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JCI Insight. 2018 Jun 7;3(11). pii: 121000. doi: 10.1172/jci.insight.121000. [Epub ahead of print]

NaV1.1 inhibition can reduce visceral hypersensitivity.

Author information

1
Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
2
Visceral Pain Research Group, Human Physiology, Centre for Neuroscience, College of Medicine and Public Health, Flinders University, Australia.
3
Centre for Nutrition and Gastrointestinal Diseases, Discipline of Medicine, University of Adelaide, South Australian Health and Medical Research Institute, Adelaide, Australia.
4
Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
5
Department of Anatomy, UCSF, California, USA.
6
Johns Hopkins Drug Discovery and Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
7
Institute for Molecular Bioscience, the University of Queensland, Brisbane, Australia.
8
Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

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.

KEYWORDS:

Gastroenterology; Ion channels; Neuroscience; Pain

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