The psychoactive plant cannabinoid, Δ9‐tetrahydrocannabinol, is antagonized by Δ8‐ and Δ9‐tetrahydrocannabivarin in micein vivo

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Abstract
Background and purpose: To follow upin vitroevidence that Δ9‐tetrahydrocannabivarin extracted from cannabis (eΔ9‐THCV) is a CB1receptor antagonist by establishing whether synthetic Δ9‐tetrahydrocannabivarin (O‐4394) and Δ8‐tetrahydrocannabivarin (O‐4395) behave as CB1antagonistsin vivo.Experimental approach: O‐4394 and O‐4395 were compared with eΔ9‐THCV as displacers of [3H]‐CP55940 from specific CB1binding sites on mouse brain membranes and as antagonists of CP55940 in [35S]GTPγS binding assays performed with mouse brain membranes and ofR‐(+)‐WIN55212 in mouse isolated vasa deferentia. Their ability to antagonizein vivoeffects of 3 or 10 mg kg−1(i.v.) Δ9‐tetrahydrocannabinol in mice was then investigated.Key results: O‐4394 and O‐4395 exhibited similar potencies to eΔ9‐THCV as displacers of [3H]‐CP55940 (Ki=46.6 and 64.4 nM, respectively) and as antagonists of CP55940 in the [35S]GTPγS binding assay (apparentKB=82.1 and 125.9 nM, respectively) andR‐(+)‐WIN55212 in the vas deferens (apparentKB=4.8 and 3.9 nM respectively). At i.v. doses of 0.1, 0.3, 1.0 and/or 3 mg kg−1O‐4394 and O‐4395 attenuated Δ9‐tetrahydrocannabinol‐induced anti‐nociception (tail‐flick test) and hypothermia (rectal temperature). O‐4395 but not O‐4394 also antagonized Δ9‐tetrahydrocannabinol‐induced ring immobility. By themselves, O‐4395 and O‐4394 induced ring immobility at 3 or 10 mg kg−1(i.v.) and antinociception at doses above 10 mg kg−1(i.v.). O‐4395 also induced hypothermia at 3 mg kg−1(i.v.) and above.Conclusions and implications: O‐4394 and O‐4395 exhibit similarin vitropotencies to eΔ9‐THCV as CB1receptor ligands and as antagonists of cannabinoid receptor agonists and can antagonize Δ9‐tetrahydrocannabinolin vivo.British Journal of Pharmacology(2007)150, 586–594. doi:10.1038/sj.bjp.0707124