Molecular Pharmacology, Vol 10, 868-879, Copyright © 1974 by the American Society for Pharmacology and Experimental Therapeutics

Opiate Receptor Binding of Agonists and Antagonists Affected Differentially by Sodium

¹ Department of Pharmacology and Experimental Therapeutics and Department of Psychiatry and the Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

Receptor binding of the tritiated opiate antagonists naloxone, nalorphine, and levallorphan is enhanced by sodium ion, while binding of the tritiated agonists oxymorphone, dihydromorphine, and levorphanol is diminished. This differential effect of Na⁺ is highly specific, since it is elicited by Na⁺ and Li⁺ but not by other monovalent or divalent cations. The relative effectiveness of nonradioactive opiates in inhibiting [³H]naloxone binding in the absence and presence of Na⁺ in vitro correlates impressively with their relative agonist-antagonist properties in vivo. It is hypothesized that sodium allosterically transforms opiate receptor sites from conformations which bind agonists more readily to conformations which bind antagonists more readily. This hypothesis is supported by the competition of opiate agonists and antagonists for receptor sites, the marked temperature dependence of binding, the similar extent of binding of tritiated agonists and antagonists at maximal saturation, the concurrent increase in naloxone binding sites and decrease in dihydromorphine binding sites caused by the addition of Na⁺, and the ability of Na⁺ to increase [³H]dihydromorphine dissociation with no effect on [³H]naloxone dissociation.

Note:
ACKNOWLEDGMENTS We gratefully acknowledge the excellent technical assistance of Adele M. Snowman.

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