Cargando…
Multiple roles for Na(V)1.9 in the activation of visceral afferents by noxious inflammatory, mechanical, and human disease–derived stimuli
Chronic visceral pain affects millions of individuals worldwide and remains poorly understood, with current therapeutic options constrained by gastrointestinal adverse effects. Visceral pain is strongly associated with inflammation and distension of the gut. Here we report that the voltage-gated sod...
Autores principales: | , , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Lippincott Williams & Wilkins
2014
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4220011/ https://www.ncbi.nlm.nih.gov/pubmed/24972070 http://dx.doi.org/10.1016/j.pain.2014.06.015 |
_version_ | 1782342681017450496 |
---|---|
author | Hockley, James R.F. Boundouki, George Cibert-Goton, Vincent McGuire, Cian Yip, Ping K. Chan, Christopher Tranter, Michael Wood, John N. Nassar, Mohammed A. Blackshaw, L. Ashley Aziz, Qasim Michael, Gregory J. Baker, Mark D. Winchester, Wendy J. Knowles, Charles H. Bulmer, David C. |
author_facet | Hockley, James R.F. Boundouki, George Cibert-Goton, Vincent McGuire, Cian Yip, Ping K. Chan, Christopher Tranter, Michael Wood, John N. Nassar, Mohammed A. Blackshaw, L. Ashley Aziz, Qasim Michael, Gregory J. Baker, Mark D. Winchester, Wendy J. Knowles, Charles H. Bulmer, David C. |
author_sort | Hockley, James R.F. |
collection | PubMed |
description | Chronic visceral pain affects millions of individuals worldwide and remains poorly understood, with current therapeutic options constrained by gastrointestinal adverse effects. Visceral pain is strongly associated with inflammation and distension of the gut. Here we report that the voltage-gated sodium channel subtype Na(V)1.9 is expressed in half of gut-projecting rodent dorsal root ganglia sensory neurons. We show that Na(V)1.9 is required for normal mechanosensation, for direct excitation and for sensitization of mouse colonic afferents by mediators from inflammatory bowel disease tissues, and by noxious inflammatory mediators individually. Excitatory responses to ATP or PGE(2) were substantially reduced in Na(V)1.9(−/−) mice. Deletion of Na(V)1.9 substantially attenuates excitation and subsequent mechanical hypersensitivity after application of inflammatory soup (IS) (bradykinin, ATP, histamine, PGE(2), and 5HT) to visceral nociceptors located in the serosa and mesentery. Responses to mechanical stimulation of mesenteric afferents were also reduced by loss of Na(V)1.9, and there was a rightward shift in stimulus–response function to ramp colonic distension. By contrast, responses to rapid, high-intensity phasic distension of the colon are initially unaffected; however, run-down of responses to repeat phasic distension were exacerbated in Na(V)1.9(−/−) afferents. Finally colonic afferent activation by supernatants derived from inflamed human tissue was greatly reduced in Na(V)1.9(−/−) mice. These results demonstrate that Na(V)1.9 is required for persistence of responses to intense mechanical stimulation, contributes to inflammatory mechanical hypersensitivity, and is essential for activation by noxious inflammatory mediators, including those from diseased human bowel. These observations indicate that Na(V)1.9 represents a high-value target for development of visceral analgesics. |
format | Online Article Text |
id | pubmed-4220011 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Lippincott Williams & Wilkins |
record_format | MEDLINE/PubMed |
spelling | pubmed-42200112014-11-06 Multiple roles for Na(V)1.9 in the activation of visceral afferents by noxious inflammatory, mechanical, and human disease–derived stimuli Hockley, James R.F. Boundouki, George Cibert-Goton, Vincent McGuire, Cian Yip, Ping K. Chan, Christopher Tranter, Michael Wood, John N. Nassar, Mohammed A. Blackshaw, L. Ashley Aziz, Qasim Michael, Gregory J. Baker, Mark D. Winchester, Wendy J. Knowles, Charles H. Bulmer, David C. Pain Article Chronic visceral pain affects millions of individuals worldwide and remains poorly understood, with current therapeutic options constrained by gastrointestinal adverse effects. Visceral pain is strongly associated with inflammation and distension of the gut. Here we report that the voltage-gated sodium channel subtype Na(V)1.9 is expressed in half of gut-projecting rodent dorsal root ganglia sensory neurons. We show that Na(V)1.9 is required for normal mechanosensation, for direct excitation and for sensitization of mouse colonic afferents by mediators from inflammatory bowel disease tissues, and by noxious inflammatory mediators individually. Excitatory responses to ATP or PGE(2) were substantially reduced in Na(V)1.9(−/−) mice. Deletion of Na(V)1.9 substantially attenuates excitation and subsequent mechanical hypersensitivity after application of inflammatory soup (IS) (bradykinin, ATP, histamine, PGE(2), and 5HT) to visceral nociceptors located in the serosa and mesentery. Responses to mechanical stimulation of