title: EphrinBs/EphBs signaling is involved in modulation of spinal nociceptive processing through a mitogen-activated protein kinases-dependent mechanism.
abstract: BACKGROUND
  Our previous studies have demonstrated that EphBs receptors and ephrinBs ligands were involved in modulation of spinal nociceptive information. However, the downstream mechanisms that control this process are not well understood. The aim of this study was to further investigate whether mitogen-activated protein kinases (MAPKs), as the downstream effectors, participate in modulation of spinal nociceptive information related to ephrinBs/EphBs.
  
  
  METHODS
  Thermal hyperalgesia and mechanical allodynia were measured using radiant heat and von Frey filaments test. Immunofluorescence staining was used to detect the expression of p-MAPKs and of p-MAPKs/neuronal nuclei, or p-MAPKs/glial fibrillary acidic protein double label. C-Fos expression was determined by immunohistochemistry. The expression of p-MAPKs was also determined by Western blot assay.
  
  
  RESULTS
  Intrathecal injection of ephrinB1-Fc produced a dose- and time-dependent thermal and mechanical hyperalgesia, accompanied by the increase of spinal p-MAPKs and c-Fos expression. Immunofluorescence staining revealed that p-MAPKs colocalized with the neuronal marker (neuronal nuclei) and the astrocyte marker (glial fibrillary acidic protein). Inhibition of MAPKs prevented and reversed pain behaviors and the increase of spinal c-Fos expression induced by intrathecal injection of ephrinB1-Fc. Inhibition of EphBs receptors by intrathecal injection of EphB1-Fc reduced formalin-induced inflammation and chronic constrictive injury-induced neuropathic pain behaviors accompanied by decreased expression of spinal p-MAPKs and c-Fos protein. Furthermore, pretreatment with MK-801, an N-methyl-d-aspartate receptor antagonist, prevented behavioral hyperalgesia and activation of spinal MAPKs induced by intrathecal injection of ephrinB1-Fc.
  
  
  CONCLUSIONS
  These results demonstrated that activation of MAPKs contributed to modulation of spinal nociceptive information related to ephrinBs/EphBs.
authors.affiliation: Jiangsu Key Laboratory of Anesthesiology, Xuzhou Medical College, Xuzhou, China.
authors.forename: Jia-Ping
authors.initials: JP
authors.lastname: Ruan
authors.forename: Hong-Xing
authors.initials: HX
authors.lastname: Zhang
authors.forename: Xian-Fu
authors.initials: XF
authors.lastname: Lu
authors.forename: Yue-Peng
authors.initials: YP
authors.lastname: Liu
authors.forename: Jun-Li
authors.initials: JL
authors.lastname: Cao
mesh_terms: D000818:Animals; D002070:Butadienes / Q000008:administration & dosage; D036387:Ephrin-B1 / Q000008:administration & dosage* / Q000633:toxicity; D006930:Hyperalgesia / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology; D018836:Inflammation Mediators / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000502:physiology / Q000633:toxicity; D007278:Injections, Spinal; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D009570:Nitriles / Q000008:administration & dosage; D010146:Pain / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology; D010147:Pain Measurement / Q000379:methods; D036081:Receptors, Eph Family / Q000502:physiology*
chemical_list: D002070:Butadienes; D036387:Ephrin-B1; D018836:Inflammation Mediators; D009570:Nitriles; C113580:U 0126; D036081:Receptors, Eph Family; D020928:Mitogen-Activated Protein Kinases