Endocannabinoid Regulation of Nausea and Emesis: The Role of 2-arachidonoylglycerol in LiCl-induced Vomiting in Suncus Murinus and Conditioned Gaping in Rats

Sticht, Martin
Journal Title
Journal ISSN
Volume Title
University of Guelph

The anti-emetic effects of anandamide are well established; however, the role of 2-arhachidonoylglycerol (2-AG) is less clear. In Chapter II, I assessed the effects of exogenous 2-AG in the house musk shrew, Suncus murinus. It was found that 2-AG alone did not induce emesis, but rather interfered with lithium chloride (LiCl)-induced vomiting. The anti-emetic effects of 2-AG were not mediated by CB1 receptors, as concomitant pretreatment with the CB1 receptor antagonist, SR141716, did not reverse the suppressive effects of 2-AG. These findings serve to highlight species differences in emesis research. Next, the role of the endocannabinoid system in nausea was investigated using conditioned gaping in rats. However, prior to assessing endocannabinoid manipulations, the gaping model itself was scrutinized in Chapter III. To determine whether a LiCl-paired stimulus elicits nausea in the absence of pharmacologically-induced illness, rats received second-order conditioning to a novel stimulus experienced in a nausea-paired context. Rats were injected with LiCl or saline prior to confinement in a chamber (CS1). Subsequently, second-order conditioning consisted of a five min intraoral infusion of saccharin (CS2) upon exposure to the drug-free CS1. Rats were tested during a drug-free taste reactivity test in a novel environment and it was found that saccharin elicited nausea-induced gaping among rats receiving four or eight first-order conditioning trials. In the final two chapters, I assessed endocannabinoid suppression of nausea via manipulations of the visceral insular cortex (VIC). Rats received intra-VIC pharmacological manipulations inhibiting endocannabinoid metabolism prior to a saccharin-LiCl association, and gaping was assessed to the nausea-paired taste in a drug-free taste reactivity test. Acute LiCl selectively increased VIC 2-AG, whereas levels of anandamide remained unchanged. Furthermore, inhibition of 2-AG metabolism increased VIC 2-AG and suppressed conditioned gaping, while reduced anandamide metabolism did not elevate VIC anandamide, nor did it reduce gaping. Lastly, systemic inhibition of 2-AG metabolism reduced nausea-induced c-Fos expression in the VIC. Taken together, these findings suggest that the VIC eCB system modulates nausea primarily through 2-AG. Thus, manipulations selectively targeting 2-AG may have therapeutic potential in reducing nausea, likely by reducing neuronal activation in this brain region during an episode of nausea.

2-arachidonoylglycerol, anandamide, nausea, emesis, rat, shrew, endocannabinoid