μ and κ Opioid Receptors Activate ERK/MAPK via Different Protein Kinase C Isoforms and Secondary Messengers in Astrocytes

Belcheva, Mariana M.; Clark, Amy L.; Haas, Paul D.; Serna, Jannie S.; Hahn, Jason W.; Kiss, Alexi; Coscia, Carmine J.

doi:10.1074/jbc.m502593200

Cited by 162 publications

(162 citation statements)

References 62 publications

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“…Galanin, opioid, and DA receptors are GPCRs that modulate many signaling pathways including those involving ERK1/2 (Belcheva et al, 2005(Belcheva et al, , 2001Hawes et al, 2006a;Loh and Smith, 1990;Williams et al, 2001). Chronic morphine exposure (Berhow et al, 1996) and stimulation of several GPCRs, including opioid receptors, leads to ERK activation in the VTA (Eitan et al, 2003) and inhibition of ERK activity in the VTA suppresses the rewarding effects of morphine (Ozaki et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Galanin Protects Against Behavioral and Neurochemical Correlates of Opiate Reward

Hawes

Brunzell

Narasimhaiah

et al. 2007

Neuropsychopharmacol

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The mechanisms underlying responses to drugs of abuse have been widely investigated; however, less is known about pathways normally protective against the development of drug reinforcement. These pathways are also important since they may regulate individual differences in vulnerability to addiction. The neuropeptide galanin and its binding sites are expressed in brain areas important for drug reward. Previous studies have shown that centrally infused galanin attenuates morphine place preference and peripheral injection of galnon, a galanin agonist, decreases opiate withdrawal signs. The current studies in galanin knockout (GKO) mice examined the hypothesis that galanin is an endogenous negative regulator of opiate reward and identified downstream signaling pathways regulated by galanin. We show that GKO mice demonstrate increased locomotor activation following morphine administration, which is inhibited by acute administration of galnon. GKO mice also show enhanced morphine place preference, supporting the idea that galanin normally antagonizes opiate reward. In addition, morphine-induced ERK1/2 phosphorylation was increased in the VTA of both wild-type and GKO mice, but only the GKO mice showed increases in ERK1/2 and CREB phosphorylation in the amygdala or nucleus accumbens. Furthermore, a single systemic injection of galnon in GKO mice was sufficient to reverse some of the biochemical changes brought about by morphine administration. These data suggest that galanin normally attenuates behavioral and neurochemical effects of opiates; thus, galanin agonists may represent a new class of therapeutic targets for opiate addiction.

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Section: Discussionmentioning

confidence: 99%

Galanin Protects Against Behavioral and Neurochemical Correlates of Opiate Reward

Hawes

Brunzell

Narasimhaiah

et al. 2007

Neuropsychopharmacol

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“…Horseradish peroxidase-linked IgG (goat antirabbit, 1:2,000; Cell Signaling Technology, Beverly, MA) was applied as the secondary antibody. Bands were visualized by chemiluminescence detection as described (55), and band intensities were normalized to those for a mouse monoclonal antibody against ␤-actin (1:500,000; Chemicon, Temecula, CA) on the same film as a loading control. Band intensities were determined by densitometric analysis using a OneTouch 9220 USB scanner (Visioneer), MagnaFire software (version 2.1C; Olympus, Melville, NY), and NIH ImageJ version 1.34e.…”

Section: Methodsmentioning

confidence: 99%

Central serotonergic neurons are differentially required for opioid analgesia but not for morphine tolerance or morphine reward

