title: TNF-α contributes to up-regulation of Nav1.3 and Nav1.8 in DRG neurons following motor fiber injury.
abstract: A large body of evidence has demonstrated that the ectopic discharges of action potentials in primary afferents, resulted from the abnormal expression of voltage gated sodium channels (VGSCs) in dorsal root ganglion (DRG) neurons following peripheral nerve injury are important for the development of neuropathic pain. However, how nerve injury affects the expression of VGSCs is largely unknown. Here, we reported that selective injury of motor fibers by L5 ventral root transection (L5-VRT) up-regulated Nav1.3 and Nav1.8 at both mRNA and protein level and increased current densities of TTX-S and TTX-R channels in DRG neurons, suggesting that nerve injury may up-regulate functional VGSCs in sensory neurons indirectly. As the up-regulated Nav1.3 and Nav1.8 were highly co-localized with TNF-α, we tested the hypothesis that the increased TNF-α may lead to over-expression of the sodium channels. Indeed, we found that peri-sciatic administration of recombinant rat TNF-α (rrTNF) without any nerve injury, which produced lasting mechanical allodynia, also up-regulated Nav1.3 and Nav1.8 in DRG neurons in vivo and that rrTNF enhanced the expression of Nav1.3 and Nav1.8 in cultured adult rat DRG neurons in a dose-dependent manner. Furthermore, inhibition of TNF-α synthesis, which prevented neuropathic pain, strongly inhibited the up-regulation of Nav1.3 and Nav1.8. The up-regulation of the both channels following L5-VRT was significantly lower in TNF receptor 1 knockout mice than that in wild type mice. These data suggest that increased TNF-α may be responsible for up-regulation of Nav1.3 and Nav1.8 in uninjured DRG neurons following nerve injury.
authors.affiliation: Pain Research Center and Department of Physiology, Zhongshan School of Medicine of Sun Yat-Sen University, 74 Zhongshan Rd. 2, Guangzhou 510080, PR China Center for Genome Research and Department of Medical Genetics, Zhongshan School of Medicine of Sun Yat-Sen University, 74 Zhongshan Rd. 2, Guangzhou 510080, PR China National Laboratory of Biomacromolecules, Chinese Academy of Sciences-University of Tokyo Joint Laboratory of Structural Virology and Immunology, PR China.
authors.forename: Xin-Hua
authors.initials: XH
authors.lastname: He
authors.forename: Ying
authors.initials: Y
authors.lastname: Zang
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.forename: Rui-Ping
authors.initials: RP
authors.lastname: Pang
authors.forename: Ji-Tian
authors.initials: JT
authors.lastname: Xu
authors.forename: Xiang
authors.initials: X
authors.lastname: Zhou
authors.forename: Xu-Hong
authors.initials: XH
authors.lastname: Wei
authors.forename: Yong-Yong
authors.initials: YY
authors.lastname: Li
authors.forename: Wen-Jun
authors.initials: WJ
authors.lastname: Xin
authors.forename: Zhi-Hai
authors.initials: ZH
authors.lastname: Qin
authors.forename: Xian-Guo
authors.initials: XG
authors.lastname: Liu
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004558:Electric Stimulation / Q000379:methods; D007839:Functional Laterality; D005727:Ganglia, Spinal / Q000187:drug effects / Q000473:pathology*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology; D062552:NAV1.3 Voltage-Gated Sodium Channel; D062559:NAV1.8 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000172:deficiency; D012585:Sciatica / Q000139:chemically induced / Q000473:pathology*; D011984:Sensory Receptor Cells / Q000145:classification / Q000187:drug effects / Q000378:metabolism*; D026941:Sodium Channel Blockers / Q000494:pharmacology; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism*; D013779:Tetrodotoxin / Q000494:pharmacology; D013792:Thalidomide / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000009:adverse effects* / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects* / Q000235:genetics
chemical_list: D007166:Immunosuppressive Agents; D062552:NAV1.3 Voltage-Gated Sodium Channel; D062559:NAV1.8 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D047888:Receptors, Tumor Necrosis Factor, Type I; C568318:Scn10a protein, mouse; C568319:Scn10a protein, rat; C478638:Scn3a protein, rat; D026941:Sodium Channel Blockers; D015222:Sodium Channels; C506236:Tnfrsf1a protein, mouse; D014409:Tumor Necrosis Factor-alpha; D013779:Tetrodotoxin; D013792:Thalidomide