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The optical isomers of methadone, alpha-methadol, alpha-acetylmethadol and their N-demethylated derivatives have been systematically studied for their effects on the binding of 3H-dihydromorphine (3H-DHM) and 3H-naloxone (3H-NLX) to opiate receptors in rat brain homogenate. The relative affinities of these agents in competing for both 3H-DHM and 3H-NLX binding parallel their analgesic effects. 1-Methadone is about 30 times as effective as d-methadone in competing for both 3H-DHM and 3H-NLX binding sites. The reduction of 1-methadone to alpha-d-methadol and subsequent N-demethylation to alpha-d-normethadol reduce its effectiveness as indicated by the increase in the IC50 values for both 3H-DHM and 3H-NLX binding. The reduction of d-methadone followed by N-demethylation produces a potent derivative, alpha-1-normethadol, which has IC50 values on 3H-DHM and 3H-NLX binding similar to those of 1-methadone. The affinity of alpha-1-acetyl-methadol on the binding of both 3H-ligands falls between those of 1-methadone and d-methadone, and increases as it is N-demethylated. alpha-d-Acetyl-methadol is more effective than alpha-1-acetylmethadol in competing for both 3H-ligands from the opiate receptors, and its affinity, unlike that of alpha-1-acetylmethadol, decreases when it is N-demethylated. The affinities of the methadone isomers and related compounds on the binding of 3H-NLX fall in the presence of Na+. The latter property indicates the agonistic nature of this series of druges.

Jumping behavior in mice was precipitated by naloxone after single doses of morphine. The time-effect curves showed that this jumping behavior was delayed compared to the ability of morphine to inhibit writhing and to increase locomotor activity. This dissociation suggests that the jumping response is a true measure of physical dependence rather than the result of a stimulant effect of morphine in the presence of naloxone. The minimum dose of morphine needed to initiate measurable physical dependence fell within the analgesic range. With a constant dose of morphine, the frequency of jumping was directly related to the dose of naloxone employed. The ability to follow the initiation of physical dependence might be useful in conjunction with receptor and neurohumoral studies to uncover the basic mechanisms involved.

Single-dose physical dependence on morphine, as indicated by the mouse withdrawal jumping test, was reduced in a dose-related fashion by co-administration of naloxone. In the same dose range, naloxone also antagonized the antinociceptive effect of morphine in the mouse writhing test. Dose-response data revealed essentially the same ED50's for naloxone in both tests. These results indicate that naloxone does indeed block the development of morphine-induced single-dose physical dependence in mice and that it does so as effectively as it blocks morphine-induced inhibition of writhing.