Naloxazone, a long-acting opiate antagonist: Effects on analgesia in intact animals and on opiate receptor binding in vitro

Administration of naloxazone, a hydrazone derivative of naloxone, to intact mice produces a prolonged inhibition of in vitro [³H]opiate binding lasting up to 3 days. The effect is selective since naloxazone treatment produces no changes in alpha or beta adrenergic, muscarinic or benzodiazepine receptor binding and the effects on opiate binding sites are not reproduced by non-narcotic hydrazines. Scatchard analyses of saturation experiments 24 hr after in vivo naloxazone treatment show an absence of high affinity binding sites of [³H]naloxone, [³H]dihydromorphine and 2-D-[³H]ala-met-enkephalinamide, although low affinity sites are relatively unaffected. Blockade of high affinity sites by naloxazone produces an 11-fold increase in the ED₅₀ value for morphine analgesia at 24 hr with both tail-flick and writhing assays. By contrast, naloxazone produces no change in the LD₅₀ value of morphine. As high affinity binding returns to control levels over 3 days, the ED₅₀ for morphine analgesia in naloxazone-pretreated mice returns to control values. Accordingly, the analgetic, but not lethal, effects of morphine may be mediated by the high affinity subpopulation of opiate receptors.