The psychoactive plant cannabinoid, Δ9-tetrahydrocannabinol, is antagonized by Δ8- and Δ9-tetrahydrocannabivarin in mice in vivo

Roger Guy Pertwee, Adele Thomas, Lesley Ann Stevenson, Ruth Alexandra Ross, S. A. Varvel, A. H. Lichtman, B. R. Martin, R. K. Razdan

Research output: Contribution to journalArticle

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Abstract

Background and purpose: To follow up in vitro evidence that Delta(9)-tetrahydrocannabivarin extracted from cannabis (e Delta(9)-THCV) is a CB1 receptor antagonist by establishing whether synthetic Delta(9)-tetrahydrocannabivarin (O-4394) and Delta(8)-tetrahydrocannabivarin (O-4395) behave as CB1 antagonists in vivo.

Experimental approach: O-4394 and O-4395 were compared with e Delta(9)-THCV as displacers of [H-3]-CP55940 from specific CB1 binding sites on mouse brain membranes and as antagonists of CP55940 in [S-35]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(-1) (i.v.) Delta(9)-tetrahydrocannabinol in mice was then investigated.

Key results: O-4394 and O-4395 exhibited similar potencies to e Delta(9)-THCV as displacers of [H-3]-CP55940 (K-i = 46.6 and 64.4 nM, respectively) and as antagonists of CP55940 in the [S-35]GTP gamma S 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 e Delta(9)-THCV as CB1 receptor ligands and as antagonists of cannabinoid receptor agonists and can antagonize Delta(9)-tetrahydrocannabinol in vivo.

Original languageEnglish
Pages (from-to)586-594
Number of pages9
JournalBritish Journal of Pharmacology
Volume150
Issue number5
DOIs
Publication statusPublished - Mar 2007

Keywords

  • tetrahydrocannabivarin
  • tetrahydrocannabinol
  • CP55940
  • R-(+)
  • WIN55212
  • cannabinoid CB1 receptor antagonist
  • mouse vas deferens
  • anti-nociception
  • tail
  • flick test
  • ring test
  • hypothermia
  • receptor knockout mice
  • vas-deferens
  • CB1
  • pharmacology
  • analogs
  • brain
  • classification
  • metabolites
  • anandamide
  • agonists

Cite this

The psychoactive plant cannabinoid, Δ9-tetrahydrocannabinol, is antagonized by Δ8- and Δ9-tetrahydrocannabivarin in mice in vivo. / Pertwee, Roger Guy; Thomas, Adele; Stevenson, Lesley Ann; Ross, Ruth Alexandra; Varvel, S. A.; Lichtman, A. H.; Martin, B. R.; Razdan, R. K.

In: British Journal of Pharmacology, Vol. 150, No. 5, 03.2007, p. 586-594.

Research output: Contribution to journalArticle

Pertwee, Roger Guy ; Thomas, Adele ; Stevenson, Lesley Ann ; Ross, Ruth Alexandra ; Varvel, S. A. ; Lichtman, A. H. ; Martin, B. R. ; Razdan, R. K. / The psychoactive plant cannabinoid, Δ9-tetrahydrocannabinol, is antagonized by Δ8- and Δ9-tetrahydrocannabivarin in mice in vivo. In: British Journal of Pharmacology. 2007 ; Vol. 150, No. 5. pp. 586-594.
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abstract = "Background and purpose: To follow up in vitro evidence that Delta(9)-tetrahydrocannabivarin extracted from cannabis (e Delta(9)-THCV) is a CB1 receptor antagonist by establishing whether synthetic Delta(9)-tetrahydrocannabivarin (O-4394) and Delta(8)-tetrahydrocannabivarin (O-4395) behave as CB1 antagonists in vivo. Experimental approach: O-4394 and O-4395 were compared with e Delta(9)-THCV as displacers of [H-3]-CP55940 from specific CB1 binding sites on mouse brain membranes and as antagonists of CP55940 in [S-35]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(-1) (i.v.) Delta(9)-tetrahydrocannabinol in mice was then investigated. Key results: O-4394 and O-4395 exhibited similar potencies to e Delta(9)-THCV as displacers of [H-3]-CP55940 (K-i = 46.6 and 64.4 nM, respectively) and as antagonists of CP55940 in the [S-35]GTP gamma S 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 e Delta(9)-THCV as CB1 receptor ligands and as antagonists of cannabinoid receptor agonists and can antagonize Delta(9)-tetrahydrocannabinol in vivo.",
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author = "Pertwee, {Roger Guy} and Adele Thomas and Stevenson, {Lesley Ann} and Ross, {Ruth Alexandra} and Varvel, {S. A.} and Lichtman, {A. H.} and Martin, {B. R.} and Razdan, {R. K.}",
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TY - JOUR

