NaV1.1 inhibition can reduce visceral hypersensitivity

Juan Salvatierra, Joel Castro, Andelain Erickson, Qian Li, Joao Braz, John Gilchrist, Luke Grundy, Grigori Rychkov, Annemie Deiteren, Rana Rais, Glenn F. King, Barbara S. Slusher, Allan Basbaum, Pankaj J. Pasricha, Stuart Brierley, Frank Bosmans

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Functional bowel disorder patients can suffer from chronic abdominal pain, likely due to visceral hypersensitivity to mechanical stimuli. As there is only a limited understanding of the basis of chronic visceral hypersensitivity (CVH), drug-based management strategies are ill defined, vary considerably, and include NSAIDs, opioids, and even anticonvulsants. We previously reported that the 1.1 subtype of the voltage-gated sodium (NaV; NaV1.1) channel family regulates the excitability of sensory nerve fibers that transmit a mechanical pain message to the spinal cord. Herein, we investigated whether this channel subtype also underlies the abdominal pain that occurs with CVH. We demonstrate that NaV1.1 is functionally upregulated under CVH conditions and that inhibiting channel function reduces mechanical pain in 3 mechanistically distinct mouse models of chronic pain. In particular, we use a small molecule to show that selective NaV1.1 inhibition (a) decreases sodium currents in colon-innervating dorsal root ganglion neurons, (b) reduces colonic nociceptor mechanical responses, and (c) normalizes the enhanced visceromotor response to distension observed in 2 mouse models of irritable bowel syndrome. These results provide support for a relationship between NaV1.1 and chronic abdominal pain associated with functional bowel disorders.

LanguageEnglish
JournalJCI insight
Volume3
Issue number11
Early online date7 Jun 2018
DOIs
Publication statusPublished - 7 Jun 2018

Keywords

  • Gastroenterology
  • Ion channels
  • Neuroscience
  • Pain

Cite this

Salvatierra, Juan ; Castro, Joel ; Erickson, Andelain ; Li, Qian ; Braz, Joao ; Gilchrist, John ; Grundy, Luke ; Rychkov, Grigori ; Deiteren, Annemie ; Rais, Rana ; King, Glenn F. ; Slusher, Barbara S. ; Basbaum, Allan ; Pasricha, Pankaj J. ; Brierley, Stuart ; Bosmans, Frank. / NaV1.1 inhibition can reduce visceral hypersensitivity. In: JCI insight. 2018 ; Vol. 3, No. 11.
@article{163a0130edb54e709351d1753e60bc1e,
title = "NaV1.1 inhibition can reduce visceral hypersensitivity",
abstract = "Functional bowel disorder patients can suffer from chronic abdominal pain, likely due to visceral hypersensitivity to mechanical stimuli. As there is only a limited understanding of the basis of chronic visceral hypersensitivity (CVH), drug-based management strategies are ill defined, vary considerably, and include NSAIDs, opioids, and even anticonvulsants. We previously reported that the 1.1 subtype of the voltage-gated sodium (NaV; NaV1.1) channel family regulates the excitability of sensory nerve fibers that transmit a mechanical pain message to the spinal cord. Herein, we investigated whether this channel subtype also underlies the abdominal pain that occurs with CVH. We demonstrate that NaV1.1 is functionally upregulated under CVH conditions and that inhibiting channel function reduces mechanical pain in 3 mechanistically distinct mouse models of chronic pain. In particular, we use a small molecule to show that selective NaV1.1 inhibition (a) decreases sodium currents in colon-innervating dorsal root ganglion neurons, (b) reduces colonic nociceptor mechanical responses, and (c) normalizes the enhanced visceromotor response to distension observed in 2 mouse models of irritable bowel syndrome. These results provide support for a relationship between NaV1.1 and chronic abdominal pain associated with functional bowel disorders.",
keywords = "Gastroenterology, Ion channels, Neuroscience, Pain",
author = "Juan Salvatierra and Joel Castro and Andelain Erickson and Qian Li and Joao Braz and John Gilchrist and Luke Grundy and Grigori Rychkov and Annemie Deiteren and Rana Rais and King, {Glenn F.} and Slusher, {Barbara S.} and Allan Basbaum and Pasricha, {Pankaj J.} and Stuart Brierley and Frank Bosmans",
year = "2018",
month = "6",
day = "7",
doi = "10.1172/jci.insight.121000",
language = "English",
volume = "3",
journal = "JCI insight",
issn = "2379-3708",
number = "11",

