The activation of extracellular signal-regulated protein kinase 5 in spinal cord and dorsal root ganglia contributes to inflammatory pain

Xiao, Chengshan; Zhang, Lin; Cheng, Qiuping; Zhang, Licai

doi:10.1016/j.brainres.2008.03.065

Cited by 26 publications

(21 citation statements)

References 41 publications

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“…7) In addition, complete Freund's adjuvant (CFA) induced inflammation evokes ERK5 expression in both DRG and spinal cord, and ERK5 knockdown significantly reduces pain and spinal Fos elevation. 8) Support to these findings, we observed that the elevated phosphorylation of ERK1/2 and ERK5 by zymosan detected in spinal lamina I-II, which was similar location of zymosan induced Fos expression. Subsequent double labelling study further confirmed zymosan induced ERK1/2 and ERK5 phosphorylation occurred in spinal neurons.…”

Section: Discussionsupporting

confidence: 84%

“…There is accumulative evidence indicating that activation of MAPK in both primary afferents and the spinal cord may participate in the establishment and maintenance of nociceptive-induced plasticity. [7][8][9] Present study show that zymosan induced inflammation significantly increased phosphorylation of MAPKs including ERK1/2 and ERK5 in the spinal dorsal horn. The ERK1/2 is activated by membrane depolarization and calcium influx, and activated by an upstream kinase, MAPK/ERK kinase (MEK).…”

Section: Discussionsupporting

confidence: 49%

“…5,6) Accumulative data have been revealed that activation of mitogen activated protein kinases (MAPKs, i.e., extracellular signal-regulated protein kinase (ERK) 1/2, p38 MAPK, and ERK5) in both spinal neurons and microglia may have a pivotal role in development of pain symptom following nerve injury and peripheral inflammation. [7][8][9] In this context, we aimed to evaluate whether the spinal activation of MAPKs signaling pathway in both neuron and microglia is involved in the antinociceptive effect of pregabalin in zymosan induced peripheral inflammatory pain model. …”

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confidence: 99%

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Inhibition of Mitogen-Activated Protein Kinases Phosphorylation Plays an Important Role in the Anti-nociceptive Effect of Pregabalin in Zymosan-Induced Inflammatory Pain Model

Jeong

Pyun

Kwon

2014

Biological & Pharmaceutical Bulletin

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Although pregabalin has been shown to have preclinical and clinical efficacy in neuropathic pain, the mechanism of its antinociceptive action is still unknown in other pain states. This study aimed to evaluate the antinociceptive effect of pregabalin and its underlying spinal mechanisms related to mitogen activated protein kinases (MAPKs) in neuron and microglia following intraplantar injection of zymosan model. Zymosan evoked thermal hyperalgesia, mechanical hyperalgesia, and mechanical allodynia starting from 1 h and persistent until 5 h post-injection, which were dose-dependently reversed by oral pretreatment of pregabalin (3, 10, and 30 mg/kg). Pregabalin dramatically inhibited zymosan-induced Fos expression (a marker for neuronal activation) and microglia activation (using markers CD11b and ED1) in the spinal dorsal horn. Moreover, zymosan significantly increased phosphorylation of extracellular signal-regulated protein kinase (ERK) 1/2 (double labeling with neuron), ERK5 (double labelling with neuron and microglia) and p38 MAPK (double labeling with microglia) in the spinal dorsal horn, which overall elevations were reversed by pregabalin. These findings suggest that blockage of MAPKs activation in neuron and microglia might be closely related to the antinociceptive effect of pregabalin on zymosan-induced peripheral inflammatory pain.Key words pregabalin; pain; mitogen activated protein kinase (MAPK); zymosan Pregabalin as a new-generation anti-epileptic drug with fewer side effects and less tolerance has been shown to have preclinical and clinical efficacy in neuropathic pain. Accumulative clinical studies in different types of neuropathic pain (i.e., peripheral diabetic neuropathy, fibromyalgia, postherpetic neuralgia, cancer chemotherapy-induced neuropathic pain) have demonstrated its effectiveness in treating the neurological symptoms including allodynia and hyperalgesia.1) In several type of neuropathic pain models, it has been further demonstrated that pregabalin has an influence on various neuronal targets and the signaling systems including calcium channel-mediated neurotransmitter release and activation of excitatory amino acid pathway in the spinal level.1) Despite widespread clinical use and characterization of antinociceptive activity of pregabalin in neuropathic pain, potential antinociceptive effect and its underlying molecular mechanisms in other pain state remain poorly understood. Thus, present study was focus on the potential antinociceptive effect of pregabalin in the peripheral inflammatory pain state.In recent years, microglia has been increasingly implicated in the mechanisms underlying abnormal pain states. Spinal microglia activation (using markers CD11b and ED1) has been observed in the early phase of neuropathic pain, 2) which is closely correlated with induction and maintenance of allodynia and hyperalgesia.3) In line with this view, microglia inhibitors successfully alleviate neuropathic pain in experimental models.3,4) Similar with neuropathic condition, peripheral inflammation...

