Differential in Vivo Potencies of Naltrexone and 6β-Naltrexol in the Monkey

Abstract

6␤-Naltrexol is the major metabolite of the opioid receptor antagonist, naltrexone, in humans. However, there are no functional studies of 6␤-naltrexol in primates. The aim of this study was to compare the in vitro and in vivo potencies of naltrexone and 6␤-naltrexol in rhesus monkeys. Affinity and potency were determined using radioligand displacement and stimulation of 5Ј-O-(3-[35 S]thio)triphosphate ([ 35 S]GTP␥S) binding in monkey brain membranes. In vivo apparent pA 2 analysis was applied to compare the -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 6␤-naltrexol for the MOR binding site and for MOR agonist-stimulated [35 S]GTP␥S binding, respectively. 6␤-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 pA 2 value of 6␤-naltrexol (6.5) was 100-fold less potent than that of naltrexone (8.5) determined previously. 6␤-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 6␤-naltrexol (0.32-3.2 mg/kg) retained the same potency difference in precipitating withdrawal to a similar degree. Furthermore, 6␤-naltrexol failed to block naltrexone-precipitated withdrawal in morphine-dependent monkeys. These results indicate that naltrexone and 6␤-naltrexol display similar pharmacological actions with a large in vivo potency difference in monkeys such that 6␤-naltrexol may play a minimal role in the therapeutic or antagonist effects of naltrexone in primates.

Comparison of the opioid receptor antagonist properties of naltrexone and 6β-naltrexol in morphine-naïve and morphine-dependent mice

“…The present results do confirm that in the mouse (Wang et al, 2004;Raehal et al, 2005), as with previous work in the monkey (Ko et al, 2006), naltrexone is a more potent inducer of withdrawal than 6β-naltrexol in morphine-dependence, but shows that both compounds induce qualitatively similar withdrawal symptoms. However, the present findings suggest the difference between naltrexone and 6β-naltrexol in precipitating morphine withdrawal in the mouse is due to different abilities to reach the site of action and the rapidity of access needed to precipitate a robust withdrawal response.…”

“…Since displacement of naltrexone by 6β-naltrexol must happen over this longer time period, as indicated by the antagonism of BU72-mediated antinociception, then the compounds must be indistinguishable to the receptor. We have also observed similar results in the monkey (Ko et al, 2006). These findings suggest that under the relatively short temporal conditions of the opioid withdrawal assay the two compounds have differential abilities to bind to the μ-opioid receptor following systemic administration rather than different actions at the receptor (Raehal et al, 2005).…”

“…This result indicates a similar in vivo affinity of naltrexone and 6β-naltrexol for the μ-opioid receptor as measured by pharmacological assay (pK B or pA 2 ) and in agreement with ligand binding studies in cloned cells (Wang et al, 2001), guinea-pig brain (Nelson et al 1994) and monkey brain tissue (Ko et al, 2006). Although the pA 2 values for naltrexone and 6β-naltrexol were the same, they are approximately 10-fold greater than the pA 2 for naltrexone reported in male ND4 Swiss-Webster mice (Garner et al, 1997).…”

“…Moreover, in the monkey we have shown similar actions of naltrexone and 6β-naltrexol to reduce morphine-induced respiratory depression, scratching, and to precipitate acute morphine withdrawal, even though 6β-naltrexol is 100-fold less potent than naltrexone (Ko et al, 2006). Together, these finding support the idea that 6β-naltrexol is a weaker opioid receptor antagonist than naltrexone (Blumberg and Ikeda, 1976) and suggests the differences between the compounds are due to differential potency rather than dissimilar efficacy (Wang et al, 2004;Raehal et al, 2005).…”

The Therapeutic Potential of Nociceptin/Orphanin FQ Receptor Agonists as Analgesics without Abuse Liability

“…26 In contrast, 6β-naltrexol failed to block naltrexone-precipitated withdrawal in morphine-dependent monkeys; instead, it potentiated the effects of naltrexone when the dose of 6β-naltrexol was increased, indicating that both naltrexone and 6β-naltrexol have the same pharmacological actions only with large potency differences in primates. 27 These findings suggest that there might be difference between primates and rodents in terms of the MOP basal signaling activity changed by repeated MOP agonist administration.…”