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.