title: SDF1-CXCR4 signaling contributes to persistent pain and hypersensitivity via regulating excitability of primary nociceptive neurons: involvement of ERK-dependent Nav1.8 up-regulation.
abstract: BACKGROUND
  Pain is one critical hallmark of inflammatory responses. A large number of studies have demonstrated that stromal cell-derived factor 1 (SDF1, also named as CXCL12) and its cognate receptor C-X-C chemokine receptor type 4 (CXCR4) play an important role in immune reaction and inflammatory processes. However, whether and how SDF1-CXCR4 signaling is involved in inflammatory pain remains unclear.
  
  
  METHODS
  Under the intraplantar (i.pl.) bee venom (BV) injection-induced persistent inflammatory pain state, the changes of SDF1 and CXCR4 expression and cellular localization in the rat dorsal root ganglion (DRG) were detected by immunofluorescent staining. The role of SDF1 and CXCR4 in the hyperexcitability of primary nociceptor neurons was assessed by electrophysiological recording. Western blot analysis was used to quantify the DRG Nav1.8 and phosphorylation of ERK (pERK) expression. Behavioral tests were conducted to evaluate the roles of CXCR4 as well as extracellular signal-regulated kinase (ERK) and Nav1.8 in the BV-induced persistent pain and hypersensitivity.
  
  
  RESULTS
  We showed that both SDF1 and CXCR4 were dramatically up-regulated in the DRG in i.pl. BV-induced inflammatory pain model. Double immunofluorescent staining showed that CXCR4 was localized in all sizes (large, medium, and small) of DRG neuronal soma, while SDF1 was exclusively expressed in satellite glial cells (SGCs). Electrophysiological recording showed that bath application with AMD3100, a potent and selective CXCR4 inhibitor, could reverse the hyperexcitability of medium- and small-sized DRG neurons harvested from rats following i.pl. BV injection. Furthermore, we demonstrated that the BV-induced ERK activation and Nav1.8 up-regulation in the DRG could be blocked by pre-antagonism against CXCR4 in the periphery with AMD3100 as well as by blockade of ERK activation by intrathecal (i.t.) or intraplantar (i.pl.) U0126. At behavioral level, the BV-induced persistent spontaneous pain as well as primary mechanical and thermal hypersensitivity could also be significantly suppressed by blocking CXCR4 and Nav1.8 in the periphery as well as by inhibition of ERK activation at the DRG level.
  
  
  CONCLUSIONS
  The present results suggest that peripheral inflammatory pain state can trigger over release of SDF1 from the activated SGCs in the DRG by which SGC-neuronal cross-talk is mediated by SDF1-CXCR4 coupling that result in subsequent ERK-dependent Nav1.8 up-regulation, leading to hyperexcitability of tonic type of the primary nociceptor cells and development and maintenance of persistent spontaneous pain and hypersensitivity.
authors.affiliation: Institute for Biomedical Sciences of Pain, Tangdu Hospital, The Fourth Military Medical University, #569 Xinsi Road, Baqiao, Xi'an, 710038, People's Republic of China.
authors.forename: Fei
authors.initials: F
authors.lastname: Yang
authors.affiliation: Institute for Biomedical Sciences of Pain, Tangdu Hospital, The Fourth Military Medical University, #569 Xinsi Road, Baqiao, Xi'an, 710038, People's Republic of China.|Key Laboratory of Brain Stress and Behavior, PLA, Xi'an, 710038, People's Republic of China.
authors.forename: Wei
authors.initials: W
authors.lastname: Sun
authors.affiliation: Beijing Institute for Brain Disorders, Beijing, 100069, People's Republic of China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Institute for Biomedical Sciences of Pain, Tangdu Hospital, The Fourth Military Medical University, #569 Xinsi Road, Baqiao, Xi'an, 710038, People's Republic of China.|Key Laboratory of Brain Stress and Behavior, PLA, Xi'an, 710038, People's Republic of China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Institute for Biomedical Sciences of Pain, Tangdu Hospital, The Fourth Military Medical University, #569 Xinsi Road, Baqiao, Xi'an, 710038, People's Republic of China.|Key Laboratory of Brain Stress and Behavior, PLA, Xi'an, 710038, People's Republic of China.
authors.forename: Chun-Li
authors.initials: CL
authors.lastname: Li
authors.affiliation: Institute for Biomedical Sciences of Pain, Tangdu Hospital, The Fourth Military Medical University, #569 Xinsi Road, Baqiao, Xi'an, 710038, People's Republic of China.|Key Laboratory of Brain Stress and Behavior, PLA, Xi'an, 710038, People's Republic of China.
authors.forename: Han
authors.initials: H
authors.lastname: Fu
authors.affiliation: Institute for Biomedical Sciences of Pain, Tangdu Hospital, The Fourth Military Medical University, #569 Xinsi Road, Baqiao, Xi'an, 710038, People's Republic of China.|Key Laboratory of Brain Stress and Behavior, PLA, Xi'an, 710038, People's Republic of China.
authors.forename: Xiao-Liang
authors.initials: XL
authors.lastname: Wang
authors.affiliation: Beijing Institute for Brain Disorders, Beijing, 100069, People's Republic of China.
authors.forename: Fan
authors.initials: F
authors.lastname: Yang
authors.affiliation: Institute for Biomedical Sciences of Pain, Tangdu Hospital, The Fourth Military Medical University, #569 Xinsi Road, Baqiao, Xi'an, 710038, People's Republic of China.|Key Laboratory of Brain Stress and Behavior, PLA, Xi'an, 710038, People's Republic of China.
authors.forename: Ting
authors.initials: T
authors.lastname: He
authors.affiliation: Institute for Biomedical Sciences of Pain, Tangdu Hospital, The Fourth Military Medical University, #569 Xinsi Road, Baqiao, Xi'an, 710038, People's Republic of China. junchen@fmmu.edu.cn.|Key Laboratory of Brain Stress and Behavior, PLA, Xi'an, 710038, People's Republic of China. junchen@fmmu.edu.cn.|Beijing Institute for Brain Disorders, Beijing, 100069, People's Republic of China. junchen@fmmu.edu.cn.
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
mesh_terms: D000818:Animals; D054377:Chemokine CXCL12 / Q000096:biosynthesis*; D006930:Hyperalgesia / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008297:Male; D062559:NAV1.8 Voltage-Gated Sodium Channel / Q000096:biosynthesis*; D009474:Neurons / Q000378:metabolism; D009619:Nociceptors / Q000378:metabolism*; D010146:Pain / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D019718:Receptors, CXCR4 / Q000096:biosynthesis*; D015854:Up-Regulation / Q000502:physiology
chemical_list: D054377:Chemokine CXCL12; C486264:Cxcr4 protein, rat; D062559:NAV1.8 Voltage-Gated Sodium Channel; D019718:Receptors, CXCR4; C568319:Scn10a protein, rat