title: In vivo characterization of 6beta-naltrexol, an opioid ligand with less inverse agonist activity compared with naltrexone and naloxone in opioid-dependent mice.
abstract: The mu-opioid receptor displays basal signaling activity, which seems to be enhanced by exposure to opioid agonists. This study assesses the in vivo pharmacology of the putative "neutral" antagonist 6beta-naltrexol in comparison to other ligands with varying efficacy, such as naloxone, an inverse agonist in the opioid-dependent state. ICR mice were used to generate full antagonist dose-response curves for naloxone, naltrexone, nalbuphine, and 6beta-naltrexol in blocking acute antinociceptive effects of morphine and precipitating opioid withdrawal in models of physical dependence. 6beta-Naltrexol was roughly equipotent to naloxone and between 4.5- and 10-fold less potent than naltrexone in blocking morphine-induced antinociception and locomotor activity, showing that 6beta-naltrexol enters the central nervous system. In contrast to naloxone and naltrexone, 6beta-naltrexol precipitated only minimal withdrawal at high doses in an acute dependence model and was approximately 77- and 30-fold less potent than naltrexone and naloxone, respectively, in precipitating withdrawal in a chronic dependence model. 6beta-Naltrexol reduced the inverse agonist effects of naloxone in vitro and in vivo, as expected for a neutral antagonist. Therefore, the pharmacological effects of 6beta-naltrexol differ markedly from those of naloxone and naltrexone in the opioid-dependent state. A reduction of withdrawal effects associated with neutral mu-opioid receptor antagonists may offer advantages in treating opioid overdose and addiction.
authors.affiliation: Department of Pharmacology, University of New England College of Osteopathic Medicine, Biddeford, ME 04005, USA.
authors.forename: Kirsten M
authors.initials: KM
authors.lastname: Raehal
authors.forename: John J
authors.initials: JJ
authors.lastname: Lowery
authors.forename: Castigliano M
authors.initials: CM
authors.lastname: Bhamidipati
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Paolino
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Blair
authors.forename: Danxin
authors.initials: D
authors.lastname: Wang
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sadée
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Bilsky
mesh_terms: D000818:Animals; D001597:Benzylidene Compounds / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009020:Morphine / Q000037:antagonists & inhibitors; D009043:Motor Activity / Q000187:drug effects; D009270:Naloxone / Q000494:pharmacology*; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000494:pharmacology*; D009292:Narcotic Antagonists / Q000494:pharmacology*; D009293:Opioid-Related Disorders / Q000188:drug therapy*
chemical_list: D001597:Benzylidene Compounds; D009292:Narcotic Antagonists; C077358:7-benzylidenenaltrexone; D009270:Naloxone; D016244:Guanosine 5'-O-(3-Thiotriphosphate); C010410:6 beta-hydroxynaltrexone; D009271:Naltrexone; D009020:Morphine