Cannabinoids inhibit emesis through CB1 receptors in the brainstem of the ferret

Background & Aims: Marijuana and other cannabinoids are effective anti-emetics. Despite ongoing controversy over their usage, the receptor distribution and the site of the anti-emetic action of these compounds are not known. Our aim was to investigate whether the cannabinoid I receptor (CB1r) and endocannabinoids play a role in the anti-emetic action of cannabinoids. Methods: Ferrets were given an emetic stimulus and the number of episodes of retching and vomiting were observed after administration of CB1r agonists and a CB1r antagonist. CB1r and fatty acid amide hydrolase (FAAH), which degrades endocannabinoids, were localized by immunohistochemistry. Results: CB1r and FAAH were localized in the dorsal vagal complex, consisting of the area postrema, nucleus of the solitary tract, and the dorsal motor nucleus of the vagus in the brainstem. CB1r was found in the myenteric plexus of the stomach and duodenum. Activation of CB1r by the agonists (delta)(9)-tetrahydrocannabinol, WIN 55,212-2, and methanandamide inhibited emesis and their action was reversed by a selective CB1r antagonist, which alone had no effect, but potentiated vomiting in response to an emetic stimulus. Conclusions: CB1r mediates the antiemetic action of cannabinoids in the dorsal vagal complex. Endocannabinoids are a novel neuroregulatory system involved in the control of emesis.