Zhao¹,

Gao²,

Sun³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Opioids remain the most effective analgesics despite their potential adverse effects such as tolerance and addiction. Mechanisms underlying these opiate-mediated processes remain the subject of much debate. Here we describe opioid-induced behaviors of Lmx1b conditional knockout mice (Lmx1b f/f/p ), which lack central serotonergic neurons, and we report that opioid analgesia is differentially dependent on the central serotonergic system. Analgesia induced by a opioid receptor agonist administered at the supraspinal level was abolished in Lmx1b f/f/p mice compared with their wild-type littermates. Furthermore, compared with their wild-type littermates Lmx1b f/f/p mice exhibited significantly reduced analgesic effects of and ␦ opioid receptor agonists at both spinal and supraspinal sites. In contrast to the attenuation in opioid analgesia, Lmx1b f/f/p mice developed tolerance to morphine analgesia and displayed normal morphine reward behavior as measured by conditioned place preference. Our results provide genetic evidence supporting the view that the central serotonergic system is a key component of supraspinal pain modulatory circuitry mediating opioid analgesia. Furthermore, our data suggest that the mechanisms of morphine tolerance and morphine reward are independent of the central serotonergic system. serotonin ͉ pain ͉ conditioned place preference ͉ behavior ͉ mouse

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“…The particular effects seen for each receptor type are contextual and differ among cell types and at different stages of development. Immature neurons Eisch and Harburg, 2006;Narita et al, 2006a), astrocytes (Stiene-Martin and Hauser, 1990;Eriksson et al, 1990;Eriksson et al, 1991;Stiene-Martin and Hauser, 1991;Hauser et al, 1996;Stiene-Martin et al, 1998;Belcheva et al, 2005), oligodendrocytes (Knapp et al, 1998;Stiene-Martin et al, 2001), and their precursors (Persson et al, 2003a;Persson et al, 2003b;Persson et al, 2006;Kim et al, 2006) can respond uniquely to opioids. For example, MOR receptor activation can inhibit proliferation in immature astroglia, while activation of the same receptor type in immature oligodendroglia increases proliferation (Knapp et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Glial-restricted precursors: Patterns of expression of opioid receptors and relationship to human immunodeficiency virus-1 Tat and morphine susceptibility in vitro

et al. 2007

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Recent evidence suggests that HIV-induced pathogenesis is exacerbated by opioid abuse and that the synergistic toxicity may result from direct actions of opioids in immature glia or glial precursors. To assess whether opioids and HIV proteins are directly toxic to glial-restricted precursors (GRPs), we isolated neural stem cells from the incipient spinal cord of embryonic day 10.5 ICR mice. GRPs were characterized immunocytochemically and by RTPCR. At 1 day in vitro (DIV), GRPs failed to express μ (MOR or MOP) or κ-opioid receptors (KOR or KOP); however, at 5 DIV, most GRPs expressed MOR and KOR. The effects of morphine (500 nM) and/or Tat (100 nM) on GRP viability were assessed in GRPs at 5 DIV by examining the apoptotic effector caspase-3 and cell viability (ethidium monoazide exclusion) at 96 h following continuous exposure. Tat or morphine alone or in combination caused significant increases in GRP cell death at 96 h, but not at 24 h, following exposure. Although morphine or Tat caused increases in caspase-3 activity at 4 h, this was not accompanied with increased cleaved caspase-3 immunoreactive or ethidium monoazide-positive dying cells at 24 h. The results indicate that prolonged morphine or Tat exposure is intrinsically toxic to isolated GRPs and/or their progeny in vitro. Moreover, MOR and KOR are widely expressed by Sox2 and/or Nkx2.2-positive GRPs in vitro and the pattern of receptor expression appears to be developmentally regulated. The temporal requirement for prolonged morphine and HIV-1 Tat exposure to evoke toxicity in glia may coincide with the attainment of a particular stage of maturation and/or the development of particular apoptotic effector pathways and may be unique to spinal cord GRPs. Should similar patterns occur in vivo then we predict that immature astroglia and oligodendroglia may be preferentially vulnerable to HIV-1 infection or chronic opiate exposure.

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μ and κ Opioid Receptors Activate ERK/MAPK via Different Protein Kinase C Isoforms and Secondary Messengers in Astrocytes

Cited by 162 publications

References 62 publications

Galanin Protects Against Behavioral and Neurochemical Correlates of Opiate Reward

Galanin Protects Against Behavioral and Neurochemical Correlates of Opiate Reward

Central serotonergic neurons are differentially required for opioid analgesia but not for morphine tolerance or morphine reward

Glial-restricted precursors: Patterns of expression of opioid receptors and relationship to human immunodeficiency virus-1 Tat and morphine susceptibility in vitro

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