title: CXCL13/CXCR5 enhances sodium channel Nav1.8 current density via p38 MAP kinase in primary sensory neurons following inflammatory pain.
abstract: CXCL13 is a B lymphocyte chemoattractant and activates CXCR5 receptor in the immune system. Here we investigated whether CXCL13/CXCR5 mediates inflammatory pain in dorsal root ganglia (DRG) and the underlying mechanisms. Peripheral injection of complete Freund's Adjuvant (CFA) increased the expression of CXCL13 and CXCR5 in DRG neurons. In Cxcr5-/-mice, CFA-induced pain hypersensitivity were attenuated. Whole-cell patch-clamp recording showed that the excitability of dissociated DRG neurons was increased after CFA injection or CXCL13 incubation from wild-type (WT) mice, but not from Cxcr5-/-mice. Additionally, sodium channel Nav1.8 was co-expressed with CXCR5 in dissociated DRG neurons, and the increased neuronal excitability induced by CFA or CXCL13 was reduced by Nav1.8 blocker. Intrathecal injection of Nav1.8 blocker also attenuated intrathecal injection of CXCL13-induced pain hypersensitivity. Furthermore, CXCL13 increased Nav1.8 current density in DRG neurons, which was inhibited by p38 MAP kinase inhibitor. CFA and CXCL13 increased p38 phosphorylation in the DRG of WT mice but not Cxcr5-/-mice. Finally, intrathecal p38 inhibitor alleviated CXCL13-induced pain hypersensitivity. Taken together, these results demonstrated that CXCL13, upregulated by peripheral inflammation, acts on CXCR5 on DRG neurons and activates p38, which increases Nav1.8 current density and further contributes to the maintenance of inflammatory pain.
authors.affiliation: Pain Research Laboratory, Institute of Nautical Medicine, Jiangsu Key Laboratory of Inflammation and Molecular Drug Target, Nantong University, Nantong, Jiangsu 226019, China.
authors.forename: Xiao-Bo
authors.initials: XB
authors.lastname: Wu
authors.affiliation: Pain Research Laboratory, Institute of Nautical Medicine, Jiangsu Key Laboratory of Inflammation and Molecular Drug Target, Nantong University, Nantong, Jiangsu 226019, China.
authors.forename: De-Li
authors.initials: DL
authors.lastname: Cao
authors.affiliation: Pain Research Laboratory, Institute of Nautical Medicine, Jiangsu Key Laboratory of Inflammation and Molecular Drug Target, Nantong University, Nantong, Jiangsu 226019, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Pain Research Laboratory, Institute of Nautical Medicine, Jiangsu Key Laboratory of Inflammation and Molecular Drug Target, Nantong University, Nantong, Jiangsu 226019, China.
authors.forename: Bao-Chun
authors.initials: BC
authors.lastname: Jiang
authors.affiliation: Pain Research Laboratory, Institute of Nautical Medicine, Jiangsu Key Laboratory of Inflammation and Molecular Drug Target, Nantong University, Nantong, Jiangsu 226019, China.
authors.forename: Lin-Xia
authors.initials: LX
authors.lastname: Zhao
authors.affiliation: Department of Anesthesiology, The First People's Hospital of Yancheng, Jiangsu 224005, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Qian
authors.affiliation: Pain Research Laboratory, Institute of Nautical Medicine, Jiangsu Key Laboratory of Inflammation and Molecular Drug Target, Nantong University, Nantong, Jiangsu 226019, China.|Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, China.
authors.forename: Yong-Jing
authors.initials: YJ
authors.lastname: Gao
mesh_terms: D000818:Animals; D002452:Cell Count; D054382:Chemokine CXCL13 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005620:Freund's Adjuvant / Q000633:toxicity; D005727:Ganglia, Spinal / Q000166:cytology / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D062559:NAV1.8 Voltage-Gated Sodium Channel / Q000235:genetics / Q000378:metabolism*; D010146:Pain / Q000378:metabolism*; D054380:Receptors, CXCR5 / Q000235:genetics / Q000378:metabolism*; D011984:Sensory Receptor Cells / Q000378:metabolism* / Q000473:pathology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C513179:CXCR5 protein, mouse; D054382:Chemokine CXCL13; C486386:Cxcl13 protein, mouse; D062559:NAV1.8 Voltage-Gated Sodium Channel; D054380:Receptors, CXCR5; C568318:Scn10a protein, mouse; D005620:Freund's Adjuvant; D048051:p38 Mitogen-Activated Protein Kinases