Increased resurgent sodium currents in nav1.8 contribute to nociceptive sensory neuron hyperexcitability associated with peripheral neuropathies

Yucheng Xiao, Cindy Barbosa, Zifan Pei, Wenrui Xie, Judith A. Strong, Jun Ming Zhang, Theodore R. Cummins

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

Neuropathic pain is a significant public health challenge, yet the underlying mechanisms remain poorly understood. Painful small fiber neuropathy (SFN) may be caused by gain-of-function mutations in Nav1.8, a sodium channel subtype predominantly expressed in peripheral nociceptive neurons. However, it is not clear how Nav1.8 disease mutations induce sensory neuron hyperexcitability. Here we studied two mutations in Nav1.8 associated with hypersensitive sensory neurons: G1662S reported in painful SFN; and T790A, which underlies increased pain behaviors in the Possum transgenic mouse strain. We show that, in male DRG neurons, these mutations, which impair inactivation, significantly increase TTX-resistant resurgent sodium currents mediated by Nav1.8. The G1662S mutation doubled resurgent currents, and the T790A mutation increased them fourfold. These unusual currents are typically evoked during the repolar-ization phase of action potentials. We show that the T790A mutation greatly enhances DRG neuron excitability by reducing current threshold and increasing firing frequency. Interestingly, the mutation endows DRG neurons with multiple early afterdepolarizations and leads to substantial prolongation of action potential duration. In DRG neurons, siRNA knockdown of sodium channel β4 subunits fails to significantly alter T790A current density but reduces TTX-resistant resurgent currents by 56%. Furthermore, DRG neurons expressing T790A channels exhibited reduced excitability with fewer early afterdepolarizations and narrower action potentials after β4 knockdown. Together, our data demonstrate that open-channel block of TTX-resistant currents, enhanced by gain-of-function mutations in Nav1.8, can make major contributions to the hyperexcitability of nociceptive neurons, likely leading to altered sensory phenotypes including neuropathic pain in SFN.

Original languageEnglish (US)
Pages (from-to)1539-1550
Number of pages12
JournalJournal of Neuroscience
Volume39
Issue number8
DOIs
StatePublished - Feb 20 2019

Keywords

  • Beta subunit
  • Hyperexcitability
  • Pain
  • Resurgent
  • Sodium channel

ASJC Scopus subject areas

  • Neuroscience(all)

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