title: Activation of ERK/CREB pathway in spinal cord contributes to chronic constrictive injury-induced neuropathic pain in rats.
abstract: OBJECTIVE
  To investigate whether activation and translocation of extracellular signal-regulated kinase (ERK) is involved in the induction and maintenance of neuropathic pain, and effects of activation and translocation of ERK on expression of pCREB and Fos in the chronic neuropathic pain.
  
  
  METHODS
  Lumbar intrathecal catheters were chronically implanted in male Sprague-Dawley rats. The left sciatic nerve was loosely ligated proximal to the sciaticaos trifurcation at approximately 1.0 mm intervals with 4-0 silk sutures. The mitogen-activated protein kinase kinase (MEK) inhibitor U0126 or phosphorothioate-modified antisense oligonucleotides (ODN) were intrathecally administered every 12 h, 1 d pre-chronic constriction injury (CCI) and 3 d post-CCI. Thermal and mechanical nociceptive thresholds were assessed with the paw withdrawal latency (PWL) to radiant heat and von Frey filaments. The expression of pERK, pCREB, and Fos were assessed by both Western blotting and immunohistochemical analysis.
  
  
  RESULTS
  Intrathecal injection of U0126 or ERK antisense ODN significantly attenuated CCI-induced mechanical allodynia and thermal hyperalgesia. CCI significantly increased the expression of p-ERK-IR neurons in the ipsilateral spinal dorsal horn to injury, not in the contralateral spinal dorsal horn. The time courses of pERK expression showed that the levels of both cytosol and nuclear pERK, but not total ERK, were increased at all points after CCI and reached a peak level on postoperative d 5. CCI also significantly increased the expression of pCREB and Fos. Phospho-CREB-positive neurons were distributed in all laminae of the bilateral spinal cord and Fos was expressed in laminae I and II of the ipsilateral spinal dorsal horn. Intrathecal injection of U0126 or ERK antisense ODN markedly suppressed the increase of CCI-induced pERK, pCREB and c-Fos expression in the spinal cord.
  
  
  CONCLUSIONS
  The activation of ERK pathways contributes to neuropathic pain in CCI rats, and the function of pERK may partly be accomplished via the cAMP response element binding protein (CREB)-dependent gene expression.
authors.affiliation: Department of Anesthesiology, First Clinical College of N.Bethune Centre of Health Sciences, Jilin University, Changchun 130021, China.
authors.forename: Xue-Song
authors.initials: XS
authors.lastname: Song
authors.forename: Jun-Li
authors.initials: JL
authors.lastname: Cao
authors.forename: Yan-Bing
authors.initials: YB
authors.lastname: Xu
authors.forename: Jian-Hua
authors.initials: JH
authors.lastname: He
authors.forename: Li-Cai
authors.initials: LC
authors.lastname: Zhang
authors.forename: Yin-Ming
authors.initials: YM
authors.lastname: Zeng
mesh_terms: D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006930:Hyperalgesia / Q000378:metabolism; D008297:Male; D009570:Nitriles / Q000494:pharmacology; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D010766:Phosphorylation; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020426:Sciatic Neuropathy / Q000378:metabolism*; D013116:Spinal Cord / Q000378:metabolism*
chemical_list: D002070:Butadienes; D017362:Cyclic AMP Response Element-Binding Protein; D009570:Nitriles; D020319:Oligodeoxyribonucleotides, Antisense; D016760:Proto-Oncogene Proteins c-fos; C113580:U 0126; D048049:Extracellular Signal-Regulated MAP Kinases