The Role of TNF-alpha/NF-kappa B Pathway on the Up-Regulation of Voltage-Gated Sodium Channel Nav1.7 in DRG Neurons of Rats With Diabetic Neuropathy

Neurochem Int. 2014 Sep;75:112-9. doi: 10.1016/j.neuint.2014.05.012. Epub 2014 Jun 2.

Abstract

Diabetic neuropathy (DN) is a common form of peripheral neuropathy, yet the mechanisms responsible for chronic pain in this disease are poorly understood. The up-regulation of the expression and function of voltage-gated sodium channel Nav1.7 has been implicated in DN, however, the exact mechanism is unclear. In the present study, we found that a proportion of streptozotocin (STZ)-treated rats suffered from mechanical allodynia and thermal hyperalgesia for a long-lasting time. Nav1.7 was up-regulated in spinal dorsal root ganglia (DRG) of rats with DN, double immunofluorescence staining showed that the increased Nav1.7 was co-localized with large and small sized neurons but not satellite glial cells. Inhibiting the synthesis of tumor necrosis factor-α (TNF-α) by thalidomide prevented DN, accompanied by strongly blocking the up-regulation of Nav1.7, TNF-α and p-nucleus factor-kappa B (p-NF-κB) in DRG. Intrathecal injection of NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC) significantly attenuated the pain behaviors and over-expression of Nav1.7 in DRG neurons. These data suggest that increased TNF-α may be responsible for up-regulation of Nav1.7 in DRG neurons of rats with DN, and NF-κB signal pathway is involved in this process. The findings might provide potential target for preventing diabetic neuropathy.

Keywords: Diabetic neuropathy; Dorsal root ganglia; NF-κB; Sodium channel; TNF-α.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Diabetic Neuropathies / physiopathology*
  • Ganglia, Spinal / cytology
  • Ganglia, Spinal / drug effects
  • Ganglia, Spinal / physiology*
  • Male
  • NAV1.7 Voltage-Gated Sodium Channel / physiology*
  • NF-kappa B / physiology*
  • Neurons / physiology
  • Rats
  • Rats, Sprague-Dawley
  • Streptozocin
  • Thalidomide / pharmacology
  • Tumor Necrosis Factor-alpha / physiology*
  • Up-Regulation / physiology*

Substances

  • NAV1.7 Voltage-Gated Sodium Channel
  • NF-kappa B
  • Scn9a protein, rat
  • Tumor Necrosis Factor-alpha
  • Thalidomide
  • Streptozocin