title: TNF-α enhances the currents of voltage gated sodium channels in uninjured dorsal root ganglion neurons following motor nerve injury.
abstract: The ectopic discharges observed in uninjured dorsal root ganglion (DRG) neurons following various lesions of spinal nerves have been attributed to functional alterations of voltage-gated sodium channels (VGSCs). Such mechanisms may be important for the development of neuropathic pain. However, the pathophysiology underlying the functional modulation of VGSCs following nerve injury is largely unknown. Here, we studied this issue with use of a selective lumbar 5 ventral root transection (L5-VRT) model, in which dorsal root ganglion (DRG) neurons remain intact. We found that the L5-VRT increased the current densities of TTX-sensitive Na channels as well as currents in Nav1.8, but not Nav1.9 channels in uninjured DRG neurons. The thresholds of action potentials decreased and firing rates increased in DRG neurons following L5-VRT. As we found that levels of tumor necrosis factor-alpha (TNF-α) increased in cerebrospinal fluid (CSF) and in DRG tissue after L5-VRT, we tested whether the increased TNF-α might result in the changes in sodium channels. Indeed, recombinant rat TNF (rrTNF) enhanced the current densities of TTX-S and Nav1.8 in cultured DRG neurons dose-dependently. Furthermore, genetic deletion of TNF receptor 1 (TNFR-1) in mice attenuated the mechanical allodynia and prevented the increase in sodium currents in DRG neurons induced by L5-VRT. These data suggest that the increase in sodium currents in uninjured DRG neurons following nerve injury might be mediated by over-production of TNF-α.
authors.affiliation: Pain Research Center and Department of Physiology, Zhongshan Medical School of Sun Yat-Sen University, 74 Zhongshan Rd. 2, Guangzhou 510080, PR China.
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.forename: Rui-Ping
authors.initials: RP
authors.lastname: Pang
authors.forename: Kai-Feng
authors.initials: KF
authors.lastname: Shen
authors.forename: Manfred
authors.initials: M
authors.lastname: Zimmermann
authors.forename: Wen-Jun
authors.initials: WJ
authors.lastname: Xin
authors.forename: Yong-Yong
authors.initials: YY
authors.lastname: Li
authors.forename: Xian-Guo
authors.initials: XG
authors.lastname: Liu
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005727:Ganglia, Spinal / Q000293:injuries / Q000502:physiology*; D015640:Ion Channel Gating / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009046:Motor Neurons / Q000378:metabolism*; D062559:NAV1.8 Voltage-Gated Sodium Channel; D062558:NAV1.9 Voltage-Gated Sodium Channel; D009474:Neurons / Q000502:physiology; D009479:Neuropeptides / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015222:Sodium Channels / Q000502:physiology*; D013126:Spinal Nerve Roots / Q000293:injuries / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
chemical_list: D062559:NAV1.8 Voltage-Gated Sodium Channel; D062558:NAV1.9 Voltage-Gated Sodium Channel; D009479:Neuropeptides; C568318:Scn10a protein, mouse; C568319:Scn10a protein, rat; C113705:Scn11a protein, rat; D015222:Sodium Channels; D014409:Tumor Necrosis Factor-alpha