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NEUROREGULATION AND MOTILITY

⁹-Tetrahydrocannabinol selectively acts on CB₁ receptors in specific regions of dorsal vagal complex to inhibit emesis in ferrets

¹Gastrointestinal and Neuroscience Research Groups, Department of Physiology and Biophysics, University of Calgary, Calgary, Alberta, Canada T2N 4N1; ²Departments of Anesthesiology, Physiology, and Biophysics, University of Washington, Seattle, Washington 98195

Submitted 11 March 2003 ; accepted in final form 30 May 2003

The aim of this study was to investigate the efficacy, receptor specificity, and site of action of ⁹-tetrahydrocannabinol (THC) as an antiemetic in the ferret. THC (0.05-1 mg/kg ip) dose-dependently inhibited the emetic actions of cisplatin. The ED₅₀ for retching was 0.1 mg/kg and for vomiting was 0.05 mg/kg. A specific cannabinoid (CB)₁ receptor antagonist SR-141716A (5 mg/kg ip) reversed the effect of THC, whereas the CB₂ receptor antagonist SR-144528 (5 mg/kg ip) was ineffective. THC applied to the surface of the brain stem was sufficient to inhibit emesis induced by intragastric hypertonic saline. The site of action of THC in the brain stem was further assessed using Fos immunohistochemistry. Fos expression induced by cisplatin in the dorsal motor nucleus of the vagus (DMNX) 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 DMNX 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.

area postrema; CB₂ receptor; dorsal motor nucleus of the vagus; nucleus of the solitary tract

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