}

Salvatierra, J, Castro, J, Erickson, A, Li, Q, Braz, J, Gilchrist, J, Grundy, L, Rychkov, G, Deiteren, A, Rais, R, King, GF, Slusher, BS, Basbaum, A, Pasricha, PJ, Brierley, S & Bosmans, F 2018, 'NaV1.1 inhibition can reduce visceral hypersensitivity', JCI insight, vol. 3, no. 11. https://doi.org/10.1172/jci.insight.121000, https://doi.org/10.1172/jci.insight.121000

NaV1.1 inhibition can reduce visceral hypersensitivity. / Salvatierra, Juan; Castro, Joel; Erickson, Andelain; Li, Qian; Braz, Joao; Gilchrist, John; Grundy, Luke; Rychkov, Grigori; Deiteren, Annemie; Rais, Rana; King, Glenn F.; Slusher, Barbara S.; Basbaum, Allan; Pasricha, Pankaj J.; Brierley, Stuart; Bosmans, Frank.

In: JCI insight, Vol. 3, No. 11, 07.06.2018.

Research output: Contribution to journalArticle

TY - JOUR

T1 - NaV1.1 inhibition can reduce visceral hypersensitivity

AU - Salvatierra, Juan

AU - Castro, Joel

AU - Erickson, Andelain

AU - Li, Qian

AU - Braz, Joao

AU - Gilchrist, John

AU - Grundy, Luke

AU - Rychkov, Grigori

AU - Deiteren, Annemie

AU - Rais, Rana

AU - King, Glenn F.

AU - Slusher, Barbara S.

AU - Basbaum, Allan

AU - Pasricha, Pankaj J.

AU - Brierley, Stuart

AU - Bosmans, Frank

PY - 2018/6/7

Y1 - 2018/6/7

N2 - Functional bowel disorder patients can suffer from chronic abdominal pain, likely due to visceral hypersensitivity to mechanical stimuli. As there is only a limited understanding of the basis of chronic visceral hypersensitivity (CVH), drug-based management strategies are ill defined, vary considerably, and include NSAIDs, opioids, and even anticonvulsants. We previously reported that the 1.1 subtype of the voltage-gated sodium (NaV; NaV1.1) channel family regulates the excitability of sensory nerve fibers that transmit a mechanical pain message to the spinal cord. Herein, we investigated whether this channel subtype also underlies the abdominal pain that occurs with CVH. We demonstrate that NaV1.1 is functionally upregulated under CVH conditions and that inhibiting channel function reduces mechanical pain in 3 mechanistically distinct mouse models of chronic pain. In particular, we use a small molecule to show that selective NaV1.1 inhibition (a) decreases sodium currents in colon-innervating dorsal root ganglion neurons, (b) reduces colonic nociceptor mechanical responses, and (c) normalizes the enhanced visceromotor response to distension observed in 2 mouse models of irritable bowel syndrome. These results provide support for a relationship between NaV1.1 and chronic abdominal pain associated with functional bowel disorders.

AB - Functional bowel disorder patients can suffer from chronic abdominal pain, likely due to visceral hypersensitivity to mechanical stimuli. As there is only a limited understanding of the basis of chronic visceral hypersensitivity (CVH), drug-based management strategies are ill defined, vary considerably, and include NSAIDs, opioids, and even anticonvulsants. We previously reported that the 1.1 subtype of the voltage-gated sodium (NaV; NaV1.1) channel family regulates the excitability of sensory nerve fibers that transmit a mechanical pain message to the spinal cord. Herein, we investigated whether this channel subtype also underlies the abdominal pain that occurs with CVH. We demonstrate that NaV1.1 is functionally upregulated under CVH conditions and that inhibiting channel function reduces mechanical pain in 3 mechanistically distinct mouse models of chronic pain. In particular, we use a small molecule to show that selective NaV1.1 inhibition (a) decreases sodium currents in colon-innervating dorsal root ganglion neurons, (b) reduces colonic nociceptor mechanical responses, and (c) normalizes the enhanced visceromotor response to distension observed in 2 mouse models of irritable bowel syndrome. These results provide support for a relationship between NaV1.1 and chronic abdominal pain associated with functional bowel disorders.

KW - Gastroenterology

KW - Ion channels

KW - Neuroscience

KW - Pain

UR - http://www.scopus.com/inward/record.url?scp=85053148370&partnerID=8YFLogxK

U2 - 10.1172/jci.insight.121000

DO - 10.1172/jci.insight.121000

M3 - Article

VL - 3

JO - JCI insight

T2 - JCI insight

JF - JCI insight

SN - 2379-3708

IS - 11

ER -