Upregulation of the sodium channel Na v β4 subunit and its contributions to mechanical hypersensitivity and neuronal hyperexcitability in a rat model of radicular pain induced by local dorsal root ganglion inflammation

Wenrui Xie, Zhi Yong Tan, Cindy Barbosa, Judith A. Strong, Theodore Cummins, Jun Ming Zhang

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

High-frequency spontaneous firing in myelinated sensory neurons plays a key role in initiating pain behaviors in several different models, including the radicular pain model in which the rat lumbar dorsal root ganglia (DRG) are locally inflamed. The sodium channel isoform Na V 1.6 contributes to pain behaviors and spontaneous activity in this model. Among all isoforms in adult DRG, Na V 1.6 is the main carrier of tetrodotoxin-sensitive resurgent Na currents that allow high-frequency firing. Resurgent currents flow after a depolarization or action potential, as a blocking particle exits the pore. In most neurons, the regulatory β4 subunit is potentially the endogenous blocker. We used in vivo siRNA-mediated knockdown of Na V β4 to examine its role in the DRG inflammation model. Na V β4 but not control siRNA almost completely blocked mechanical hypersensitivity induced by DRG inflammation. Microelectrode recordings in isolated whole DRG showed that Na V β4 siRNA blocked the inflammation-induced increase in spontaneous activity of Aβ neurons and reduced repetitive firing and other measures of excitability. Na V β4 was preferentially expressed in larger diameter cells; DRG inflammation increased its expression, and this was reversed by Na V β4 siRNA, based on immunohistochemistry and Western blotting. Na V β4 siRNA also reduced immunohistochemical Na V 1.6 expression. Patch-clamp recordings of tetrodotoxin-sensitive Na currents in acutely cultured medium diameter DRG neurons showed that DRG inflammation increased transient and especially resurgent current, effects blocked by Na V β4 siRNA. Na V β4 may represent a more specific target for pain conditions that depend on myelinated neurons expressing Na V 1.6.

Original languageEnglish (US)
Pages (from-to)879-891
Number of pages13
JournalPain
Volume157
Issue number4
DOIs
StatePublished - Apr 1 2016

Fingerprint

Sodium Channels
Spinal Ganglia
Hypersensitivity
Up-Regulation
Small Interfering RNA
Inflammation
Pain
Neurons
Tetrodotoxin
Protein Isoforms
Microelectrodes
Sensory Receptor Cells
Action Potentials
Western Blotting
Immunohistochemistry

Keywords

  • Ectopic activity
  • Na v 1.6
  • Na V β4
  • Radicular pain
  • Resurgent current
  • Scn10a
  • Scn4b
  • Sodium channel

ASJC Scopus subject areas

  • Clinical Neurology
  • Anesthesiology and Pain Medicine
  • Neurology
  • Pharmacology

Cite this

Upregulation of the sodium channel Na v β4 subunit and its contributions to mechanical hypersensitivity and neuronal hyperexcitability in a rat model of radicular pain induced by local dorsal root ganglion inflammation. / Xie, Wenrui; Tan, Zhi Yong; Barbosa, Cindy; Strong, Judith A.; Cummins, Theodore; Zhang, Jun Ming.

In: Pain, Vol. 157, No. 4, 01.04.2016, p. 879-891.

Research output: Contribution to journalArticle

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