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

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 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.
CONCLUSION: 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.