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

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 K_B value (120.3 nM) well below its reported cannabinoid receptor CB₁/CB₂ K_i values. Cannabidiol (10 μM) also antagonized (-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl) cyclohexanol (CP55940; K_B=34 nM) and [D-Ala², NMePhe⁴, Gly-ol]enkephalin (DAMGO; K_B=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.