Differential effect of lacosamide on Nav1.7 variants from responsive and non-responsive patients with small fibre neuropathy

Julie I. R. Labau, Mark Estacion, Brian S. Tanaka, Bianca T. A. de Greef, Janneke G. J. Hoeijmakers, Margot Geerts, Monique M. Gerrits, Hubert J. M. Smeets, Catharina G. Faber, Ingemar S. J. Merkies, Giuseppe Lauria, Sulayman D. Dib-Hajj*, Stephen G. Waxman*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

15 Citations (Web of Science)

Abstract

Small fibre neuropathy is a common pain disorder, which in many cases fails to respond to treatment with existing medications. Gain-of-function mutations of voltage-gated sodium channel Na(v)1.7 underlie dorsal root ganglion neuronal hyperexcitability and pain in a subset of patients with small fibre neuropathy. Recent clinical studies have demonstrated that lacosamide, which blocks sodium channels in a use-dependent manner, attenuates pain in some patients with Na(v)1.7 mutations; however, only a subgroup of these patients responded to the drug. Here, we used voltage-clamp recordings to evaluate the effects of lacosamide on five Na(v)1.7 variants from patients who were responsive or non-responsive to treatment. We show that, at the clinically achievable concentration of 30 JIM, lacosamide acts as a potent sodium channel inhibitor of Na(v)1.7 variants carried by responsive patients, via a hyperpolarizing shift of voltage-dependence of both fast and slow inactivation and enhancement of use-dependent inhibition. By contrast, the effects of lacosamide on slow inactivation and use-dependence in Na(v)1.7 variants from non-responsive patients were less robust. Importantly, we found that lacosamide selectively enhances fast inactivation only in variants from responders. Taken together, these findings begin to unravel biophysical underpinnings that contribute to responsiveness to lacosamide in patients with small fibre neuropathy carrying select Na(v)1.7 variants.

Original languageEnglish
Pages (from-to)771-782
Number of pages12
JournalBrain
Volume143
DOIs
Publication statusPublished - Mar 2020

Keywords

  • small fibre neuropathy
  • lacosamide
  • Na(v)1.7 mutations
  • neuropathic pain
  • electrophysiology
  • VOLTAGE-GATED SODIUM
  • MOLECULAR DETERMINANTS
  • SLOW-INACTIVATION
  • NA+ CHANNELS
  • PAIN
  • MUTATION
  • BINDING
  • INHIBITION
  • EFFICACY
  • NEURONS

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