Cannabidiol, a non-psychotropic component of cannabis, attenuates vomiting and nausea-like behaviour via indirect agonism of 5-HT1A somatodendritic autoreceptors in the dorsal raphe nucleus

BACKGROUND AND PURPOSE To evaluate the hypothesis that activation of somatodendritic 5-HT1A 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-HT1A 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. Also, 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-HT1A receptors and to modify the ability of the 5-HT1A agonist, 8-OH-DPAT, to stimulate [S-35]GTP gamma S binding in rat brainstem membranes. KEY RESULTS CBD suppressed nicotine-, lithium chloride (LiCl)- and cisplatin (20 mg.kg(-1), but not 40 mg.kg(-1))-induced vomiting in the S. murinus and LiCl-induced conditioned gaping in rats. Anti-emetic and anti-nausea-like effects of CBD were suppressed by WAY100135 and the latter by WAY100635. When administered to the DRN: (i) WAY100635 reversed anti-nausea-like effects of systemic CBD, and (ii) 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 [35S] GTPgS binding to rat brainstem membranes in vitro. Systemically administered CBD and 8-OH-DPAT synergistically suppressed LiCl-induced conditioned gaping. CONCLUSIONS AND IMPLICATIONS These results suggest that CBD produced its anti-emetic/anti-nausea effects by indirect activation of the somatodendritic 5-HT1A autoreceptors in the DRN.