期刊
BRITISH JOURNAL OF PHARMACOLOGY
卷 165, 期 8, 页码 2620-2634出版社
WILEY
DOI: 10.1111/j.1476-5381.2011.01621.x
关键词
cannabidiol; 5-HT1A; endocannabinoid; nausea; vomiting; shrew; rat; taste reactivity; gaping; conditioned disgust; emesis
资金
- Natural Sciences and Engineering Research Council
- National Institute of Drug Abuse (US) [DA-03672, DA-09789]
- GW Pharmaceuticals
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.
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