Multiple opiate receptors: [3H]ethylketocyclazocine receptor binding and ketocyclazocine analgesia.

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Abstract
The receptor binding of the kappa .kappa. agonist [3H]ethylketocyclazocine to brain homogenates in vitro and ketocyclazocine (.kappa.) analgesia in vivo was investigated and compared to morphine, a .mu. agonist. Saturation analysis of [3H]ethylketocyclazocine binding in both mice and rats yielded biphasic Scatchard plots similar to those of opiate .mu. agonists, antagonists, enkaphalins and endorphins. Treatment of brain membranes with monovalent and divalent cations, chelating agents, protein-modifying reagents and enzymes affected [3H]ethylketocyclazocine binding in a manner similar to that of [3H]morphine. Naloxazone, a long-acting antagonist that selectively abolished high-affinity [3H]morphine, [3H]-dihydromorphine, [3H]naloxone, and [3H-D-Ala2,Met5]enkephalinamide binding in vivo, selectively blocked high-affinity [3H]ethylketocyclazocine binding. Evaluation of analgesia with writhing and tail-flick assays in animals whose high-affinity binding sites were blocked by naloxazone demonstrated at 6- to 7-fold increase in ED50 values of ketocyclazocine. This decrease in analgesic potency was comparable to morphine''s decreased potency in similarly treated mice. The analgesic properties of both .kappa. and .mu. agonists may be mediated through the same subpopulation of receptors, the high-affinity binding sites.