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


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 pA(2) 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.
Gerak
Lisa R
LR
Department of Pharmacology, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr., San Antonio, TX 78229-3900, USA.
France
Charles P
CP
D000818:Animals; D004192:Discrimination, Psychological; D004305:Dose-Response Relationship, Drug; D005260:Female; D008253:Macaca mulatta; D009020:Morphine / Q000008:administration & dosage / Q000037:antagonists & inhibitors*; D009271:Naltrexone / Q000008:administration & dosage / Q000494:pharmacology*; D009292:Narcotic Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D009294:Narcotics / Q000008:administration & dosage*; D017450:Receptors, Opioid, mu / Q000187:drug effects*; D013997:Time Factors
D009292:Narcotic Antagonists; D009294:Narcotics; D017450:Receptors, Opioid, mu; D009271:Naltrexone; D009020:Morphine