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Section: Discussionsupporting

confidence: 84%

Section: Discussionsupporting

confidence: 49%

mentioning

confidence: 99%

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Inhibition of Mitogen-Activated Protein Kinases Phosphorylation Plays an Important Role in the Anti-nociceptive Effect of Pregabalin in Zymosan-Induced Inflammatory Pain Model

Jeong

Pyun

Kwon

2014

Biological & Pharmaceutical Bulletin

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“…In addition, Akt (or PKB) phosphorylation by ERK5 inactivated Foxo3a and the following gene expression of Bim (Finegan et al, 2009). Xiao et al (2008) examined a role of ERK5 activation in peripheral inflammation in the spinal cord and DRG, and whether this activation is involved in the heat and mechanical hyperalgesia response. (Xiao et al, 2008).…”

Section: Mechanism Of Erk5 Activation and Roles Of Erk5 In Neurons 13mentioning

confidence: 99%

“…Xiao et al (2008) examined a role of ERK5 activation in peripheral inflammation in the spinal cord and DRG, and whether this activation is involved in the heat and mechanical hyperalgesia response. (Xiao et al, 2008). In their study, sustained ERK5 activation was observed in the DRG and spinal dorsal horn during inflammation induced by the injection of complete Freund's adjuvant into a hind paw, and the hyperalgesia response was suppressed by ERK5 knockdown by antisense oligonucleotides accompanied by a reduction in the numbers of phospho-CREB and c-Fos positive neurons.…”

Section: Mechanism Of Erk5 Activation and Roles Of Erk5 In Neurons 13mentioning

confidence: 99%

The Signaling Pathway Leading to Extracellular Signal-Regulated Kinase 5 (ERK5) Activation via G-Proteins and ERK5-Dependent Neurotrophic Effects

