The psychoactive plant cannabinoid, Delta super(9)-tetrahydrocannabinol, is antagonized by Delta super(8)- and Delta super(9)-tetrahydrocannabivarin in mice in vivo

• Published in: British journal of pharmacology Vol. 150; no. 5; pp. 586 - 594
• Main Authors: Pertwee, R G, Thomas, A, Stevenson, LA, Ross, R A, Varvel, SA, Lichtman, AH, Martin, B R, Razdan, R K
• Format: Journal Article
• Language: English
• Published: 01.03.2007
• ISSN: 0007-1188
• DOI: 10.1038/sj.bjp.0707124

Background and purpose: To follow up in vitro evidence that Delta super(9)-tetrahydrocannabivarin extracted from cannabis (e Delta super(9)-THCV) is a CB sub(1) receptor antagonist by establishing whether synthetic Delta super(9)-tetrahydrocannabivarin (O-4394) and Delta super(8)-tetrahydrocannabivarin (O-4395) behave as CB sub(1) antagonists in vivo. Experimental approach: O-4394 and O-4395 were compared with e Delta super(9)-THCV as displacers of [ super(3)H]-CP55940 from specific CB sub(1) binding sites on mouse brain membranes and as antagonists of CP55940 in [ super(35)S]GTP gamma S binding assays performed with mouse brain membranes and of R-(+)-WIN55212 in mouse isolated vasa deferentia. Their ability to antagonize in vivo effects of 3 or 10 mg kg super(-1) (i.v.) Delta super(9)-tetrahydrocannabinol in mice was then investigated. Key results: O-4394 and O-4395 exhibited similar potencies to e Delta super(9)-THCV as displacers of [ super(3)H]-CP55940 (K sub(i) = 46.6 and 64.4 nM, respectively) and as antagonists of CP55940 in the [ super(35)S]GTP gamma S binding assay (apparent K sub(B) = 82.1 and 125.9 nM, respectively) and R-(+)-WIN55212 in the vas deferens (apparent K sub(B) = 4.8 and 3.9 nM respectively). At i.v. doses of 0.1, 0.3, 1.0 and/or 3 mg kg super(-1) 0-4394 and O-4395 attenuated Delta super(9)-tetrahydrocannabinol-induced anti-nociception (tail-flick test) and hypothermia (rectal temperature). O-4395 but not O-4394 also antagonized Delta super(9)-tetrahydrocannabinol-induced ring immobility. By themselves, O-4395 and O-4394 induced ring immobility at 3 or 10 mg kg super(-1) (i.v.) and antinociception at doses above 10 mg kg super(-1) (i.v.). O-4395 also induced hypothermia at 3 mg kg super(-1) (i.v.) and above. Conclusions and implications: O-4394 and O-4395 exhibit similar in vitro potencies to e Delta super(9)-THCV as CB sub(1) receptor ligands and as antagonists of cannabinoid receptor agonists and can antagonize Delta super(9)-tetrahydrocannabinol in vivo.