title: Spinal CXCL5 contributes to nerve injury-induced neuropathic pain via modulating GSK-3β phosphorylation and activity in rats.
abstract: BACKGROUND
  Neuroinflammation is identified to be crucial in the development of neuropathic pain, whereas definite molecular mechanisms remain obscure. Recently, chemokine CXCL5 is manifested to participate in the inflammatory process of central nervous system, however, little is known about the potential effect of spinal CXCL5 on pathogenesis of pain. This study investigated whether and how CXCL5 and its receptor CXCR2 regulated neuropathic pain in a rat model of chronic constriction injury (CCI) of the sciatic nerves.
  
  
  METHODS
  Recombinant CXCL5, a neutralizing antibody against CXCL5, selective CXCR2 antagonist SB225002 and GSK-3β inhibitor TDZD-8 were injected intrathecally. PWT and PWL were documented to assess mechanical allodynia and thermal hyperalgesia. Simultaneously, levels of CXCL5 and CXCR2 in spinal dorsal horn were measured by RT-qPCR after nociceptive testing. Western blot was utilized to evaluate spinal GSK-3β expression and phosphorylation.
  
  
  RESULTS
  We found that CCI engendered rapid and long-lasting mechanical allodynia and thermal hyperalgesia, which was accompanied by dramatical rise of spinal CXCL5 and CXCR2 expression. CCI also caused an increase of pGSK-3β (Tyr216) and a decrease of pGSK-3β (Ser9) without affecting total protein level of GSK-3β. Moreover, spinal blockage of CXCL5/CXCR2 pathway attenuated neuropathic pain and inhibited the enhancement of GSK-3β activity. Also, intrathecal delivery of exogenous CXCL5 dose-dependently induced nociceptive hypersensitivity in naïve rats, which was prevented by the supplemental addition of TDZD-8.
  
  
  CONCLUSIONS
  These present findings indicate that up-regulation of spinal CXCL5 and CXCR2 is involved in neuropathic pain after nerve injury, through regulating GSK-3β activity in rats.
authors.affiliation: Department of Anesthesiology, Tianjin First Central Hospital, Tianjin 300192, China.
authors.forename: Weituan
authors.initials: W
authors.lastname: Xu
authors.affiliation: Department of Anesthesiology, Tianjin First Central Hospital, Tianjin 300192, China.
authors.forename: Min
authors.initials: M
authors.lastname: Zhu
authors.affiliation: Department of Anesthesiology, Tianjin First Central Hospital, Tianjin 300192, China.
authors.forename: Shaoting
authors.initials: S
authors.lastname: Yuan
authors.affiliation: Department of Anesthesiology, Tianjin First Central Hospital, Tianjin 300192, China. Electronic address: yzxmzkywl@126.com.
authors.forename: Wenli
authors.initials: W
authors.lastname: Yu
mesh_terms: D000818:Animals; D054365:Chemokine CXCL5 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D003251:Constriction, Pathologic; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism*; D006930:Hyperalgesia / Q000378:metabolism / Q000503:physiopathology; D007278:Injections, Spinal; D008297:Male; D009437:Neuralgia / Q000378:metabolism* / Q000503:physiopathology; D017288:Pain Threshold; D010671:Phenylurea Compounds / Q000494:pharmacology; D010766:Phosphorylation; D017207:Rats, Sprague-Dawley; D023063:Receptors, Interleukin-8B / Q000037:antagonists & inhibitors / Q000378:metabolism; D012584:Sciatic Nerve / Q000293:injuries*; D013116:Spinal Cord / Q000378:metabolism*; D066148:Spinal Cord Dorsal Horn / Q000378:metabolism; D013830:Thiadiazoles / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: C494356:4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione; D054365:Chemokine CXCL5; D010671:Phenylurea Compounds; D023063:Receptors, Interleukin-8B; C112019:SB 225002; D013830:Thiadiazoles; D000071679:Glycogen Synthase Kinase 3 beta
keywords: CXCL5; CXCR2; Chemokine; GSK-3β; Neuropathic pain