Endocannabinoid regulation of nausea is mediated by 2-arachidonoylglycerol (2-AG) in the rat visceral insular cortex. (March 2016)

• Record Type: Journal Article
• Authors: Sticht, Martin A.; Limebeer, Cheryl L.; Rafla, Benjamin R.; Abdullah, Rehab A.; Poklis, Justin L.; Ho, Winnie; Niphakis, Micah J.; Cravatt, Benjamin F.; Sharkey, Keith A.; Lichtman, Aron H.; Parker, Linda A.
• Is Part Of: Neuropharmacology. Volume 102(2016)
• Page Start: 92
• Page End: 102
• Publication Date: 2016-03
• Subjects: 2-arachidonoylglycerol (2-AG) -- c-Fos -- Endocannabinoid -- Insular cortex -- Monoacylglycerol lipase (MAGL) -- Nausea; 2-AG 2-arachidonoylglycerol -- 5-HT3 5-hydroxytryptamine 3 -- AEA anandamide -- CB cannabinoid -- CTA conditioned taste avoidance -- COX cyclooxygenase -- FAAH fatty acid amide hydrolase -- GIV gustatory insular cortex -- IC insular cortex -- IO intraoral -- LiCl lithium chloride -- LOB lying on belly -- MAGL monoacylglycerol lipase -- OEA oleoylethanolamide -- OEA palmitoylethanolamide -- TR taste reactivity -- VIC visceral insular cortex; Anandamide (PubChem CID: 5281969) -- JZL195 (PubChem CID: 46232606) -- Lithium chloride (PubChem CID: 433294) -- MJN110 (PubChem CID: N/A) -- Oleoylethanolamide (PubChem CID: 5283454) -- Palmitoylethanolamide (PubChem CID: 4671) -- PF3845 (PubChem CID: -- 25154867) -- Saccharin (PubChem CID: 5143) -- Tween 80 (PubChem CID: 5281955) -- URB597 (PubChem CID: 1383884); Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2015.10.039
• Languages: English
• ISSNs: 0028-3908

Abstract

Abstract: Cannabinoid (CB) agonists suppress nausea in humans and animal models; yet, their underlying neural substrates remain largely unknown. Evidence suggests that the visceral insular cortex (VIC) plays a critical role in nausea. Given the expression of CB1 receptors and the presence of endocannabinoids in this brain region, we hypothesized that the VIC endocannabinoid system regulates nausea. In the present study, we assessed whether inhibiting the primary endocannabinoid hydrolytic enzymes in the VIC reduces acute lithium chloride (LiCl)-induced conditioned gaping, a rat model of nausea. We also quantified endocannabinoid levels during an episode of nausea, and assessed VIC neuronal activation using the marker, c-Fos. Local inhibition of monoacylglycerol lipase (MAGL), the main hydrolytic enzyme of 2-arachidonylglycerol (2-AG), reduced acute nausea through a CB1 receptor mechanism, whereas inhibition of fatty acid amide hydrolase (FAAH), the primary catabolic enzyme of anandamide (AEA), was without effect. Levels of 2-AG were also selectively elevated in the VIC during an episode of nausea. Inhibition of MAGL robustly increased 2-AG in the VIC, while FAAH inhibition had no effect on AEA. Finally, we demonstrated that inhibition of MAGL reduced VIC Fos immunoreactivity in response to LiCl treatment. Taken together, these findings provide compelling evidence that acute nausea selectively increases 2-AG in the VIC, and suggests that 2-AG signaling within the VIC regulates nausea by reducing neuronal activity in this forebrain region. Highlights: Visceral insular cortex (VIC) 2-AG is increased during LiCl-induced nausea in rats. Intra-VIC MAGL inhibition supresses nausea-induced conditioned gaping. The anti-nausea effects of MAGL inhibition are attenuated following CB1 antagonism. MAGL inhibition reduces LiCl-induced Fos immunoreactivity within the VIC. The endocannabinoid system regulates nausea via 2-AG and CB1 signaling in the VIC.