TY - JOUR T1 - In Vivo Characterization of 6β-Naltrexol, an Opioid Ligand with Less Inverse Agonist Activity Compared with Naltrexone and Naloxone in Opioid-Dependent Mice JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 1150 LP - 1162 DO - 10.1124/jpet.104.082966 VL - 313 IS - 3 AU - Kirsten M. Raehal AU - John J. Lowery AU - Castigliano M. Bhamidipati AU - Ryan M. Paolino AU - Jennifer R. Blair AU - Danxin Wang AU - Wolfgang Sadée AU - Edward J. Bilsky Y1 - 2005/06/01 UR - http://jpet.aspetjournals.org/content/313/3/1150.abstract N2 - The μ-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 6β-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 6β-naltrexol in blocking acute antinociceptive effects of morphine and precipitating opioid withdrawal in models of physical dependence. 6β-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 6β-naltrexol enters the central nervous system. In contrast to naloxone and naltrexone, 6β-naltrexol precipitated only minimal withdrawal at high doses in an acute dependence model and was ∼77- and 30-fold less potent than naltrexone and naloxone, respectively, in precipitating withdrawal in a chronic dependence model. 6β-Naltrexol reduced the inverse agonist effects of naloxone in vitro and in vivo, as expected for a neutral antagonist. Therefore, the pharmacological effects of 6β-naltrexol differ markedly from those of naloxone and naltrexone in the opioid-dependent state. A reduction of withdrawal effects associated with neutral μ-opioid receptor antagonists may offer advantages in treating opioid overdose and addiction. The American Society for Pharmacology and Experimental Therapeutics ER -