mesenteric afferents were also reduced by loss of Na(V)1.9, and there was a rightward shift in stimulus–response function to ramp colonic distension. By contrast, responses to rapid, high-intensity phasic distension of the colon are initially unaffected; however, run-down of responses to repeat phasic distension were exacerbated in Na(V)1.9(−/−) afferents. Finally colonic afferent activation by supernatants derived from inflamed human tissue was greatly reduced in Na(V)1.9(−/−) mice. These results demonstrate that Na(V)1.9 is required for persistence of responses to intense mechanical stimulation, contributes to inflammatory mechanical hypersensitivity, and is essential for activation by noxious inflammatory mediators, including those from diseased human bowel. These observations indicate that Na(V)1.9 represents a high-value target for development of visceral analgesics. Lippincott Williams & Wilkins 2014-10 /pmc/articles/PMC4220011/ /pubmed/24972070 http://dx.doi.org/10.1016/j.pain.2014.06.015 Text en Crown Copyright © 2014 Published by Elsevier B.V. on behalf of International Association for the Study of Pain. All rights reserved. https://creativecommons.org/licenses/by/3.0/This work is licensed under a Creative Commons Attribution 3.0 Unported License (https://creativecommons.org/licenses/by/3.0/) . |
spellingShingle | Article Hockley, James R.F. Boundouki, George Cibert-Goton, Vincent McGuire, Cian Yip, Ping K. Chan, Christopher Tranter, Michael Wood, John N. Nassar, Mohammed A. Blackshaw, L. Ashley Aziz, Qasim Michael, Gregory J. Baker, Mark D. Winchester, Wendy J. Knowles, Charles H. Bulmer, David C. Multiple roles for Na(V)1.9 in the activation of visceral afferents by noxious inflammatory, mechanical, and human disease–derived stimuli |
title | Multiple roles for Na(V)1.9 in the activation of visceral afferents by noxious inflammatory, mechanical, and human disease–derived stimuli |
title_full | Multiple roles for Na(V)1.9 in the activation of visceral afferents by noxious inflammatory, mechanical, and human disease–derived stimuli |
title_fullStr | Multiple roles for Na(V)1.9 in the activation of visceral afferents by noxious inflammatory, mechanical, and human disease–derived stimuli |
title_full_unstemmed | Multiple roles for Na(V)1.9 in the activation of visceral afferents by noxious inflammatory, mechanical, and human disease–derived stimuli |
title_short | Multiple roles for Na(V)1.9 in the activation of visceral afferents by noxious inflammatory, mechanical, and human disease–derived stimuli |
title_sort | multiple roles for na(v)1.9 in the activation of visceral afferents by noxious inflammatory, mechanical, and human disease–derived stimuli |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4220011/ https://www.ncbi.nlm.nih.gov/pubmed/24972070 http://dx.doi.org/10.1016/j.pain.2014.06.015 |
work_keys_str_mv | AT hockleyjamesrf multiplerolesfornav19intheactivationofvisceralafferentsbynoxiousinflammatorymechanicalandhumandiseasederivedstimuli AT boundoukigeorge multiplerolesfornav19intheactivationofvisceralafferentsbynoxiousinflammatorymechanicalandhumandiseasederivedstimuli AT cibertgotonvincent multiplerolesfornav19intheactivationofvisceralafferentsbynoxiousinflammatorymechanicalandhumandiseasederivedstimuli AT mcguirecian multiplerolesfornav19intheactivationofvisceralafferentsbynoxiousinflammatorymechanicalandhumandiseasederivedstimuli AT yippingk multiplerolesfornav19intheactivationofvisceralafferentsbynoxiousinflammatorymechanicalandhumandiseasederivedstimuli AT chanchristopher multiplerolesfornav19intheactivationofvisceralafferentsbynoxiousinflammatorymechanicalandhumandiseasederivedstimuli AT trantermichael multiplerolesfornav19intheactivationofvisceralafferentsbynoxiousinflammatorymechanicalandhumandiseasederivedstimuli AT woodjohnn multiplerolesfornav19intheactivationofvisceralafferentsbynoxiousinflammatorymechanicalandhumandiseasederivedstimuli AT nassarmohammeda multiplerolesfornav19intheactivationofvisceralafferentsbynoxiousinflammatorymechanicalandhumandiseasederivedstimuli AT blackshawlashley multiplerolesfornav19intheactivationofvisceralafferentsbynoxiousinflammatorymechanicalandhumandiseasederivedstimuli AT azizqasim multiplerolesfornav19intheactivationofvisceralafferentsbynoxiousinflammatorymechanicalandhumandiseasederivedstimuli AT michaelgregoryj multiplerolesfornav19intheactivationofvisceralafferentsbynoxiousinflammatorymechanicalandhumandiseasederivedstimuli AT bakermarkd multiplerolesfornav19intheactivationofvisceralafferentsbynoxiousinflammatorymechanicalandhumandiseasederivedstimuli AT winchesterwendyj multiplerolesfornav19intheactivationofvisceralafferentsbynoxiousinflammatorymechanicalandhumandiseasederivedstimuli AT knowlescharlesh multiplerolesfornav19intheactivationofvisceralafferentsbynoxiousinflammatorymechanicalandhumandiseasederivedstimuli AT bulmerdavidc multiplerolesfornav19intheactivationofvisceralafferentsbynoxiousinflammatorymechanicalandhumandiseasederivedstimuli |