T1 - The psychoactive plant cannabinoid, Δ9-tetrahydrocannabinol, is antagonized by Δ8- and Δ9-tetrahydrocannabivarin in mice in vivo

AU - Pertwee, Roger Guy

AU - Thomas, Adele

AU - Stevenson, Lesley Ann

AU - Ross, Ruth Alexandra

AU - Varvel, S. A.

AU - Lichtman, A. H.

AU - Martin, B. R.

AU - Razdan, R. K.

PY - 2007/3

Y1 - 2007/3

N2 - Background and purpose: To follow up in vitro evidence that Delta(9)-tetrahydrocannabivarin extracted from cannabis (e Delta(9)-THCV) is a CB1 receptor antagonist by establishing whether synthetic Delta(9)-tetrahydrocannabivarin (O-4394) and Delta(8)-tetrahydrocannabivarin (O-4395) behave as CB1 antagonists in vivo. Experimental approach: O-4394 and O-4395 were compared with e Delta(9)-THCV as displacers of [H-3]-CP55940 from specific CB1 binding sites on mouse brain membranes and as antagonists of CP55940 in [S-35]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(-1) (i.v.) Delta(9)-tetrahydrocannabinol in mice was then investigated. Key results: O-4394 and O-4395 exhibited similar potencies to e Delta(9)-THCV as displacers of [H-3]-CP55940 (K-i = 46.6 and 64.4 nM, respectively) and as antagonists of CP55940 in the [S-35]GTP gamma S 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 e Delta(9)-THCV as CB1 receptor ligands and as antagonists of cannabinoid receptor agonists and can antagonize Delta(9)-tetrahydrocannabinol in vivo.

AB - Background and purpose: To follow up in vitro evidence that Delta(9)-tetrahydrocannabivarin extracted from cannabis (e Delta(9)-THCV) is a CB1 receptor antagonist by establishing whether synthetic Delta(9)-tetrahydrocannabivarin (O-4394) and Delta(8)-tetrahydrocannabivarin (O-4395) behave as CB1 antagonists in vivo. Experimental approach: O-4394 and O-4395 were compared with e Delta(9)-THCV as displacers of [H-3]-CP55940 from specific CB1 binding sites on mouse brain membranes and as antagonists of CP55940 in [S-35]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(-1) (i.v.) Delta(9)-tetrahydrocannabinol in mice was then investigated. Key results: O-4394 and O-4395 exhibited similar potencies to e Delta(9)-THCV as displacers of [H-3]-CP55940 (K-i = 46.6 and 64.4 nM, respectively) and as antagonists of CP55940 in the [S-35]GTP gamma S 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 e Delta(9)-THCV as CB1 receptor ligands and as antagonists of cannabinoid receptor agonists and can antagonize Delta(9)-tetrahydrocannabinol in vivo.

KW - tetrahydrocannabivarin

KW - tetrahydrocannabinol

KW - CP55940

KW - R-(+)

KW - WIN55212

KW - cannabinoid CB1 receptor antagonist

KW - mouse vas deferens

KW - anti-nociception

KW - tail

KW - flick test

KW - ring test

KW - hypothermia

KW - receptor knockout mice

KW - vas-deferens

KW - CB1

KW - pharmacology

KW - analogs

KW - brain

KW - classification

KW - metabolites

KW - anandamide

KW - agonists

U2 - 10.1038/sj.bjp.0707124

DO - 10.1038/sj.bjp.0707124

M3 - Article

VL - 150

SP - 586

EP - 594

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

SN - 0007-1188

IS - 5

ER -