Pharmacological analysis of the calcium-dependence of mu-receptor agonism.

1 A number of studies in isolated tissues have shown that mu-opioid-receptor-mediated agonism can be augmented or potentiated with reduction in extracellular calcium concentration [( Ca2+]o). These effects have been ascribed to alterations in post-receptor coupling but the nature of the changes involved have not been quantitatively elucidated. 2 In this paper, logistic curve-fitting and operational model-fitting (Black & Leff, 1983) were used to analyse the effects of variations in [Ca2+]o on the mu-receptor-mediated effects of [D-Ala2, MePhe4, Gly-ol5]enkephalin (DAGOL) in the isolated, coaxially-stimulated ileum of the guinea-pig. At each value of [Ca2+]o, the effects of irreversible receptor alkylation by beta-chlornaltrexamine (beta-CNA) were also investigated. 3 From these analyses it is concluded that with reduction in [Ca2+]o the efficacy of DAGOL in this system is increased and the sensitivity of the transducer relation is also enhanced, the latter indicating a trend towards positive co-operativity. Reduction of [Ca2+]o also appeared to produce a reduction in agonist affinity. 4 Experimental manipulation of [Ca2+]o may provide a useful means of enhancing mu-agonist efficacy, allowing detection of agonism in compounds with low intrinsic efficacies. However, the accompanying change in co-operativity of the transducer relation must be considered when quantifying agonism under these conditions.