The Journal of Neuroscience, November 19, 2008, 28(47):12183-12189; doi:10.1523/JNEUROSCI.2326-08.2008
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Behavioral/Systems/Cognitive
A Novel Gβ
-Subunit Inhibitor Selectively Modulates µ-Opioid-Dependent Antinociception and Attenuates Acute Morphine-Induced Antinociceptive Tolerance and Dependence
Jennifer L. Mathews,
Alan V. Smrcka, and
Jean M. Bidlack
Department of Pharmacology and Physiology, University of Rochester, School of Medicine and Dentistry, Rochester, New York 14642-8711
Correspondence should be addressed to Dr. Jean M. Bidlack, Department of Pharmacology and Physiology, P.O. Box 711, University of Rochester, School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, NY 14642-8711. Email: jean_bidlack{at}urmc.rochester.edu
The Gβ
subunit has been implicated in many downstream signaling events associated with opioids. We previously demonstrated that a small molecule inhibitor of Gβ-subunit-dependent phospholipase (PLC) activation potentiated morphine-induced analgesia (Bonacci et al., 2006). Here, we demonstrate that this inhibitor, M119 (cyclohexanecarboxylic acid [2-(4,5,6-trihydroxy-3-oxo-3H-xanthen-9-yl)-(9Cl)]), is selective for µ-opioid receptor-dependent analgesia and has additional efficacy in mouse models of acute tolerance and dependence. When administered by an intracerebroventricular injection in mice, M119 caused 10-fold and sevenfold increases in the potencies of morphine and the µ-selective peptide, DAMGO, respectively. M119 had little or no effect on analgesia induced by the 
agonist U50,488 or 
agonists DPDPE or Deltorphin II. Similar results were obtained in vitro, as only activation of the µ-opioid receptor stimulated PLC activation, whereas no effect was seen with the - and -opioid receptors. M119 inhibited µ-receptor-dependent PLC activation. In studies to further explore the in vivo efficacy of M119, systemic administration M119 also resulted in a fourfold shift increase in potency of systemically administered morphine. Of particular interest, M119 was also able to attenuate acute, antinociceptive tolerance and dependence in mice treated concomitantly with both M119 and morphine. These studies suggest that small organic molecules, such as M119, that specifically regulate Gβ subunit signaling may have important therapeutic applications in enhancing opioid analgesia, while attenuating the development of tolerance and dependence.
Key words: opioid; Gβ-subunit; tolerance; dependence; antinociception; mice
Received May 9, 2008;
revised Sept. 17, 2008;
accepted Oct. 6, 2008.
Correspondence should be addressed to Dr. Jean M. Bidlack, Department of Pharmacology and Physiology, P.O. Box 711, University of Rochester, School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, NY 14642-8711. Email: jean_bidlack{at}urmc.rochester.edu
