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

Lisa R. Gerak, Charles P. France

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)315-321
Number of pages7
JournalPsychopharmacology
Volume193
Issue number3
DOIs
StatePublished - Aug 1 2007

Keywords

  • Drug discrimination
  • Monkeys
  • Morphine
  • Naltrexone
  • Schild analyses

ASJC Scopus subject areas

  • Pharmacology

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