The aim of this study was to investigate the efficacy, receptor specificity and site of action of (delta)⁹-tetrahydrocannabinol (THC) as an anti-emetic in the ferret. Pretreatment with THC (0.05-1 mg/kg, i.p.) dose-dependently inhibited the emetic actions of cisplatin (10 mg/kg, i.v.). The ED₅₀ for retching was approximately 0.1 mg/kg and for vomiting 0.05 mg/kg. A specific CB₁ receptor antagonist, SR 141716A (5 mg/kg, i.p.), reversed the effect of THC, while a CB₂ receptor antagonist, SR 144528 (5 mg/kg, i.p.), was ineffective, confirming the selectivity of action at CB₁ receptors. A low dose of THC applied to the surface of the brainstem was sufficient to inhibit the emesis induced by intragastric hypertonic saline. The site of action of THC in the brainstem was further assessed using Fos immunohistochemistry. Fos expression induced by cisplatin in the dorsal motor nucleus of the vagus and the medial subnucleus of the nucleus of the solitary tract (NTS), but not other subnuclei of the NTS, was significantly reduced by THC rostral to obex. At the level of the obex, THC reduced Fos expression in the area postrema and the dorsal subnucleus of the NTS. The highest density of CB₁ receptor immunoreactivity was found in the dorsal motor nucleus of the vagus and the medial subnucleus of the NTS. Lower densities were observed in the area postrema and dorsal subnucleus of the NTS. Caudal to obex there was moderate density of staining in the commissural subnucleus of the NTS. These results show that THC selectively acts at CB₁ receptors to reduce neuronal activation in response to emetic stimuli in specific regions of the dorsal vagal complex.