Voltage-gated sodium channels regulating action potential generation in itch-, nociceptive-, and low-threshold mechanosensitive cutaneous C-fibers

Danica Jurcakova, Fei Ru, Marian Kollarik, Hui Sun, Jeffrey Krajewski, Bradley J Undem

Research output: Contribution to journalArticle

Abstract

We evaluated the effect of voltage-gated sodium channel 1 (NaV1) blockers in three nonoverlapping C-fiber subtypes in the mouse skin: chloroquine (CQ)-sensitive C-fibers with high mechanical thresholds—itch C-fibers; second, CQ-insensitive, capsaicin-sensitive C-fibers with high mechanical thresholds—nociceptors; and CQ and capsaicin-insensitive C-fibers with a very low mechanical threshold—C-LTMs. NaV1-blocking drugs were applied to the nerve terminal receptive fields using an innervated isolated dorsal mouse skin-nerve preparation where the drugs are delivered into the skin intra-arterially. We combined these studies with an analysis of the mRNA expression of the a-subunits of NaV1 in individual dorsal root ganglia neurons labeled from the same region of the skin. Our results show that virtually all nociceptors and itch C-fibers expressed the tetrodotoxin (TTX)-resistant channels NaV1.8 and NaV1.9. However, TTX applied selectively into the skin abolished the action potential firing in response to mechanical stimulation in 75% of the itch C-fibers, 100% of the nociceptors, and 100% of C-LTMs. NaV1.7 was the most commonly expressed TTX-sensitive NaV1 in all three C-fiber subtypes innervating the dorsal skin. Selectively blocking NaV1.7 abolished responses in about 40% of itch C-fibers, 65% of nociceptors, but only 20% of C-LTMs. Blocking NaV1.8 alone had no affect on the firing sensitivity of the C-fibers. However, in itch and nociceptive C-fibers where the activation was not inhibited with a NaV1.7 blocker, adding the NaV1.8 blocker silenced action potential discharge.

Original languageEnglish (US)
Pages (from-to)1047-1056
Number of pages10
JournalMolecular Pharmacology
Volume94
Issue number3
StatePublished - Sep 1 2018

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Voltage-Gated Sodium Channels
Unmyelinated Nerve Fibers
Action Potentials
Skin
Nociceptors
Tetrodotoxin
Chloroquine
Capsaicin
Drug Compounding
Spinal Ganglia

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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Voltage-gated sodium channels regulating action potential generation in itch-, nociceptive-, and low-threshold mechanosensitive cutaneous C-fibers. / Jurcakova, Danica; Ru, Fei; Kollarik, Marian; Sun, Hui; Krajewski, Jeffrey; Undem, Bradley J.

In: Molecular Pharmacology, Vol. 94, No. 3, 01.09.2018, p. 1047-1056.

Research output: Contribution to journalArticle

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abstract = "We evaluated the effect of voltage-gated sodium channel 1 (NaV1) blockers in three nonoverlapping C-fiber subtypes in the mouse skin: chloroquine (CQ)-sensitive C-fibers with high mechanical thresholds—itch C-fibers; second, CQ-insensitive, capsaicin-sensitive C-fibers with high mechanical thresholds—nociceptors; and CQ and capsaicin-insensitive C-fibers with a very low mechanical threshold—C-LTMs. NaV1-blocking drugs were applied to the nerve terminal receptive fields using an innervated isolated dorsal mouse skin-nerve preparation where the drugs are delivered into the skin intra-arterially. We combined these studies with an analysis of the mRNA expression of the a-subunits of NaV1 in individual dorsal root ganglia neurons labeled from the same region of the skin. Our results show that virtually all nociceptors and itch C-fibers expressed the tetrodotoxin (TTX)-resistant channels NaV1.8 and NaV1.9. However, TTX applied selectively into the skin abolished the action potential firing in response to mechanical stimulation in 75{\%} of the itch C-fibers, 100{\%} of the nociceptors, and 100{\%} of C-LTMs. NaV1.7 was the most commonly expressed TTX-sensitive NaV1 in all three C-fiber subtypes innervating the dorsal skin. Selectively blocking NaV1.7 abolished responses in about 40{\%} of itch C-fibers, 65{\%} of nociceptors, but only 20{\%} of C-LTMs. Blocking NaV1.8 alone had no affect on the firing sensitivity of the C-fibers. However, in itch and nociceptive C-fibers where the activation was not inhibited with a NaV1.7 blocker, adding the NaV1.8 blocker silenced action potential discharge.",
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