6beta-naltrexol preferentially antagonizes opioid effects on gastrointestinal transit compared to antinociception in mice.
OBJECTIVE
The current studies were designed to compare the in vivo potencies of the opioid antagonists 6beta-naltrexol and naltrexone in blocking the effects of the opioid agonist hydrocodone following intravenous (i.v.) or oral (p.o.) administration.


METHODS
Adult male CD-1 mice were used for all experiments. The 55 degrees 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. 6beta-naltrexol and naltrexone were generated to determine ID(50) antagonist potency estimates against fixed doses of hydrocodone.


RESULTS
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 6beta-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 6beta-naltrexol for antagonism of hydrocodone-induced inhibition of gastrointestinal transit versus antinociception, whereas naltrexone blocked both effects with near equal potency. 6beta-naltrexol produced a longer duration of antagonist blockade and had a slower time to peak effect compared to naltrexone.


CONCLUSIONS
The pharmacology of 6beta-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.
Yancey-Wrona
Janet E
JE
AIKO Biotechnology, Portland, ME 04101, United States.
Raymond
Tyler J
TJ
Mercer
Hannah K
HK
Sadée
Wolfgang
W
Bilsky
Edward J
EJ
D000284:Administration, Oral; D000701:Analgesics, Opioid / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005772:Gastrointestinal Transit / Q000187:drug effects*; D006853:Hydrocodone / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000494:pharmacology; D009292:Narcotic Antagonists; D010147:Pain Measurement / Q000187:drug effects; D011930:Reaction Time / Q000187:drug effects
D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; C010410:6 beta-hydroxynaltrexone; D009271:Naltrexone; D006853:Hydrocodone