Role of extracellular signal‐regulated kinase in the ventral tegmental area in the suppression of the morphine‐induced rewarding effect in mice with sciatic nerve ligation

Ozaki, Satoru; Narita, Minoru; Narita, Michiko; Ozaki, Masahiko; Khotib, Junaidi; Suzuki, Tsutomu

doi:10.1046/j.1471-4159.2003.02272.x

Cited by 65 publications

(50 citation statements)

References 35 publications

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“…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). The current data support these findings, showing significant morphine-CPP and increases in phosphorylation of ERK1/2 in the VTA of both galanin WT and GKO mice following acute administration of a rewarding dose of morphine.…”

Section: Discussionsupporting

confidence: 79%

“…In addition, together with evidence indicating that phosphorylation of ERK is necessary for drug reinforcement (Ozaki et al, 2004;Valjent et al, 2001Valjent et al, , 2006aValjent et al, , b, 2004Valjent et al, , 2005, these data suggest that galanin may modulate drug-dependent behaviors via activation of ERK in brain areas such as the VTA, NAc, and amygdala. Thus, galanin agonists may prove useful in attenuating the rewarding properties of opiates.…”

Section: Discussionmentioning

confidence: 74%

“…No changes in total ERK and CREB were observed at any dose and no changes in P-ERK or P-CREB were observed in animals of either genotype treated with 0.25 mg/kg morphine (not shown). Since inhibition of ERK1/2 phosphorylation in the VTA blocks the rewarding effects of morphine (Berhow et al, 1996;Ozaki et al, 2004), the observed increases in ERK1/2 activation may regulate (a) Galanin wild-type (WT; n ¼ 10) and knockout (GKO; n ¼ 11) mice were administered an acute i.p. injection of saline followed by 0, 5, 10, or 20 mg/kg morphine 15 min later.…”

Section: Neurochemical Changes Downstream Of Morphine Signalingmentioning

confidence: 99%

“…At the molecular level, morphine administration leads to enhanced phosphorylation, and thus activation of extracellularregulated kinase (ERK1/2) in the VTA, hippocampus, NAc, cingulate cortex, and amygdala (Berhow et al, 1996;Valjent et al, 2004). Increased ERK1/2 phosphorylation in the VTA is associated with morphine and psychostimulant reward (Ozaki et al, 2004) and systemic inhibition of ERK1/2 phosphorylation blocks expression of morphine and cocaine CPP (Valjent et al, 2006a). To assess galanin effects on changes in signaling, we measured the effects of morphine administration on levels of total and phosphorylated ERK1/2 in the VTA, NAc, amygdala, cingulate cortex, substantia nigra (SN), LC, caudate putamen, and hippocampus of WT and GKO mice and assessed whether the galanin receptor agonist galnon could reverse these changes.…”

Section: Introductionmentioning

confidence: 99%

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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: Discussionsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 74%

Section: Neurochemical Changes Downstream Of Morphine Signalingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Galanin Protects Against Behavioral and Neurochemical Correlates of Opiate Reward

Hawes

Brunzell

Narasimhaiah

et al. 2007

Neuropsychopharmacol

View full text Add to dashboard Cite

show abstract

“…Morphineinduced ERK1/2 phosphorylation was largely demonstrated in cellular models, and also evidenced in vivo following both acute and chronic treatments in rodent models (Eitan et al, 2003;Valjent et al, 2004). Further, ERK1/2 inhibitors modulate responses to morphine, including acquisition (Ozaki et al, 2004), reconsolidation, (Valjent et al, 2006) and reinstatement (Li et al, 2008) of morphine-conditioned place preference, as well as morphine withdrawal (Cao et al, 2005). RSKs are direct downstream effectors of ERK1/2 (Anjum and Blenis, 2008) and may therefore contribute to morphine activity in vivo.…”

Section: Introductionmentioning

confidence: 99%

RSK2 Signaling in Medial Habenula Contributes to Acute Morphine Analgesia

Darcq

Befort

Koebel

et al. 2012

Neuropsychopharmacol

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It has been established that mu opioid receptors activate the ERK1/2 signaling cascade both in vitro and in vivo. The Ser/Thr kinase RSK2 is a direct downstream effector of ERK1/2 and has a role in cellular signaling, cell survival growth, and differentiation; however, its role in biological processes in vivo is less well known. Here we determined whether RSK2 contributes to mu-mediated signaling in vivo. Knockout mice for the rsk2 gene were tested for main morphine effects, including analgesia, tolerance to analgesia, locomotor activation, and sensitization to this effect, as well as morphine withdrawal. The deletion of RSK2 reduced acute morphine analgesia in the tail immersion test, indicating a role for this kinase in mu receptor-mediated nociceptive processing. All other morphine effects and adaptations to chronic morphine were unchanged. Because the mu opioid receptor and RSK2 both show high density in the habenula, we specifically downregulated RSK2 in this brain metastructure using an adeno-associated-virally mediated shRNA approach. Remarkably, morphine analgesia was significantly reduced, as observed in the total knockout animals. Together, these data indicate that RSK2 has a role in nociception, and strongly suggest that a mu opioid receptor-RSK2 signaling mechanism contributes to morphine analgesia at the level of habenula. This study opens novel perspectives for both our understanding of opioid analgesia, and the identification of signaling pathways operating in the habenular complex.

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Role of MEK‐ERK pathway in morphine‐induced conditioned place preference in ventral tegmental area of rats

Lin

Wang

et al. 2010

J of Neuroscience Research

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A major goal of research on drug addiction is to develop the effective treatments to deal with the long-term behavioral disorders especially reinstatement induced by the addictive drugs such as opiates, cocaine, and cannabinoid. The molecular mechanisms underlying these substance-related disorders remain unclear so far. Here we used the model of morphine-induced conditioned place preference (CPP) in rats to mimic the progress of drug-taking, withdrawal and relapse in human. The tissue of ventral tegmental area (VTA), one of the most important brain structures associated with abused drug-related disorders, was taken and two-dimensional electrophoresis (2-DE) was performed to analyze and compare the changes of protein expression patterns during the different stages of morphine-induced CPP. First, we found that there were 80 proteins identified to be changed in the process of morphine-induced CPP. Furthermore, as the mitogen-activated protein kinase kinase 1 (MAPKK1) was increased significantly in the stages of establishment and reinstatement, we confirmed the change of activated extracellular signal-regulated kinase (ERK) by Western blotting in VTA tissue and cultured cell. The results demonstrated that the activated MEK-ERK pathway by chronic morphine treatment in VTA was involved in morphine-induced reinstatement. Moreover, inhibition of MEK-ERK pathway by infusion the MEK inhibitor U0126 in VTA blocked the establishment of morphine-induced CPP. The present study found significant changes in a group of protein expressions in VTA during morphine-induced CPP and further confirmed the role of MEK-ERK cell signaling pathway of VTA in morphine addiction.

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Role of extracellular signal‐regulated kinase in the ventral tegmental area in the suppression of the morphine‐induced rewarding effect in mice with sciatic nerve ligation

Cited by 65 publications

References 35 publications

Galanin Protects Against Behavioral and Neurochemical Correlates of Opiate Reward

Galanin Protects Against Behavioral and Neurochemical Correlates of Opiate Reward

RSK2 Signaling in Medial Habenula Contributes to Acute Morphine Analgesia

Role of MEK‐ERK pathway in morphine‐induced conditioned place preference in ventral tegmental area of rats

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