The psychoactive plant cannabinoid, Delta9-tetrahydrocannabinol, is antagonized by Delta8- and Delta9-tetrahydrocannabivarin in mice in vivo

Br J Pharmacol. 2007 Mar;150(5):586-94. doi: 10.1038/sj.bjp.0707124. Epub 2007 Jan 22.

Abstract

Background and purpose: To follow up in vitro evidence that Delta(9)-tetrahydrocannabivarin extracted from cannabis (eDelta(9)-THCV) is a CB(1) receptor antagonist by establishing whether synthetic Delta(9)-tetrahydrocannabivarin (O-4394) and Delta(8)-tetrahydrocannabivarin (O-4395) behave as CB(1) antagonists in vivo.

Experimental approach: O-4394 and O-4395 were compared with eDelta(9)-THCV as displacers of [(3)H]-CP55940 from specific CB(1) binding sites on mouse brain membranes and as antagonists of CP55940 in [(35)S]GTPgammaS 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(-1) (i.v.) Delta(9)-tetrahydrocannabinol in mice was then investigated.

Key results: O-4394 and O-4395 exhibited similar potencies to eDelta(9)-THCV as displacers of [(3)H]-CP55940 (K (i)=46.6 and 64.4 nM, respectively) and as antagonists of CP55940 in the [(35)S]GTPgammaS binding assay (apparent K (B)=82.1 and 125.9 nM, respectively) and R-(+)-WIN55212 in the vas deferens (apparent K (B)=4.8 and 3.9 nM respectively). At i.v. doses of 0.1, 0.3, 1.0 and/or 3 mg kg(-1) O-4394 and O-4395 attenuated Delta(9)-tetrahydrocannabinol-induced anti-nociception (tail-flick test) and hypothermia (rectal temperature). O-4395 but not O-4394 also antagonized Delta(9)-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 similar in vitro potencies to eDelta(9)-THCV as CB(1) receptor ligands and as antagonists of cannabinoid receptor agonists and can antagonize Delta(9)-tetrahydrocannabinol in vivo.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Analgesics, Non-Narcotic / antagonists & inhibitors
  • Animals
  • Benzoxazines / pharmacology
  • Binding, Competitive
  • Body Temperature / drug effects
  • Brain / drug effects*
  • Brain / metabolism
  • Cannabinoid Receptor Agonists
  • Cannabinoid Receptor Antagonists*
  • Cyclohexanes / metabolism
  • Cyclohexanes / pharmacology
  • Cyclohexanols
  • Dose-Response Relationship, Drug
  • Dronabinol / analogs & derivatives*
  • Dronabinol / antagonists & inhibitors*
  • Dronabinol / metabolism
  • Dronabinol / pharmacology
  • Electric Stimulation
  • Guanosine 5'-O-(3-Thiotriphosphate) / metabolism
  • In Vitro Techniques
  • Locomotion / drug effects
  • Male
  • Mice
  • Mice, Inbred ICR
  • Morpholines / pharmacology
  • Muscle Contraction / drug effects
  • Muscle, Smooth / drug effects
  • Muscle, Smooth / metabolism
  • Naphthalenes / pharmacology
  • Pain Measurement
  • Pain Threshold / drug effects
  • Phenols / metabolism
  • Phenols / pharmacology
  • Protein Binding
  • Psychotropic Drugs / antagonists & inhibitors*
  • Receptor, Cannabinoid, CB1 / antagonists & inhibitors
  • Receptor, Cannabinoid, CB2 / antagonists & inhibitors
  • Receptors, Cannabinoid / metabolism
  • Vas Deferens / drug effects*
  • Vas Deferens / metabolism

Substances

  • Analgesics, Non-Narcotic
  • Benzoxazines
  • Cannabinoid Receptor Agonists
  • Cannabinoid Receptor Antagonists
  • Cyclohexanes
  • Cyclohexanols
  • Morpholines
  • Naphthalenes
  • Phenols
  • Psychotropic Drugs
  • Receptor, Cannabinoid, CB1
  • Receptor, Cannabinoid, CB2
  • Receptors, Cannabinoid
  • tetrahydrocannabivarin 9
  • Guanosine 5'-O-(3-Thiotriphosphate)
  • (3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone
  • Dronabinol
  • 3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol