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 King, Barbara Slusher, Allan Basbaum, Pankaj Pasricha, Stuart Brierley, Frank Bosmans

Research output: Contribution to journalArticle

13 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.

Original languageEnglish
Article numbere121000
Number of pages13
JournalJCI insight
Volume3
Issue number11
DOIs
Publication statusPublished - 2018

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    Salvatierra, J., Castro, J., Erickson, A., Li, Q., Braz, J., Gilchrist, J., Grundy, L., Rychkov, G., Deiteren, A., Rais, R., King, G., Slusher, B., Basbaum, A., Pasricha, P., Brierley, S., & Bosmans, F. (2018). NaV1.1 inhibition can reduce visceral hypersensitivity. JCI insight, 3(11), [e121000]. https://doi.org/10.1172/jci.insight.121000