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.

Download full-text


Available from: Jean Bidlack, Jun 29, 2015
27 Reads
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Neuronal voltage-gated calcium channels have evolved as one of the most important players for calcium entry into presynaptic endings responsible for the release of neurotransmitter. In turn, and in order to fine tune synaptic activity and neuronal communication, numerous neurotransmitters exert a potent negative autocrine and/or paracrine control over the calcium signal provided by G-protein-coupled receptors. This regulation pathway of essential physiological importance is also extensively exploited for therapeutic purposes, for instance in the treatment of neuropathic pain by morphine and other mu-opioid receptor agonists. However, despite more than three decades of intensive research, important questions remain unsolved regarding the molecular and cellular mechanisms of direct G-protein inhibition of voltage-gated calcium channels. Here, we revisit this particular regulation and explore new considerations. The American Society for Pharmacology and Experimental Therapeutics.
    Molecular pharmacology 12/2014; 87(6). DOI:10.1124/mol.114.096008 · 4.13 Impact Factor
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Considerable insight has been gained into the comorbid, interactive effects of HIV and drug abuse in the brain using experimental models. This review, which considers opiates, methamphetamine, and cocaine, emphasizes the importance of host genetics and glial plasticity in driving the pathogenic neuron remodeling underlying neuro-acquired immunodeficiency syndrome and drug abuse comorbidity. Clinical findings are less concordant than experimental work, and the response of individuals to HIV and to drug abuse can vary tremendously. Host-genetic variability is important in determining viral tropism, neuropathogenesis, drug responses, and addictive behavior. However, genetic differences alone cannot account for individual variability in the brain "connectome." Environment and experience are critical determinants in the evolution of synaptic circuitry throughout life. Neurons and glia both exercise control over determinants of synaptic plasticity that are disrupted by HIV and drug abuse. Perivascular macrophages, microglia, and to a lesser extent astroglia can harbor the infection. Uninfected bystanders, especially astroglia, propagate and amplify inflammatory signals. Drug abuse by itself derails neuronal and glial function, and the outcome of chronic exposure is maladaptive plasticity. The negative consequences of coexposure to HIV and drug abuse are determined by numerous factors including genetics, sex, age, and multidrug exposure. Glia and some neurons are generated throughout life, and their progenitors appear to be targets of HIV and opiates/psychostimulants. The chronic nature of HIV and drug abuse appears to result in sustained alterations in the maturation and fate of neural progenitors, which may affect the balance of glial populations within multiple brain regions.
    International Review of Neurobiology 09/2014; 118C:231-313. DOI:10.1016/B978-0-12-801284-0.00009-9 · 1.92 Impact Factor
  • Source
    • "Morphine may also indirectly increase neuron excitability through actions in astroglia. Morphine can augment [Ca 2+ ] i via G [172] [173] (or perhaps uniquely via G q/11 -in astroglia [76]) to drive increases in phospholipase C (PLC), further increasing excitation. The resultant IP 3 -dependent increases in [Ca 2+ ] i potentiate Ca 2+ -induced Ca 2+ release (or regenerative Ca 2+ ) via ryanodine receptors in astroglia [76]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Opiate abuse and HIV-1 have been described as interrelated epidemics, and even in the advent of combined anti-retroviral therapy, the additional abuse of opiates appears to result in greater neurologic and cognitive deficits. The central nervous system (CNS) is particularly vulnerable to interactive opiate-HIV-1 effects, in part because of the unique responses of microglia and astroglia. Although neurons are principally responsible for behavior and cognition, HIV-1 infection and replication in the brain is largely limited to microglia, while astroglia and perhaps glial progenitors can be latently infected. Thus, neuronal dysfunction and injury result from cellular and viral toxins originating from HIV-1 infected/exposed glia. Importantly, subsets of glial cells including oligodendrocytes, as well as neurons, express µ-opioid receptors and therefore can be direct targets for heroin and morphine (the major metabolite of heroin in the CNS), which preferentially activate µ-opioid receptors. This review highlights findings that neuroAIDS is a glially driven disease, and that opiate abuse may act at multiple glial-cell types to further compromise neuron function and survival. The ongoing, reactive cross-talk between opiate drug and HIV-1 co-exposed microglia and astroglia appears to exacerbate critical proinflammatory and excitotoxic events leading to neuron dysfunction, injury, and potentially death. Opiates enhance synaptodendritic damage and a loss of synaptic connectivity, which is viewed as the substrate of cognitive deficits. We especially emphasize that opioid signaling and interactions with HIV-1 are contextual, differing among cell types, and even within subsets of the same cell type. For example, astroglia even within a single brain region are heterogeneous in their expression of µ-, δ-, and κ-opioid receptors, as well as CXCR4 and CCR5, and Toll-like receptors. Thus, defining the distinct targets engaged by opiates in each cell type, and among brain regions, is critical to an understanding of how opiate abuse exacerbates neuroAIDS.
    Current HIV research 05/2012; 10(5):435-52. DOI:10.2174/157016212802138779 · 1.76 Impact Factor
Show more