Opiate receptor binding of agonists and antagonists affected differentially by sodium

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 well 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.