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Time-dependent decreases in apparent pA2 values for naltrexone studied in combination with morphine in rhesus monkeys

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Abstract

Rationale

One assumption of Schild analyses, which have been used extensively to characterize opioids in vitro and in vivo, is that the concentration of antagonist is at equilibrium; violation of this assumption would yield slopes of Schild plots that deviate from unity. For in vivo studies, the concentration of antagonist changes as it is eliminated; however, if studies are conducted at a time when the antagonist is maximally effective, the assumption of equilibrium is not violated.

Objective

The goal of these studies was to determine how increasing the delay between antagonist administration and determination of dose–effect curves alters results of Schild analyses.

Materials and methods

Monkeys received 3.2 mg/kg/day of morphine and discriminated naltrexone while responding under a fixed-ratio 5 schedule of stimulus-shock termination. In monkeys acutely deprived of morphine (27 h), naltrexone was administered 1, 2, 4, or 6 h before determination of morphine dose–effect curves.

Results

Morphine-deprived monkeys responded on the naltrexone-appropriate lever, and this effect was reversed by morphine. Naltrexone dose- and time-dependently antagonized morphine. Schild analyses yielded slopes that did not deviate from unity; however, as the delay between naltrexone administration and determination of morphine dose–effect curves increased, apparent pA2 values decreased.

Conclusions

The assumption of equilibrium of antagonist at receptor sites does not appear to be violated, regardless of when it is administered, and changes in naltrexone concentration as it is eliminated are reflected in orderly decreases in potency. These results further indicate the strength of Schild analyses for describing interactions between drugs and receptors in vivo.

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Acknowledgments

The authors wish to thank R. Gump and S. Wegert for their excellent technical assistance and Dr. Wouter Koek for his help with data analyses. Monkeys used in these studies were maintained in accordance with the Institutional Animal Care and Use Committee, Louisiana State University Health Sciences Center, and guidelines of the Committee on Care and Use of Laboratory Animal Resources, National Research Council (Department of Health, Education and Welfare, publication No. (NIH) 85-23, revised 1996). These studies were supported by United States Public Health Service Grant DA05018 and Senior Scientist Award K05 DA17918 (CPF).

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Correspondence to Charles P. France.

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Gerak, L.R., France, C.P. Time-dependent decreases in apparent pA2 values for naltrexone studied in combination with morphine in rhesus monkeys. Psychopharmacology 193, 315–321 (2007). https://doi.org/10.1007/s00213-007-0787-y

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  • DOI: https://doi.org/10.1007/s00213-007-0787-y

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