Quaternary naltrexone: Evidence for the central mediation of discriminative stimulus effects of narcotic agonists and antagonists

R. J. Valentino, S. Herling, J. H. Woods, F. Medzihradsky, H. Merz

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65 Scopus citations


A quaternary derivative of naltrexone was compared to naltrexone in its ability to antagonize the discriminative stimulus [effects of narcotics in pigeons and rhesus monkeys and to substitute as a discriminative stimulus] for naltrexone in narcotic-naive pigeons and in pigeons chronically administered morphine. Quaternary naltrexone was ineffective as an antagonist of the morphine discriminative stimulus in pigeons and of the etorphine discriminative stimulus in rhesus monkeys when administered in doses 300 times greater than the effective antagonist dose of naltrexone. When tested in narcotic-naive pigeons trained to discriminate naltrexone (32 mg/kg) from saline, the quaternary analog of naltrexone failed to produce discriminative control of behavior comparable to that produced by naltrexone, although quaternary naltrexone was as effective and as potent as naltrexone in suppressing the rate of responding. In addition, doses of quaternary naltrexone up to 32 mg/kg did not generalize to naltrexone in pigeons that were chronically treated with morphine (100 mg/kg/day) and trained to discriminate 0.10 to 0.32 mg/kg of naltrexone from saline. Although quaternary naltrexone was ineffective in these drug discrimination assays, it did displace the stereospecific binding of [ 3H]etorphine from rat brain membranes. In addition, quaternary naltrexone was as effective as naltrexone in antagonizing the effect of morphine upon the electrically induced contraction of the isolated guinea-pig ileum and in eliciting a contraction of ilea isolated from morphine-treated guinea pigs. Only a potency difference distinguished naltrexone from its quaternary derivative in these in vitro assays, with quaternary naltrexone being 26 to 74 times less potent. Because the efficacy and potency of quaternary naltrexone in the behavioral assays were much less than would be predicted on the basis of the activity of the compound in vitro, the discriminative stimulus effects of narcotics and the antagonism of these effects by naltrexone, and the discriminative stimulus effects of narcotic antagonists in organisms chronically treated with morphine, are probably the result of central mechanisms.

Original languageEnglish (US)
Pages (from-to)652-659
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number3
StatePublished - 1981
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology


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