Show simple item record

dc.contributor.authorHockley, James
dc.contributor.authorBoundouki, George
dc.contributor.authorCibert-Goton, Vincent
dc.contributor.authorMcGuire, Cian
dc.contributor.authorYip, Ping K
dc.contributor.authorChan, Christopher
dc.contributor.authorTranter, Michael
dc.contributor.authorWood, John N
dc.contributor.authorNassar, Mohammed A
dc.contributor.authorBlackshaw, L Ashley
dc.contributor.authorAziz, Qasim
dc.contributor.authorMichael, Gregory J
dc.contributor.authorBaker, Mark D
dc.contributor.authorWinchester, Wendy J
dc.contributor.authorKnowles, Charles H
dc.contributor.authorBulmer, David
dc.date.accessioned2018-09-11T17:32:02Z
dc.date.available2018-09-11T17:32:02Z
dc.date.issued2014-10
dc.identifier.issn0304-3959
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/280190
dc.description.abstractChronic 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 NaV1.9 is expressed in half of gut-projecting rodent dorsal root ganglia sensory neurons. We show that NaV1.9 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 PGE2 were substantially reduced in NaV1.9(-/-) mice. Deletion of NaV1.9 substantially attenuates excitation and subsequent mechanical hypersensitivity after application of inflammatory soup (IS) (bradykinin, ATP, histamine, PGE2, and 5HT) to visceral nociceptors located in the serosa and mesentery. Responses to mechanical stimulation of mesenteric afferents were also reduced by loss of NaV1.9, 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 NaV1.9(-/-) afferents. Finally colonic afferent activation by supernatants derived from inflamed human tissue was greatly reduced in NaV1.9(-/-) mice. These results demonstrate that NaV1.9 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 NaV1.9 represents a high-value target for development of visceral analgesics.
dc.format.mediumPrint-Electronic
dc.languageeng
dc.publisherOvid Technologies (Wolters Kluwer Health)
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectColon
dc.subjectGanglia, Spinal
dc.subjectVisceral Afferents
dc.subjectAnimals
dc.subjectMice, Knockout
dc.subjectHumans
dc.subjectMice
dc.subjectInflammatory Bowel Diseases
dc.subjectHyperalgesia
dc.subjectInflammation
dc.subjectDinoprostone
dc.subjectAdenosine Triphosphate
dc.subjectPhysical Stimulation
dc.subjectAction Potentials
dc.subjectAdolescent
dc.subjectAdult
dc.subjectAged
dc.subjectMiddle Aged
dc.subjectFemale
dc.subjectMale
dc.subjectYoung Adult
dc.subjectNAV1.9 Voltage-Gated Sodium Channel
dc.titleMultiple roles for NaV1.9 in the activation of visceral afferents by noxious inflammatory, mechanical, and human disease-derived stimuli.
dc.typeArticle
prism.endingPage1975
prism.issueIdentifier10
prism.publicationDate2014
prism.publicationNamePain
prism.startingPage1962
prism.volume155
dc.identifier.doi10.17863/CAM.27557
dcterms.dateAccepted2014-06-19
rioxxterms.versionofrecord10.1016/j.pain.2014.06.015
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2014-10
dc.contributor.orcidHockley, James [0000-0002-9578-6071]
dc.contributor.orcidBulmer, David [0000-0002-4703-7877]
dc.identifier.eissn1872-6623
rioxxterms.typeJournal Article/Review


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record

Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International