ABSTRACT:
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Δ9-tetrahydrocannabivarin (THCV) displaced [3H]CP55940 from specific binding sites on mouse brain and CHO-hCB2 cell membranes (Ki=75.4 and 62.8 nm, respectively).
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THCV (1 μm) also antagonized CP55940-induced stimulation of [35S]GTPγS binding to these membranes (apparent KB=93.1 and 10.1 nm, respectively).
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In the mouse vas deferens, the ability of Δ9-tetrahydrocannabinol (THC) to inhibit electrically evoked contractions was antagonized by THCV, its apparent KB-value (96.7 nm) approximating the apparent KB-values for its antagonism of CP55940- and R-(+)-WIN55212-induced stimulation of [35S]GTPγS binding to mouse brain membranes.
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THCV also antagonized R-(+)-WIN55212, anandamide, methanandamide and CP55940 in the vas deferens, but with lower apparent KB-values (1.5, 1.2, 4.6 and 10.3 nm, respectively).
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THCV (100 nm) did not oppose clonidine, capsaicin or (−)-7-hydroxy-cannabidiol-dimethylheptyl-induced inhibition of electrically evoked contractions of the vas deferens.
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Contractile responses of the vas deferens to phenylephrine hydrochloride or β,γ-methylene-ATP were not reduced by 1 μm THCV or R-(+)-WIN55212, suggesting that THCV interacts with R-(+)-WIN55212 at prejunctional sites.
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At 32 μm, THCV did reduce contractile responses to phenylephrine hydrochloride and β,γ-methylene-ATP, and above 3 μm it inhibited electrically evoked contractions of the vas deferens in an SR141716A-independent manner.
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In conclusion, THCV behaves as a competitive CB1 and CB2 receptor antagonist. In the vas deferens, it antagonized several cannabinoids more potently than THC and was also more potent against CP55940 and R-(+)-WIN55212 in this tissue than in brain membranes. The bases of these agonist- and tissue-dependent effects remain to be established.
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