BACKGROUND AND PURPOSE: To evaluate the hypothesis that activation
of somatodendritic 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.
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-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-, lithium chloride
(LiCl) - and cisplatin (20 murinus mg·kg(-1) , but not 40 mg·kg(-1) )-induced
vomiting in the S. 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 [(35) S]GTPγS 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-HT (1A) autoreceptors in the DRN.
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