6β-naltrexol preferentially antagonizes opioid effects on gastrointestinal transit compared to antinociception in mice

Abstract

Aims The current studies were designed to compare the in vivo potencies of the opioid antagonists 6β-naltrexol and naltrexone in blocking the effects of the opioid agonist hydrocodone following intravenous (i.v.) or oral (p.o.) administration. Main methods Adult male CD-1 mice were used for all experiments. The 55 °C tail-flick assay was used to assess the CNS antinociceptive activity of hydrocodone, and a charcoal meal gastrointestinal transit assay was used to assess the peripheral effects of hydrocodone. Graded antagonist dose–response curves for i.v. and p.o. 6β-naltrexol and naltrexone were generated to determine ID 50 antagonist potency estimates against fixed doses of hydrocodone. Key findings Both antagonists produced dose-related blockade of hydrocodone-induced antinociception and inhibition of gastrointestinal transit. Naltrexone was between 5- and 13-fold more potent than 6β-naltrexol in blocking a CNS effect of hydrocodone, whereas the drugs were nearly equipotent in blocking inhibition of gastrointestinal transit. Co-administration studies indicated an approximate 10-fold greater potency of 6β-naltrexol for antagonism of hydrocodone-induced inhibition of gastrointestinal transit versus antinociception, whereas naltrexone blocked both effects with near equal potency. 6β-naltrexol produced a longer duration of antagonist blockade and had a slower time to peak effect compared to naltrexone. Significance The pharmacology of 6β-naltrexol differentiates it from currently available opioid antagonists. This includes an intermediate selectivity for peripheral versus central opioid receptors, a long duration of action, and neutral antagonist qualities in opioid exposed systems. These properties render it a drug candidate for a co-formulation product with opioid analgesics to reduce peripheral opioid side effects and limit abuse potential.