Pharmacological analysis of cannabinoid receptor activity in the rat vas deferens

A. Christopoulos, P. Coles, L. Lay, M. J. Lew, J. A. Angus

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1. The interaction between the cannabinoid agonists, WIN 55,212-2 or CP 55,940 with the CB1 receptor-selective antagonists, SR141716A or LY320135 was investigated using the rat electrically-stimulated vas deferens bioassay. 2. Tissues were stimulated by single-field pulses (150 V, 0.5 ms) delivered every 30 mins. In the presence of nifedipine (3 μM), agonists elicited a concentration-dependent inhibition of the contractile response, with pEC50 values of 7.93 and 6.84 for WIN 55,212-2 and CP 55,940, respectively. 3. SR141716A and LY320135 caused parallel dextral displacements of the agonist concentrationresponse curves. However, the shift of the agonist curves by either antagonist was accompanied by a concentration-dependent enhancement of basal (agonist-independent) tissue contraction. 4. Addition of the amidase inhibitor, phenylmethylsulphonylfluoride (200 μm), resulted in a significant reduction of the basal twitch response, an effect consistent with the presence of tonic receptor activation mediated by the endogenous cannabinoid, anandamide. 5. In light of these findings, we propose a theoretical model of competitive agonist-antagonist interaction in the presence of endogenous agonist tone that was used to derive an optimized analytical approach for the determination of antagonist potency estimates under conditions of tonic receptor activation. 6. This approach yielded pKB estimates for SR141716A and LY320135 that were in good agreement with their activity at cannabinoid CB1 receptors. 7. It is concluded that the rat vas deferens contains prejunctional cannabinoid CB1 receptors that are under tonic activation from endogenous substances; under these conditions our analytical approach is preferable to the standard methods for the determination of antagonist potency.

Original languageEnglish
Pages (from-to)1281-1291
Number of pages11
JournalBritish Journal of Pharmacology
Issue number6
Publication statusPublished - 1 Jan 2001
Externally publishedYes


  • Cannabinoid receptors
  • Constitutive activity
  • Endogenous agonist tone
  • Inverse agonist
  • LY320135
  • Rat vas deferens
  • Receptor theory
  • SR141716A

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