acute nausea in the gaping model (Sticht et al, 2015b). Here we report that bilateral infusion of the MAGL inhibitor, MJN110 (but neither the FAAH inhibitor, PF3845, nor ondansetron) into the VIC suppressed contextually – elicited conditioned gaping and this effect was reversed by co-administration of the CB1 antagonist, AM251. These findings suggest that 2-AG within the VIC plays a critical role in the regulation of both acute nausea and AN. As there are currently no specific therapeutics for chemotherapy patients that develop anticipatory nausea, MAGL inhibition by MJN110 may be a candidate treatment.

Cannabinoid Regulation of Acute and Anticipatory Nausea

“…Recent findings in our laboratory indicate that infusion of the MAGL inhibitor, MJN110 (but not the FAAH inhibitor PF-3845 nor ondansetron), into the interoceptive IC suppressed contextually elicited conditioned gaping, a CB 1 receptor-mediated effect. 83 These results suggest that the interoceptive IC may be a critical region for AN (in addition to acute nausea), mediated by 2-AG activity at the CB 1 receptor.…”

Endocannabinoid regulation of homeostatic feeding and stress‐induced alterations in food intake in male rats

“…To date, there are no reports assessing i.c.v. administration of MJN110, although several studies have demonstrated CB 1 receptor‐dependent effects of localized injection (2 μg) into distinct brain regions (Limebeer et al ., ; Sticht et al ., ; Wills et al ., ). As the current study assessed i.c.v.…”

Cannabinoids As Potential Treatment for Chemotherapy-Induced Nausea and Vomiting

“…; Parker et al, 2015 ). Furthermore, intra-interoceptive IC, MJN110 (2 μg, but not PF3845, nor ondansetron) suppressed contextually elicited conditioned gaping, blocked by CB 1 receptor antagonism (Limebeer et al, 2016 ). The MAGL inhibitor, AM4301 (10, 20 mg/kg, i.p.…”