A Novel G -Subunit Inhibitor Selectively Modulates -Opioid-Dependent Antinociception and Attenuates Acute Morphine-Induced Antinociceptive Tolerance and Dependence

Department of Pharmacology and Physiology, University of Rochester, School of Medicine and Dentistry, Rochester, New York 14642-8711, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 12/2008; 28(47):12183-9. DOI: 10.1523/JNEUROSCI.2326-08.2008
Source: PubMed


The Gbetagamma subunit has been implicated in many downstream signaling events associated with opioids. We previously demonstrated that a small molecule inhibitor of Gbetagamma-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 mu-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 mu-selective peptide, DAMGO, respectively. M119 had little or no effect on analgesia induced by the kappa agonist U50,488 or delta agonists DPDPE or Deltorphin II. Similar results were obtained in vitro, as only activation of the mu-opioid receptor stimulated PLC activation, whereas no effect was seen with the kappa- and delta-opioid receptors. M119 inhibited mu-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 Gbetagamma subunit signaling may have important therapeutic applications in enhancing opioid analgesia, while attenuating the development of tolerance and dependence.

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Available from: Jean Bidlack, Jun 29, 2015
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    • "It is likely that more discrete interactions that have not yet been characterized support this inhibition, and the recent structural information obtained from structurally similar channels will certainly help to find out the molecular basis of G protein inhibition. In addition, the use of small molecules and peptides to selectively disrupt interaction of G protein bg dimer with some effectors has been demonstrated in vitro and in vivo on various models of heart failure and morphine tolerance (Bonacci et al., 2006; Mathews et al., 2008; Casey et al., 2010). A deeper biochemical and functional characterization of Gbg channel interaction will certainly provide important information to identified molecules targeting G protein inhibition of VGCCs with potential therapeutic benefits. "
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    • "Morphine exacerbates this cycle (El-Hage et al., 2005; El-Hage et al., 2006a; El-Hage et al., 2006b; El-Hage et al., 2008), presumably by augmenting Tat-induced increases [Ca 2+ ] i . Unlike other neural cell types, MOR can couple to Gβγ (Bonacci et al., 2006; Mathews, Smrcka, & Bidlack, 2008), G q/11 -α (Hauser et al., 1996), and/or G s α via MOR-1K splice variants (Dever et al., 2014) in astroglia resulting in cellular excitation. Opiate and HIV-induced increases in astroglialderived cytokines in turn enhance microglial recruitment and activation (El-Hage et al., 2006b). "
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