Evidence that the plant cannabinoid Δ9-tetrahydrocannabivarin is a cannabinoid CB1 and CB2 receptor antagonist

1. Delta(9)-tetrahydrocannabivarin (THCV) displaced [H-3]CP55940 from specific binding sites on mouse brain and CHO-hCB(2) cell membranes (K-i = 75.4 and 62.8 nm, respectively). 2 THCV (1 mu M) also antagonized CP55940-incluced stimulation of [S-35]GTP S binding to these membranes (apparent K-B = 93.1 and 10.1 nM, respectively). 3 In the mouse vas deferens, the ability of Delta(9)-tetrahydrocannabinol (THC) to inhibit electrically evoked contractions was antagonized by THCV, its apparent K-B-value (96.7nm) approximating the apparent K-B-values for its antagonism of CP55940- and R-(+)-WIN55212-induced stimulation of [S-35]GTP gamma S binding to mouse brain membranes. 4 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). 5 THCV (100nm) did not oppose clonidine, capsaicin or (-)-7-liydroxy-cannabidiol-dimethylheptyl-induced inhibition of electrically evoked contractions of the vas deferens. 6 Contractile responses of the vas deferens to phenylephrine hydrochloride or beta,gamma-methylene-ATP were not reduced by 1 mu m THCV or R-(+)-WIN55212, suggesting that THCV interacts with R-(+)WIN55212 at prejunctional sites. 7 At 32 mu m, THCV did reduce contractile responses to phenylephrine hydrochloride and beta,gamma-methylene-ATP, and above 3 pm it inhibited electrically evoked contractions of the vas deferens in an SR141716A-independent manner. 8 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.