Modulation of Voltage-Gated Sodium Channels by Activation of Tumor Necrosis Factor Receptor-1 and Receptor-2 in Small DRG Neurons of Rats

Mediators Inflamm. 2015;2015:124942. doi: 10.1155/2015/124942. Epub 2015 Oct 4.

Abstract

Tumor necrosis factor- (TNF-) α is a proinflammatory cytokine involved in the development and maintenance of inflammatory and neuropathic pain. Its effects are mediated by two receptors, TNF receptor-1 (TNFR-1) and TNF receptor-2 (TNFR-2). These receptors play a crucial role in the sensitization of voltage-gated sodium channels (VGSCs), a key mechanism in the pathogenesis of chronic pain. Using the whole-cell patch-clamp technique, we examined the influence of TNFR-1 and TNFR-2 on VGSCs and TTX-resistant NaV1.8 channels in isolated rat dorsal root ganglion neurons by using selective TNFR agonists. The TNFR-1 agonist R32W (10 pg/mL) caused an increase in the VGSC current (I(Na(V))) by 27.2 ± 5.1%, while the TNFR-2 agonist D145 (10 pg/mL) increased the current by 44.9 ± 2.6%. This effect was dose dependent. Treating isolated NaV1.8 with R32W (100 pg/mL) resulted in an increase in I(NaV(1.8)) by 18.9 ± 1.6%, while treatment with D145 (100 pg/mL) increased the current by 14.5 ± 3.7%. Based on the current-voltage relationship, 10 pg of R32W or D145 led to an increase in I(Na(V)) in a bell-shaped, voltage-dependent manner with a maximum effect at -30 mV. The effects of TNFR activation on VGSCs promote excitation in primary afferent neurons and this might explain the sensitization mechanisms associated with neuropathic and inflammatory pain.

MeSH terms

  • Animals
  • Cytokines / metabolism
  • Dose-Response Relationship, Drug
  • Ganglia, Spinal / metabolism*
  • Inflammation
  • Male
  • NAV1.8 Voltage-Gated Sodium Channel / drug effects*
  • Neuralgia / drug therapy
  • Neurons / metabolism*
  • Neurons, Afferent / drug effects
  • Patch-Clamp Techniques
  • Rats
  • Rats, Wistar
  • Receptors, Tumor Necrosis Factor, Type I / agonists
  • Receptors, Tumor Necrosis Factor, Type I / metabolism*
  • Receptors, Tumor Necrosis Factor, Type II / agonists
  • Receptors, Tumor Necrosis Factor, Type II / metabolism*
  • Tumor Necrosis Factor-alpha / chemistry*
  • Voltage-Gated Sodium Channels / metabolism*

Substances

  • Cytokines
  • NAV1.8 Voltage-Gated Sodium Channel
  • Receptors, Tumor Necrosis Factor, Type I
  • Receptors, Tumor Necrosis Factor, Type II
  • Scn10a protein, rat
  • Tnfrsf1a protein, rat
  • Tumor Necrosis Factor-alpha
  • Voltage-Gated Sodium Channels