Pharmacological analysis of the calcium‐dependence of μ‐receptor agonism

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Abstract
A number of studies in isolated tissues have shown that μ‐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. 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 μ‐receptor‐mediated effects of [d‐Ala2, MePhe4, Glyol5]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 β‐chlornaltrexamine (β‐CNA) were also investigated. 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. Experimental manipulation of [Ca2+]o may provide a useful means of enhancing μ‐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.