Comparison of naltrexone, 6alpha-naltrexol, and 6beta-naltrexol in morphine-dependent and in nondependent rhesus monkeys.
BACKGROUND
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).


OBJECTIVE
This study compared the opioid receptor antagonist naltrexone and its metabolites 6alpha-naltrexol and 6beta-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 mu 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 6alpha- and 6beta-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.


CONCLUSIONS
Naltrexone and 6alpha- and 6beta-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.
Li
Jun-Xu
JX
Department of Pharmacology, The University of Texas Health Science Center, San Antonio, TX 78229-3900, USA.
McMahon
Lance R
LR
France
Charles P
CP
D000818:Animals; D001070:Appetitive Behavior / Q000187:drug effects*; D004193:Discrimination Learning / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D054314:Drug Inverse Agonism; D005260:Female; D008253:Macaca mulatta; D008297:Male; D009020:Morphine / Q000819:agonists* / Q000037:antagonists & inhibitors*; D009021:Morphine Dependence / Q000523:psychology*; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000494:pharmacology*; D009292:Narcotic Antagonists / Q000494:pharmacology*; D017450:Receptors, Opioid, mu / Q000187:drug effects
D009292:Narcotic Antagonists; D017450:Receptors, Opioid, mu; C010410:6 beta-hydroxynaltrexone; D009271:Naltrexone; D009020:Morphine