Evidence that the plant cannabinoid Δ 9 ‐tetrahydrocannabivarin is a cannabinoid CB 1 and CB 2 receptor antagonist

Δ 9 ‐tetrahydrocannabivarin (THCV) displaced [ 3 H]CP55940 from specific binding sites on mouse brain and CHO‐hCB 2 cell membranes ( K i =75.4 and 62.8 n M , respectively). THCV (1  μ M ) also antagonized CP55940‐induced stimulation of [ 35 S]GTP γ S binding to these membranes (apparent K B =93.1 and 10.1 n M , respectively). In the mouse vas deferens, the ability of Δ 9 ‐tetrahydrocannabinol (THC) to inhibit electrically evoked contractions was antagonized by THCV, its apparent K B ‐value (96.7 n M ) approximating the apparent K B ‐values for its antagonism of CP55940‐ and R ‐(+)‐WIN55212‐induced stimulation of [ 35 S]GTP γ S binding to mouse brain membranes. THCV also antagonized R ‐(+)‐WIN55212, anandamide, methanandamide and CP55940 in the vas deferens, but with lower apparent K B ‐values (1.5, 1.2, 4.6 and 10.3 n M , respectively). THCV (100 n M ) did not oppose clonidine, capsaicin or (−)‐7‐hydroxy‐cannabidiol‐dimethylheptyl‐induced inhibition of electrically evoked contractions of the vas deferens. Contractile responses of the vas deferens to phenylephrine hydrochloride or β,γ ‐methylene‐ATP were not reduced by 1  μ M THCV or R ‐(+)‐WIN55212, suggesting that THCV interacts with R ‐(+)‐WIN55212 at prejunctional sites. At 32  μ M , THCV did reduce contractile responses to phenylephrine hydrochloride and β,γ ‐methylene‐ATP, and above 3  μ M it inhibited electrically evoked contractions of the vas deferens in an SR141716A‐independent manner. In conclusion, THCV behaves as a competitive CB 1 and CB 2 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.British Journal of Pharmacology (2005) 146 , 917–926. doi: 10.1038/sj.bjp.0706414