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Nav1.1 inhibition can reduce visceral hypersensitivity

Juan Salvatierra, Joel Castro, Andelain Erickson, Qian Li, João Braz, John Gilchrist, Luke Grundy, Grigori Y Rychkov, Annemie Deiteren, Rana Rais, et al.
(2018) JCI INSIGHT. 3(11).
Author
Organization
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 (Na-v; Na-v 1.1) 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 Na-v 1.1 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 Na-v 1.1 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 Na-v 1.1 and chronic abdominal pain associated with functional bowel disorders.
Keywords
IRRITABLE-BOWEL-SYNDROME, COLONIC HYPERSENSITIVITY, FUNCTIONAL-DISORDERS, ABDOMINAL-PAIN, CHANNELS, EPILEPSY, MOUSE, MECHANISMS, SYMPTOMS, NA(V)1.9

Citation

Please use this url to cite or link to this publication:

MLA
Salvatierra, Juan, et al. “Nav1.1 Inhibition Can Reduce Visceral Hypersensitivity.” JCI INSIGHT, vol. 3, no. 11, 2018, doi:10.1172/jci.insight.121000.
APA
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
Chicago author-date
Salvatierra, Juan, Joel Castro, Andelain Erickson, Qian Li, João Braz, John Gilchrist, Luke Grundy, et al. 2018. “Nav1.1 Inhibition Can Reduce Visceral Hypersensitivity.” JCI INSIGHT 3 (11). https://doi.org/10.1172/jci.insight.121000.
Chicago author-date (all authors)
Salvatierra, Juan, Joel Castro, Andelain Erickson, Qian Li, João 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, and Frank Bosmans. 2018. “Nav1.1 Inhibition Can Reduce Visceral Hypersensitivity.” JCI INSIGHT 3 (11). doi:10.1172/jci.insight.121000.
Vancouver
1.
Salvatierra J, Castro J, Erickson A, Li Q, Braz J, Gilchrist J, et al. Nav1.1 inhibition can reduce visceral hypersensitivity. JCI INSIGHT. 2018;3(11).
IEEE
[1]
J. Salvatierra et al., “Nav1.1 inhibition can reduce visceral hypersensitivity,” JCI INSIGHT, vol. 3, no. 11, 2018.
@article{8584496,
  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 (Na-v; Na-v 1.1) 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 Na-v 1.1 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 Na-v 1.1 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 Na-v 1.1 and chronic abdominal pain associated with functional bowel disorders.}},
  articleno    = {{e121000}},
  author       = {{Salvatierra, Juan and Castro, Joel and Erickson, Andelain and Li, Qian and Braz, João and Gilchrist, John and Grundy, Luke and Rychkov, Grigori Y and Deiteren, Annemie and Rais, Rana and King, Glenn F and Slusher, Barbara S and Basbaum, Allan and Pasricha, Pankaj J and Brierley, Stuart M and Bosmans, Frank}},
  issn         = {{2379-3708}},
  journal      = {{JCI INSIGHT}},
  keywords     = {{IRRITABLE-BOWEL-SYNDROME,COLONIC HYPERSENSITIVITY,FUNCTIONAL-DISORDERS,ABDOMINAL-PAIN,CHANNELS,EPILEPSY,MOUSE,MECHANISMS,SYMPTOMS,NA(V)1.9}},
  language     = {{eng}},
  number       = {{11}},
  pages        = {{13}},
  title        = {{Nav1.1 inhibition can reduce visceral hypersensitivity}},
  url          = {{http://dx.doi.org/10.1172/jci.insight.121000}},
  volume       = {{3}},
  year         = {{2018}},
}
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