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

Background & Aims: Marijuana and other cannabinoids are effective anti-emet ics. Despite ongoing controversy over their usage, the receptor distributio n 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 en docannabinoids play a role in the anti-emetic action of cannabinoids. Metho ds: Ferrets were given an emetic stimulus and the number of episodes of ret ching and vomiting were observed after administration of CB1r agonists and a CB1r antagonist. CB1r and fatty acid amide hydrolase (FAAH), which degrad es 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 t he vagus in the brainstem. CB1r was found in the myenteric plexus of the st omach and duodenum. Activation of CB1r by the agonists (delta)(9)-tetrahydr ocannabinol, WIN 55,212-2, and methanandamide inhibited emesis and their ac tion 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 com plex. Endocannabinoids are a novel neuroregulatory system involved in the c ontrol of emesis.