Wang HY, Friedman E, Olmstead MC, Burns LH. Ultra-low-dose naloxone suppresses opioid tolerance, dependence and associated changes in mu opioid receptor-G protein coupling and Gbetagamma signaling. Neuroscience 135: 247-261

Department of Physiology and Pharmacology, City University of New York Medical School, 138th Street and Convent Avenue, New York, NY 10031, USA.
Neuroscience (Impact Factor: 3.36). 02/2005; 135(1):247-61. DOI: 10.1016/j.neuroscience.2005.06.003
Source: PubMed


Opiates produce analgesia by activating mu opioid receptor-linked inhibitory G protein signaling cascades and related ion channel interactions that suppress cellular activities by hyperpolarization. After chronic opiate exposure, an excitatory effect emerges contributing to analgesic tolerance and opioid-induced hyperalgesia. Ultra-low-dose opioid antagonist co-treatment blocks the excitatory effects of opiates in vitro, as well as opioid analgesic tolerance and dependence, as was demonstrated here with ultra-low-dose naloxone combined with morphine. While the molecular mechanism for the excitatory effects of opiates is unclear, a switch in the G protein coupling profile of the mu opioid receptor and adenylyl cyclase activation by Gbetagamma have both been suggested. Using CNS regions from rats chronically treated with vehicle, morphine, morphine+ultra-low-dose naloxone or ultra-low-dose naloxone alone, we examined whether altered mu opioid receptor coupling to G proteins or adenylyl cyclase activation by Gbetagamma occurs after chronic opioid treatment. In morphine-naïve rats, mu opioid receptors coupled to Go in striatum and to both Gi and Go in periaqueductal gray and spinal cord. Although chronic morphine decreased Gi/o coupling by mu opioid receptors, a pronounced coupling to Gs emerged coincident with a Gbetagamma interaction with adenylyl cyclase types II and IV. Co-treatment with ultra-low-dose naloxone attenuated both the chronic morphine-induced Gs coupling and the Gbetagamma signaling to adenylyl cyclase, while increasing Gi/o coupling toward or beyond vehicle control levels. These findings provide a molecular mechanism underpinning opioid tolerance and dependence and their attenuation by ultra-low-dose opioid antagonists.

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    • "The neural mechanisms that underlie hyperalgesic effects are poorly understood, but are dependent on the concentration of the drug and the duration of exposure (Crain and Shen, 2000; Rubovitch et al., 2003). A biphasic effect of opioids on cAMP formation and substance P release has also been demonstrated (Crain and Shen, 2000; Rubovitch et al., 2003; Suarez-Roca and Maixner, 1992; Suarez-Roca and Maixner, 1995; Suarez-Roca et al., 1992; Wang et al., 2005). There is evidence that the excitatory actions of MOR reflect a switch in the G protein coupling profile of the MOR from G i to both G s (Crain and Shen, 2000; Esmaeili-Mahani et al., 2008; Mostany et al., 2008; Wang and Burns, 2006) and G q (Rubovitch et al., 2003), as well as adenylyl cyclase (AC) activation by G βγ (Wang and Burns, 2006; Wang et al., 2005). "
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    ABSTRACT: The μ-opioid receptor (MOR) is the primary target for opioid analgesics. MOR induces analgesia through the inhibition of second messenger pathways and the modulation of ion channels activity. Nevertheless, cellular excitation has also been demonstrated, and proposed to mediate reduction of therapeutic efficacy and opioid-induced hyperalgesia upon prolonged exposure to opioids. In this mini-perspective, we review the recently identified, functional MOR isoform subclass, which consists of six transmembrane helices (6TM) and may play an important role in MOR signaling. There is evidence that 6TM MOR signals through very different cellular pathways and may mediate excitatory cellular effects rather than the classic inhibitory effects produced by the stimulation of the major (7TM) isoform. Therefore, the development of 6TM and 7TM MOR selective compounds represent a new and exciting opportunity to better understand the mechanisms of action and the pharmacodynamic properties of a new class of opioids. Copyright © 2014. Published by Elsevier Inc.
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    • "Western blot analyses were performed on lysates of the rat MrD and also on the Hippocampal tissue using a polyclonal antiserum against a peptide mapping at the C terminus of MOR. The results revealed an immunoreactive band of about 53 kDa (Figure 1 line1) that corresponds to the de-glycosylated form of MOR [48]. In the positive control group, the positive signal of the specific 53 kDa immunoreactive band was also obtained (Figure 1 line2). "
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