NaV1.1 inhibition can reduce visceral hypersensitivity

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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
JournalJCI insight
Volume3
Issue number11
DOIs
StatePublished - Jun 7 2018

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Chronic Pain
Abdominal Pain
Hypersensitivity
NAV1.1 Voltage-Gated Sodium Channel
Drug Hypersensitivity
Pain
Nociceptors
Irritable Bowel Syndrome
Spinal Ganglia
Non-Steroidal Anti-Inflammatory Agents
Nerve Fibers
Anticonvulsants
Opioid Analgesics
Spinal Cord
Colon
Sodium
Neurons
Inhibition (Psychology)

Keywords

  • Gastroenterology
  • Ion channels
  • Neuroscience
  • Pain

Cite this

Salvatierra, J., Castro, J., Erickson, A., Li, Q., Braz, J., Gilchrist, J., ... Bosmans, F. (2018). NaV1.1 inhibition can reduce visceral hypersensitivity. JCI insight, 3(11). 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 Y.; Deiteren, Annemie; Rais, Rana; King, Glenn F.; Slusher, Barbara; Basbaum, Allan; Pasricha, Pankaj Jay; Brierley, Stuart M.; Bosmans, Frank.

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

Research output: Contribution to journalArticle

Salvatierra, J, Castro, J, Erickson, A, Li, Q, Braz, J, Gilchrist, J, Grundy, L, Rychkov, GY, Deiteren, A, Rais, R, King, GF, Slusher, B, Basbaum, A, Pasricha, PJ, Brierley, SM & Bosmans, F 2018, 'NaV1.1 inhibition can reduce visceral hypersensitivity', JCI insight, vol. 3, no. 11. https://doi.org/10.1172/jci.insight.121000
Salvatierra J, Castro J, Erickson A, Li Q, Braz J, Gilchrist J et al. NaV1.1 inhibition can reduce visceral hypersensitivity. JCI insight. 2018 Jun 7;3(11). https://doi.org/10.1172/jci.insight.121000
Salvatierra, Juan ; Castro, Joel ; Erickson, Andelain ; Li, Qian ; Braz, Joao ; Gilchrist, John ; Grundy, Luke ; Rychkov, Grigori Y. ; Deiteren, Annemie ; Rais, Rana ; King, Glenn F. ; Slusher, Barbara ; Basbaum, Allan ; Pasricha, Pankaj Jay ; Brierley, Stuart M. ; Bosmans, Frank. / NaV1.1 inhibition can reduce visceral hypersensitivity. In: JCI insight. 2018 ; Vol. 3, No. 11.
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