QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.104.082966v1 313/3/1150    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Raehal, K. M. Articles by Bilsky, E. J. Search for Related Content PubMed PubMed Citation Articles by Raehal, K. M. Articles by Bilsky, E. J.

BEHAVIORAL PHARMACOLOGY

In Vivo Characterization of 6-Naltrexol, an Opioid Ligand with Less Inverse Agonist Activity Compared with Naltrexone and Naloxone in Opioid-Dependent Mice

Department of Pharmacology, University of New England College of Osteopathic Medicine, Biddeford, Maine (J.J.L., C.M.B., R.M.P., J.R.B., E.J.B.); and Department of Pharmacology, College of Medicine and Public Health, The Ohio State University, Columbus, Ohio (K.M.R., D.W., W.S.)

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 6-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 6-naltrexol in blocking acute antinociceptive effects of morphine and precipitating opioid withdrawal in models of physical dependence. 6-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 6-naltrexol enters the central nervous system. In contrast to naloxone and naltrexone, 6-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. 6-Naltrexol reduced the inverse agonist effects of naloxone in vitro and in vivo, as expected for a neutral antagonist. Therefore, the pharmacological effects of 6-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.

Address correspondence to: Dr. Edward Bilsky, Department of Pharmacology, University of New England College of Osteopathic Medicine, 11 Hills Beach Road, Biddeford, ME 04005. E-mail: ebilsky{at}une.edu

This article has been cited by other articles:

				S. Sirohi, P. Kumar, and B. C. Yoburn {micro}-Opioid Receptor Up-Regulation and Functional Supersensitivity Are Independent of Antagonist Efficacy J. Pharmacol. Exp. Ther., November 1, 2007; 323(2): 701 - 707. [Abstract] [Full Text] [PDF]

				E. D. Marczak, Y. Jinsmaa, T. Li, S. D. Bryant, Y. Tsuda, Y. Okada, and L. H. Lazarus [N-Allyl-Dmt1]-Endomorphins Are {micro}-Opioid Receptor Antagonists Lacking Inverse Agonist Properties J. Pharmacol. Exp. Ther., October 1, 2007; 323(1): 374 - 380. [Abstract] [Full Text] [PDF]

				D. Wang, X. Sun, and W. Sadee Different Effects of Opioid Antagonists on {micro}-, {delta}-, and {kappa}-Opioid Receptors with and without Agonist Pretreatment J. Pharmacol. Exp. Ther., May 1, 2007; 321(2): 544 - 552. [Abstract] [Full Text] [PDF]

				M. C. H. Ko, M. F. Divin, H. Lee, J. H. Woods, and J. R. Traynor Differential in Vivo Potencies of Naltrexone and 6beta-Naltrexol in the Monkey J. Pharmacol. Exp. Ther., February 1, 2006; 316(2): 772 - 779. [Abstract] [Full Text] [PDF]