title: The psychoactive plant cannabinoid, Delta9-tetrahydrocannabinol, is antagonized by Delta8- and Delta9-tetrahydrocannabivarin in mice in vivo.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  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
  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.
authors.affiliation: School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK.
authors.forename: R G
authors.initials: RG
authors.lastname: Pertwee
authors.forename: A
authors.initials: A
authors.lastname: Thomas
authors.forename: L A
authors.initials: LA
authors.lastname: Stevenson
authors.forename: R A
authors.initials: RA
authors.lastname: Ross
authors.forename: S A
authors.initials: SA
authors.lastname: Varvel
authors.forename: A H
authors.initials: AH
authors.lastname: Lichtman
authors.forename: B R
authors.initials: BR
authors.lastname: Martin
authors.forename: R K
authors.initials: RK
authors.lastname: Razdan
mesh_terms: D018712:Analgesics, Non-Narcotic / Q000037:antagonists & inhibitors; D000818:Animals; D048588:Benzoxazines / Q000494:pharmacology; D001667:Binding, Competitive; D001831:Body Temperature / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D063386:Cannabinoid Receptor Agonists; D063387:Cannabinoid Receptor Antagonists; D003510:Cyclohexanes / Q000378:metabolism / Q000494:pharmacology; D003511:Cyclohexanols; D004305:Dose-Response Relationship, Drug; D013759:Dronabinol / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology; D004558:Electric Stimulation; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D066298:In Vitro Techniques; D008124:Locomotion / Q000187:drug effects; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009025:Morpholines / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism; D009281:Naphthalenes / Q000494:pharmacology; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects; D010636:Phenols / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding; D011619:Psychotropic Drugs / Q000037:antagonists & inhibitors*; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors; D043885:Receptor, Cannabinoid, CB2 / Q000037:antagonists & inhibitors; D043882:Receptors, Cannabinoid / Q000378:metabolism; D014649:Vas Deferens / Q000187:drug effects* / Q000378:metabolism
chemical_list: D018712:Analgesics, Non-Narcotic; D048588:Benzoxazines; D063386:Cannabinoid Receptor Agonists; D063387:Cannabinoid Receptor Antagonists; D003510:Cyclohexanes; D003511:Cyclohexanols; D009025:Morpholines; D009281:Naphthalenes; D010636:Phenols; D011619:Psychotropic Drugs; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D043882:Receptors, Cannabinoid; C003403:tetrahydrocannabivarin 9; D016244:Guanosine 5'-O-(3-Thiotriphosphate); C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D013759:Dronabinol; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol