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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Available from: Lindsay H Burns, Oct 04, 2015
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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.
    Progress in Neuro-Psychopharmacology and Biological Psychiatry 12/2014; 62. DOI:10.1016/j.pnpbp.2014.11.009 · 3.69 Impact Factor
    • "The effects appear to be dose dependent and biphasic because high doses of naloxone, both in humans and animals, induce pain lowering the thermal and mechanical nociceptive threshold whereas low doses exert analgesia and increase the nociceptive threshold.[11] Naloxone increases pain at high doses in the presence of opioid drugs or activation of endogenous opioid system.[12] "
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    ABSTRACT: Role of nitric oxide (NO) in reversing morphine anti-nociception has been shown. However, the interaction between NO and naloxone-induced pain in the hippocampus is unknown. The present study aimed to investigate the involvement of molecule NO in naloxone-induced pain and its possible interaction with naloxone into cortical area 1 (CA1) of hippocampus. Male Wistar rats (250-350 g), provided by Pasteur Institute of Iran, were housed two per cage with food and water ad libitum. The animals' skulls were cannulated bilaterally at coordinates adjusted for CA1 of hippocampus (AP: -3.8; L: ±1.8- 2.2: V: 3) by using stereotaxic apparatus. Each experimental group included 6-8 rats. To induce inflammation pain, the rats received subcutaneous (s.c.) injections of formalin (50 μL at 2.5%) once prior to testing. To evaluate the nociceptive effect of naloxone, the main narcotic antagonist of morphine (0.1-0.4 mg/kg) was injected intraperitoneally (i.p.) 10 min before injection of formalin. Injections of L-arginine, a precursor of NO, and N(G)-Nitro-L-arginine Methyl Ester (L-NAME), an inhibitor of NO synthase (NOS), intra-CA1, were conducted orderly prior to the administration of naloxone. The pain induction was analyzed by analysis of variance (ANOVA). Naloxone at the lower doses caused a significant (P<0.01) pain in the naloxone-treated animals. However, pre-administration (1-2 min) of L-arginine (0.04, 0.08, 0.15, 0.3, 1.0, and 3.0 μg/rat, intra-CA1) reversed the response to naloxone. But, the response to L-arginine was blocked by pre-microinjection (1-2 min) of L-NAME (0.15, 0.3, 1.0, and 3.0 μg/rat), whilst, L-arginine or L-NAME alone did not induce pain behavior. NO in the rat hippocampal CA1 area is involved in naloxone-induced nociception.
    Indian Journal of Pharmacology 07/2012; 44(4):443-7. DOI:10.4103/0253-7613.99299 · 0.69 Impact Factor
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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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    ABSTRACT: Mu opioid receptor (MOR), which plays key roles in analgesia and also has effects on learning and memory, was reported to distribute abundantly in the patches of the neostriatum. The marginal division (MrD) of the neostriatum, which located at the caudomedial border of the neostriatum, was found to stain for enkephalin and substance P immunoreactivities and this region was found to be involved in learning and memory in our previous study. However, whether MOR also exists in the MrD has not yet been determined. In this study, we used western blot analysis and immunoperoxidase histochemical methods with glucose oxidase-DAB-nickel staining to investigate the expression of MOR in the MrD by comparison to the patches in the neostriatum. The results from western blot analyses revealed that the antibody to MOR detected a 53 kDa protein band, which corresponded directly to the molecular weight of MOR. Immunohistochemical results showed that punctate MOR-immunoreacted fibers were observed in the "patch" areas in the rostrodorsal part of the neostriatum but these previous studies showed neither labelled neuronal cell bodies, nor were they shown in the caudal part of the neostriatum. Dorsoventrally oriented dark MOR-immunoreactive nerve fibers with individual labelled fusiform cell bodies were firstly observed in the band at the caudomedial border, the MrD, of the neostriatum. The location of the MOR-immunoreactivity was in the caudomedial border of the neostriatum. The morphology of the labelled fusiform neuronal somatas and the dorsoventrally oriented MOR-immunoreacted fibers in the MrD was distinct from the punctate MOR-immunoreactive diffuse mosaic-patterned patches in the neostriatum. The results indicated that MOR was expressed in the MrD as well as in patches in the neostriatum of the rat brain, but with different morphological characteristics. The punctate MOR-immunoreactive and diffuse mosaic-patterned patches were located in the rostrodorsal part of the neostriatum. By contrast, in the MrD, the dorsoventrally parallel oriented MOR-immunoreactive fibers with individual labelled fusiform neuronal somatas were densely packed in the caudomedial border of the neostriatum. The morphological difference in MOR immunoreactivity between the MrD and the patches indicated potential functional differences between them. The MOR most likely plays a role in learning and memory associated functions of the MrD.
    Journal of Biomedical Science 06/2011; 18(1):34. DOI:10.1186/1423-0127-18-34 · 2.76 Impact Factor
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