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Comparison of naltrexone, 6α-naltrexol, and 6β-naltrexol in morphine-dependent and in nondependent rhesus monkeys

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Abstract

Rationale

Some opioid receptor ligands that appear to be neutral antagonists can have inverse agonist activity under conditions of increased constitutive activity (e.g., agonist treatment).

Objectives

This study compared the opioid receptor antagonist naltrexone and its metabolites 6α-naltrexol and 6β-naltrexol in nondependent and morphine-dependent monkeys to see whether their potencies varied according to drug treatment and, presumably, to differences in constitutive activity of μ opioid receptors.

Results

In monkeys (n = 4) receiving 3.2 mg/kg per day of morphine and discriminating 0.0178 mg/kg naltrexone, naltrexone and each metabolite increased responding on the naltrexone lever in a dose-related manner with naltrexone being 8- and 71-fold more potent than 6α- and 6β-naltrexol, respectively. After 27 h of no-morphine treatment, monkeys responded on the naltrexone lever, and this effect was reversed by morphine. Naltrexone and each metabolite prevented morphine reversal of naltrexone-lever responding, and their rank order potency was the same as their substitution for naltrexone; however, the potency between naltrexone and each metabolite was slightly greater in morphine-dependent as compared to morphine-deprived monkeys. In a separate group (n = 3) of nondependent monkeys discriminating 1.78 mg/kg of morphine, all three compounds antagonized morphine with the same potency as in the reversal study (morphine-dependent monkeys), with Schild analyses showing no difference in apparent affinities (pA 2) between nondependent and morphine-dependent monkeys.

Conclusion

Naltrexone and 6α- and 6β-naltrexol have qualitatively similar effects, and their potencies do not vary markedly with opioid treatment, suggesting that under these conditions, they do not vary with regard to inverse agonism.

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Acknowledgments

The authors thank Christopher Cruz, Blake Harrington, and Brandi Taylor for their expert technical assistance. This work was supported by USPHS Grant DA05018 (CPF) and a Senior Scientist Award to CPF (DA17918).

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Authors and Affiliations

  1. Department of Pharmacology, The University of Texas Health Science Center, San Antonio, TX, USA

    Jun-Xu Li, Lance R. McMahon & Charles P. France

  2. Department of Pharmacology, The University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX, 78229-3900, USA

    Charles P. France

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  1. Jun-Xu Li
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  2. Lance R. McMahon
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  3. Charles P. France
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Correspondence to Charles P. France.

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Li, JX., McMahon, L.R. & France, C.P. Comparison of naltrexone, 6α-naltrexol, and 6β-naltrexol in morphine-dependent and in nondependent rhesus monkeys. Psychopharmacology 195, 479–486 (2008). https://doi.org/10.1007/s00213-007-0914-9

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  • DOI: https://doi.org/10.1007/s00213-007-0914-9

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