Obara

Nakahata²

2009

Mol Pharmacol

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Extracellular signal-regulated kinases (ERKs) or mitogen-activated protein kinases (MAPKs) are involved in cellular proliferation, differentiation, migration, and gene expression. The MAPK family includes ERK1/2, c-Jun NH 2 -terminal kinases 1, 2, and 3, p38MAPK ␣, ␤, ␥, and -␦, and ERK5 as conventional MAPKs and ERK3, ERK4 NLK, and ERK7 as atypical MAPKs. Like other MAPKs, ERK5 is activated by variety of stimuli, including growth factors, G-protein-coupled receptor (GPCR) agonists, cytokines, and stress. However, the signaling pathway leading to ERK5 activation is not well understood compared with the other conventional MAPKs. For example, the pharmacological reagents that induce second messenger cAMP and Ca 2ϩ downstream of GPCRs do not activate ERK5 in neuronal cells. In addition, conflicting results have come from studies examining the involvement of small G-proteins in ERK5 activation by growth factors, and the details of the signaling pathway remain controversial. In addition, the physiological roles of ERK5 in neuronal cells have not been clarified. One reason was the lack of a selective ERK5 pharmacological inhibitor until the novel selective MEK5/ERK5 inhibitors BIX02188 and BIX02189 (Biochem Biophys Res Commun 377: 120 -125, 2008) reported last year. Another reason is that the use of interfering mutants is limited in neuronal cells because the transfection efficiency is low. Despite these difficulties, recent studies suggest that ERK5 mediates the promotion of neuronal survival and neuronal differentiation in vitro and in vivo. In this review, the signaling pathway leading to ERK5 activation through heterotrimeric and small G-proteins and the physiological roles of ERK5 in neuronal cells are summarized and discussed.Extracellular signal-regulated kinases (ERKs) or mitogenactivated protein kinases (MAPKs) are involved in cellular proliferation, differentiation, migration, and gene expression. The MAPK family includes ERK1/2, c-Jun N-terminal kinases 1, 2, and 3, p38MAPK ␣, ␤, ␥, and ␦, and ERK5 as conventional MAPKs, and ERK3, ERK4 NLK, and ERK7 as atypical MAPKs (Coulombe and Meloche, 2007). Threonine and tyrosine activation motifs (T-X-Y) are conserved among conventional MAPKs and ERK7, whereas the atypical MAPKs lack these motifs. The most well studied MAPK family member, ERK1/2, is activated by a variety of stimuli, and the signaling pathway leading to ERK1/2 activation has been better characterized than that to ERK5 activation (Goldsmith and Dhanasekaran, 2007). ERK5 is approximately twice the molecular size of ERK1/2. The kinase domain is encoded by its amino-terminal half and shares approximately 50% of homology with ERK1/2, whereas its unique carboxyl terminus encodes two proline-rich regions and a nuclear localization signal (Nishimoto and Nishida, 2006;Wang and Tournier, 2006). It has been reported that the autophosphorylated carboxyl terminus of ERK5 plays a critical role in activating transcription (Morimoto et al., 2007). The threonine and tyrosine residues on ERK5 are Article, publ...

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CX3CL1/CX3CR1 regulates nerve injury‐induced pain hypersensitivity through the ERK5 signaling pathway

Sun

Xiao

et al. 2013

J of Neuroscience Research

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Peripheral nerve injury induces the cleavage of CX3CL1 from the membrane of neurons, where the soluble CX3CL1 subsequently plays an important role in the transmission of nociceptive signals between neurons and microglia. Here we investigated whether CX3CL1 regulates microglia activation through the phosphorylation of extracellular signal-regulated protein kinase 5 (ERK5) in the spinal cord of rats with spinal nerve ligation (SNL). ERK5 and microglia were activated in the spinal cord after SNL. The knockdown of ERK5 by intrathecal injection of antisense oligonucleotides suppressed the hyperalgesia and nuclear impact of nuclear factor-κB induced by SNL. The blockage of CX3CR1, the receptor of CX3CL1, significantly reduced the level of ERK5 activation following SNL. In addition, the antisense knockdown of ERK5 reversed the CX3CL1-induced hyperalgesia and spinal microglia activation. Our study suggests that CX3CL1/CX3CR1 regulates nerve injury-induced pain hypersensitivity through the ERK5 signaling pathway.

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The activation of extracellular signal-regulated protein kinase 5 in spinal cord and dorsal root ganglia contributes to inflammatory pain

Cited by 26 publications

References 41 publications

Inhibition of Mitogen-Activated Protein Kinases Phosphorylation Plays an Important Role in the Anti-nociceptive Effect of Pregabalin in Zymosan-Induced Inflammatory Pain Model

Inhibition of Mitogen-Activated Protein Kinases Phosphorylation Plays an Important Role in the Anti-nociceptive Effect of Pregabalin in Zymosan-Induced Inflammatory Pain Model

The Signaling Pathway Leading to Extracellular Signal-Regulated Kinase 5 (ERK5) Activation via G-Proteins and ERK5-Dependent Neurotrophic Effects

CX3CL1/CX3CR1 regulates nerve injury‐induced pain hypersensitivity through the ERK5 signaling pathway

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