TNF-α contributes to up-regulation of Nav1.3 and Nav1.8 in DRG neurons following motor fiber injury

Pain. 2010 Nov;151(2):266-279. doi: 10.1016/j.pain.2010.06.005. Epub 2010 Jul 17.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Disease Models, Animal
  • Electric Stimulation / methods
  • Functional Laterality
  • Ganglia, Spinal / drug effects
  • Ganglia, Spinal / pathology*
  • Immunosuppressive Agents / pharmacology
  • Male
  • Membrane Potentials / drug effects
  • Membrane Potentials / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Motor Neurons / metabolism
  • Motor Neurons / pathology
  • NAV1.3 Voltage-Gated Sodium Channel
  • NAV1.8 Voltage-Gated Sodium Channel
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Patch-Clamp Techniques
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Tumor Necrosis Factor, Type I / deficiency
  • Sciatica / chemically induced
  • Sciatica / pathology*
  • Sensory Receptor Cells / classification
  • Sensory Receptor Cells / drug effects
  • Sensory Receptor Cells / metabolism*
  • Sodium Channel Blockers / pharmacology
  • Sodium Channels / genetics
  • Sodium Channels / metabolism*
  • Tetrodotoxin / pharmacology
  • Thalidomide / pharmacology
  • Tumor Necrosis Factor-alpha / adverse effects*
  • Tumor Necrosis Factor-alpha / metabolism
  • Up-Regulation / drug effects*
  • Up-Regulation / genetics


  • Immunosuppressive Agents
  • NAV1.3 Voltage-Gated Sodium Channel
  • NAV1.8 Voltage-Gated Sodium Channel
  • Nerve Tissue Proteins
  • RNA, Messenger
  • Receptors, Tumor Necrosis Factor, Type I
  • Scn10a protein, mouse
  • Scn10a protein, rat
  • Scn3a protein, rat
  • Sodium Channel Blockers
  • Sodium Channels
  • Tnfrsf1a protein, mouse
  • Tumor Necrosis Factor-alpha
  • Tetrodotoxin
  • Thalidomide