(-)-Cannabidiol antagonizes cannabinoid receptor agonists and noradrenaline in the mouse vas deferens

Roger G. Pertwee, Ruth A. Ross, Susan J. Craib, Adèle Thomas

Research output: Contribution to journalArticleResearchpeer-review

Abstract

The nonpsychoactive plant cannabinoid, (-)-cannabidiol, modulates in vivo responses to Δ9-tetrahydrocannabinol. We have found that cannabidiol can also interact with cannabinoid CB1 receptor agonists in the mouse vas deferens, a tissue in which prejunctional cannabinoid CB1 receptors mediate inhibition of electrically evoked contractions by suppressing noradrenaline and/or ATP release. Cannabidiol (0.316-10 μM) attenuated the ability of (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo-[1,2,3-de]-1,4- benzoxazin-6-yl]-1-naphthalenylmethanone (R-(+)-WIN55212) to inhibit contractions in a concentration-related, surmountable manner with a KB value (120.3 nM) well below its reported cannabinoid receptor CB1/CB2 Ki values. Cannabidiol (10 μM) also antagonized (-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl) cyclohexanol (CP55940; KB=34 nM) and [D-Ala2, NMePhe4, Gly-ol]enkephalin (DAMGO; KB=5.6 μM) and attenuated contractile responses to noradrenaline, phenylephrine and methoxamine but not to β, γ-methyleneadenosine 5′-triphosphate. At 3.16-10 μM, it increased the amplitude of evoked contractions, probably by enhancing contractile neurotransmitter release. We conclude that cannabidiol antagonizes R-(+)-WIN55212 and CP55940 by acting at prejunctional sites that are unlikely to be cannabinoid CB1 or CB2 receptors.

LanguageEnglish
Pages99-106
Number of pages8
JournalEuropean Journal of Pharmacology
Volume456
Issue number1-3
DOIs
Publication statusPublished - 5 Dec 2002
Externally publishedYes

Fingerprint

Cannabidiol
Cannabinoid Receptor Agonists
Vas Deferens
Norepinephrine
Cannabinoid Receptor CB1
Cannabinoid Receptor CB2
Ala(2)-MePhe(4)-Gly(5)-enkephalin
Methoxamine
Dronabinol
Cannabinoids
Enkephalins
Phenylephrine
Neurotransmitter Agents
Adenosine Triphosphate
3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol

Keywords

  • Cannabidiol
  • Cannabinoid CB receptor
  • CP55940
  • Drug interaction
  • Vas deferens, mouse
  • WIN55212

Cite this

Pertwee, Roger G. ; Ross, Ruth A. ; Craib, Susan J. ; Thomas, Adèle. / (-)-Cannabidiol antagonizes cannabinoid receptor agonists and noradrenaline in the mouse vas deferens. In: European Journal of Pharmacology. 2002 ; Vol. 456, No. 1-3. pp. 99-106.
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(-)-Cannabidiol antagonizes cannabinoid receptor agonists and noradrenaline in the mouse vas deferens. / Pertwee, Roger G.; Ross, Ruth A.; Craib, Susan J.; Thomas, Adèle.

In: European Journal of Pharmacology, Vol. 456, No. 1-3, 05.12.2002, p. 99-106.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Pertwee, Roger G.

AU - Ross, Ruth A.

AU - Craib, Susan J.

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AB - The nonpsychoactive plant cannabinoid, (-)-cannabidiol, modulates in vivo responses to Δ9-tetrahydrocannabinol. We have found that cannabidiol can also interact with cannabinoid CB1 receptor agonists in the mouse vas deferens, a tissue in which prejunctional cannabinoid CB1 receptors mediate inhibition of electrically evoked contractions by suppressing noradrenaline and/or ATP release. Cannabidiol (0.316-10 μM) attenuated the ability of (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo-[1,2,3-de]-1,4- benzoxazin-6-yl]-1-naphthalenylmethanone (R-(+)-WIN55212) to inhibit contractions in a concentration-related, surmountable manner with a KB value (120.3 nM) well below its reported cannabinoid receptor CB1/CB2 Ki values. Cannabidiol (10 μM) also antagonized (-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl) cyclohexanol (CP55940; KB=34 nM) and [D-Ala2, NMePhe4, Gly-ol]enkephalin (DAMGO; KB=5.6 μM) and attenuated contractile responses to noradrenaline, phenylephrine and methoxamine but not to β, γ-methyleneadenosine 5′-triphosphate. At 3.16-10 μM, it increased the amplitude of evoked contractions, probably by enhancing contractile neurotransmitter release. We conclude that cannabidiol antagonizes R-(+)-WIN55212 and CP55940 by acting at prejunctional sites that are unlikely to be cannabinoid CB1 or CB2 receptors.

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