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NaV1.1 inhibition can reduce visceral hypersensitivity
Juan Salvatierra, … , Stuart M. Brierley, Frank Bosmans
Juan Salvatierra, … , Stuart M. Brierley, Frank Bosmans
Published June 7, 2018
Citation Information: JCI Insight. 2018;3(11):e121000. https://doi.org/10.1172/jci.insight.121000.
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Research Article Gastroenterology Neuroscience

NaV1.1 inhibition can reduce visceral hypersensitivity

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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.

Authors

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 S. Slusher, Allan Basbaum, Pankaj J. Pasricha, Stuart M. Brierley, Frank Bosmans

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Figure 1

Pharmacological blockade of NaV1.1 is antinociceptive.

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Pharmacological blockade of NaV1.1 is antinociceptive.
Systemic administ...
Systemic administration of Compound B (comp B; 60 mg/kg) has no effect on baseline mechanical thresholds of naive mice (baseline, 0.760 ± 0.03 g, vs. Compound B, 0.836 ± 0.105 g, 2-way ANOVA, P = 0.501, n = 7). Three days after spared nerve injury (SNI), mice exhibit mechanical hypersensitivity (~57%) ipsilateral to the injury (baseline, 0.760 ± 0.03 g, vs. SNI, 0.330 ± 0.034 g, 2-way ANOVA, P = 0.0001). A systemic injection of a single dose of Compound B (i.p., 60 mg/kg) significantly reduces mechanical hypersensitivity 30 minutes (i.p., 60 mg/kg; 0.515 ± 0.072 g, 2-way ANOVA, P = 0.039, n = 7), but not 15 minutes after injection. Contralateral mechanical thresholds were unaffected by the compound (0.703 ± 0.051 g). One month after SNI, mice still exhibited mechanical hypersensitivity ipsilateral to the injury. Again, a single dose of Compound B (i.p., 60 mg/kg) significantly reduced mechanical hypersensitivity (60 minutes; SNI baseline, 0.277 ± 0.031 g, vs. Compound B, 0.530 ± 0.061 g, 2-way ANOVA, P = 0.003, n = 7). Data are presented as mean ± SEM with *P ≤ 0.05 and **P ≤ 0.005.

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