JPET

Home Help [Feedback] [For Subscribers] [Archive] [Search] --
QUICK SEARCH:   [advanced]


     

Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on February 16, 2005; DOI: 10.1124/jpet.104.082966

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


Received for publication December 30, 2004.
Revised February 12, 2005.
Accepted for publication February 14, 2005.

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

Kirsten M. Raehal 1, John J. Lowery 2, Castigliano M. Bhamidipati 2, Ryan M. Paolino 2, Jennifer R. Blair 2, Danxin Wang 1, Wolfgang Sadee 1, Edward J. Bilsky 2*

1 The Ohio State University 2 University of New England

* Address correspondence to: E-mail: ebilsky{at}une.edu

Abstract

The mu opioid receptor (MOR) displays basal signaling activity, which appears to be enhanced by exposure to opioid agonists. This study assesses the in vivo pharmacology of the putative "neutral" antagonist 6{beta}-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{beta}-naltrexol in blocking acute antinociceptive effects of morphine and precipitating opioid withdrawal in models of physical dependence. 6{beta}-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{beta}-naltrexol enters the CNS. In contrast to naloxone and naltrexone, 6{beta}-naltrexol precipitated only minimal withdrawal at high doses in an acute dependence model and was ~77-fold and 30-fold less potent than naltrexone and naloxone, respectively, in precipitating withdrawal in a chronic-dependence model. 6{beta}-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{beta}-naltrexol differ markedly from those of naloxone and naltrexone in the opioid dependent state. A reduction of withdrawal effects associated with neutral MOR antagonists may offer advantages in treating opioid overdose and addiction.


Key words: Addiction, Dependence, Morphine, Naloxone, Naltrexone, Opioid


This article has been cited by other articles:


Home page
 J. Pharmacol. Exp. Ther.Home page
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]

Home page
 J. Pharmacol. Exp. Ther.Home page
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]

Home page
 J. Pharmacol. Exp. Ther.Home page
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]

Home page
 J. Pharmacol. Exp. Ther.Home page
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]


Home Help [Feedback] [For Subscribers] [Archive] [Search] --
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2005 by the American Society for Pharmacology and Experimental Therapeutics.