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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 (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 3.11 (2018): n. pag. Print.
APA
Salvatierra, J., Castro, J., Erickson, A., Li, Q., Braz, J., Gilchrist, J., Grundy, L., et al. (2018). Nav1.1 inhibition can reduce visceral hypersensitivity. JCI INSIGHT, 3(11).
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).
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).
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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