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Cannabidiol, a Non-Psychotropic Component of Cannabis, Attenuates Vomiting and Nausea-like Behaviour via Indirect Agonism of 5-HT(1A) Somatodendritic: Autoreceptors in the Dorsal Raphe Nucleus.

Rock EM, Bolognini D, Limebeer CL, Cascio MG, Anavi-Goffer S, Fletcher PJ, Mechoulam R, Pertwee RG, Parker LA

Department of Psychology and Neuroscience Graduate Program, University of Guelph, Guelph, Ontario, Canada Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK Centre for Addiction and Mental Health and Department of Psychology, University of Toronto, Toronto, Ontario, Canada Institute of Drug Research, Hebrew University Medical Faculty, Jerusalem, Israel.

Background and purpose: To evaluate the hypothesis that agonism of somatodentdritic 5-HT(1A) autoreceptors in the Dorsal Raphe Nucleus (DRN) produces the anti-emetic/anti-nausea effects of cannabidiol (CBD), a primary non-psychoactive cannabinoid found in cannabis. Experimental approach: The potential of systemic and intra-DRN administration of 5-HT(1A) receptor antagonists (WAY100135 or WAY100635) to prevent the anti-emetic effect of CBD (in shrews-Suncus murinus) and the anti-nausea-like effects of CBD (conditioned gaping in rats) were evaluated. As well, the ability of intra-DRN administration of CBD to produce anti-nausea-like effects (and reversal by systemic WAY100635) was assessed. In vitro studies evaluated the potential of CBD to directly target 5-HT(1A) receptors and to modify the ability of the 5-HT(1A) agonist, 8-OH-DPAT, to stimulate [(35) S]GTPγS binding in rat brainstem membranes. Key results: CBD suppressed nicotine-, LiCl- and cisplatin (20 mg/kg, but not 40 mg/kg)-induced vomiting in the S. murinus and LiCl-induced conditioned gaping in rats. The anti-emetic and anti-nausea-like effects of CBD were suppressed by WAY100135 and the latter by WAY100635. When administered to the DRN: 1) WAY100635 reversed the anti-nausea-like effect of systemic CBD, and 2) CBD suppressed nausea-like effects, an effect that was reversed by systemic WAY100635. CBD also displayed significant potency (in a bell shaped dose-response curve) at enhancing the ability of 8-OH-DPAT to stimulate [(35) S]GTPγS binding to rat brainstem membranes in vitro. Finally, systemically administered CBD and 8-OH-DPAT synergistically suppressed LiCl-induced conditioned gaping. Conclusions and implications: These results suggest that CBD produces its anti-emetic/anti-nausea effects by indirect agonism of the somatodendritic 5-HT(1A) autoreceptors in the DRN.

Published 10 August 2011 in Br J Pharmacol.
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