Differential in vivo potencies of naltrexone and 6β-naltrexol in the monkey

6β-Naltrexol is the major metabolite of the opioid receptor antagonist, naltrexone, in humans. However, there are no functional studies of 6β-naltrexol in primates. The aim of this study was to compare the in vitro and in vivo potencies of naltrexone and 6β-naltrexol in rhesus monkeys. Affinity and potency were determined using radioligand displacement and stimulation of 5′-O-(3-[³⁵S]thio)triphosphate ([ ³⁵S]GTPγS) binding in monkey brain membranes. In vivo apparent pA₂ analysis was applied to compare the μ-opioid receptor (MOR) antagonist potency of both compounds in nondependent monkeys. In addition, the potencies of both compounds were determined in precipitating withdrawal manifested by increased respiratory parameters in acute morphine-dependent monkeys. In vitro assays revealed that naltrexone displayed 2-fold higher affinity and potency than 6β-naltrexol for the MOR binding site and for MOR agonist-stimulated [³⁵S]GTPγS binding, respectively. 6β-Naltrexol (0.32-3.2 mg/kg) dose-dependently produced parallel rightward shifts of the dose-response curve of alfentanil-induced antinociception. Nevertheless, the apparent pA₂ value of 6β-naltrexol (6.5) was 100-fold less potent than that of naltrexone (8.5) determined previously. 6β-Naltrexol was also less potent than naltrexone in antagonizing other MOR-mediated effects including respiratory depression and itch/scratching. Naltrexone (0.0032-0.032 mg/kg) and 6β-naltrexol (0.32-3.2 mg/kg) retained the same potency difference in precipitating withdrawal to a similar degree. Furthermore, 6β-naltrexol failed to block naltrexone-precipitated withdrawal in morphine-dependent monkeys. These results indicate that naltrexone and 6β-naltrexol display similar pharmacological actions with a large in vivo potency difference in monkeys such that 6β-naltrexol may play a minimal role in the therapeutic or antagonist effects of naltrexone in primates.