Two independent mouse lines carrying the Na(v)1.7 I228M gain-of-function variant display dorsal root ganglion neuron hyperexcitability but a minimal pain phenotype

L.B. Chen, N.K. Wimalasena, J. Shim, C.Y. Han, S.I. Lee, R. Gonzalez-Cano, M. Estacion, C.G. Faber, G. Lauria, S.D. Dib-Hajj, C.J. Woolf, S.G. Waxman*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

Small-fiber neuropathy (SFN), characterized by distal unmyelinated or thinly myelinated fiber loss, produces a combination of sensory dysfunction and neuropathic pain. Gain-of-function variants in the sodium channel Na(v)1.7 that produce dorsal root ganglion (DRG) neuron hyperexcitability are present in 5% to 10% of patients with idiopathic painful SFN. We created 2 independent knock-in mouse lines carrying the Na(v)1.7 I228M gain-of-function variant, found in idiopathic SFN. Whole-cell patch-clamp and multielectrode array recordings show that Na(v)1.7 I228M knock-in DRG neurons are hyperexcitable compared with wild-type littermate-control neurons, but despite this, Na(v)1.7 I228M mice do not display mechanical or thermal hyperalgesia or intraepidermal nerve fiber loss in vivo. Therefore, although these 2 Na(v)1.7 I228M knock-in mouse lines recapitulate the DRG neuron hyperexcitability associated with gain-of-function mutations in Na(v)1.7, they do not recapitulate the pain or neuropathy phenotypes seen in patients. We suggest that the relationship between hyperexcitability in sensory neurons and the pain experienced by these patients may be more complex than previously appreciated and highlights the challenges in modelling channelopathy pain disorders in mice.
Original languageEnglish
Pages (from-to)1758-1770
Number of pages13
JournalPain
Volume162
Issue number6
DOIs
Publication statusPublished - 1 Jun 2021

Keywords

  • Na(v)1
  • 7
  • I228M
  • Small-fiber neuropathy
  • 7 I228M knock-in mouse
  • Targeted homologous recombination
  • CRISPR
  • Hyperexcitability
  • IENF
  • Neuropathy
  • Pain
  • SMALL FIBER NEUROPATHY
  • SODIUM-CHANNELS
  • DIAGNOSTIC-CRITERIA

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