Cannabidiol Indirectly Activates 5-HT1A Somatodendritic Autoreceptors to Attenuate Vomiting and Nausea
Cannabidiol (CBD), a non-psychoactive cannabinoid found in cannabis suppresses vomiting in shrews (Suncus murinus, Parker et al., 2004), and conditioned gaping in rats (a selective measure of nausea-like behaviour, Parker et al., 2002). CBD‘s anti-emetic/anti-nausea mechanism of action is unknown. However, evidence suggests that CBD may act as a somatodendritic 5-hydroxytryptamine 1A (5-HT1A) autoreceptor agonist in the dorsal raphe nucleus (DRN), because the anxiolytic (Campos and Guimaraes, 2008a) and neuroprotectant (Mishima et al., 2005) properties of CBD are 5-HT1A-mediated. Therefore, here we investigated if administration of 5-HT1A receptor antagonists, (WAY100135 or WAY100635) would block CBD‘s anti-emetic/anti-nausea-like effects. Systemic administration of WAY100135 prevented the anti-emetic effect of CBD in shrews, and WAY100135 and WAY100635 attenuated the anti-nausea-like effect of CBD in rats. The effect of CBD on conditioned gaping reactions was most likely the result of its action on somatodendritic 5-HT1A receptors in the DRN, because the anti-nausea-like action of systemic CBD was reversed by intra-DRN administration of WAY100635. As well, when administered into the DRN, CBD suppressed conditioned gaping, an effect that was blocked by systemic WAY100635. In vitro studies revealed that CBD enhanced the ability of 8-OH-DPAT to stimulate [35S]GTPS binding and in vivo studies revealed that systemic subthreshold doses of combined CBD and 8-OH-DPAT synergistically suppressed conditioned gaping. These results suggest that CBD produces its anti-emetic/anti-nausea-like effects by indirect receptor agonism of DRN somatodendritic 5-HT1A autoreceptors. CBD‘s mechanism of action was explored further, by examining its interaction with cannabigerol (CBG), another cannabinoid, which acts in vitro as a 5-HT1A receptor antagonist (Cascio et al., 2010). CBG blocked the systemic CBD-, and 8-OH-DPAT-induced suppression of gaping in rats, as well as the systemic CBD-induced suppression of vomiting in shrews. Therefore, CBG and CBD may be in opposition at the 5-HT1A receptor. These findings shed light on the mechanism of action of non-psychoactive cannabinoids in the cannabis plant, and their effect on nausea and vomiting. These results suggest CBD alone may be an effective treatment in reducing nausea and vomiting.