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dc.contributor.authorHockley, James
dc.contributor.authorTranter, Michael M
dc.contributor.authorMcGuire, Cian
dc.contributor.authorBoundouki, George
dc.contributor.authorCibert-Goton, Vincent
dc.contributor.authorThaha, Mohamed A
dc.contributor.authorBlackshaw, L Ashley
dc.contributor.authorMichael, Gregory J
dc.contributor.authorBaker, Mark D
dc.contributor.authorKnowles, Charles H
dc.contributor.authorWinchester, Wendy J
dc.contributor.authorBulmer, David
dc.date.accessioned2018-10-22T06:54:26Z
dc.date.available2018-10-22T06:54:26Z
dc.date.issued2016-02-24
dc.identifier.issn1529-2401
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/284205
dc.description.abstractActivation of visceral nociceptors by inflammatory mediators contributes to visceral hypersensitivity and abdominal pain associated with many gastrointestinal disorders. Purine and pyrimidine nucleotides (e.g., ATP and UTP) are strongly implicated in this process following their release from epithelial cells during mechanical stimulation of the gut, and from immune cells during inflammation. Actions of ATP are mediated through both ionotropic P2X receptors and metabotropic P2Y receptors. P2X receptor activation causes excitation of visceral afferents; however, the impact of P2Y receptor activation on visceral afferents innervating the gut is unclear. Here we investigate the effects of stimulating P2Y receptors in isolated mouse colonic sensory neurons, and visceral nociceptor fibers in mouse and human nerve-gut preparations. Additionally, we investigate the role of Nav1.9 in mediating murine responses. The application of UTP (P2Y2 and P2Y4 agonist) sensitized colonic sensory neurons by increasing action potential firing to current injection and depolarizing the membrane potential. The application of ADP (P2Y1, P2Y12, and P2Y13 agonist) also increased action potential firing, an effect blocked by the selective P2Y1 receptor antagonist MRS2500. UTP or ADP stimulated afferents, including mouse and human visceral nociceptors, in nerve-gut preparations. P2Y1 and P2Y2 transcripts were detected in 80% and 56% of retrogradely labeled colonic neurons, respectively. Nav1.9 transcripts colocalized in 86% of P2Y1-positive and 100% of P2Y2-positive colonic neurons, consistent with reduced afferent fiber responses to UTP and ADP in Na(v)1.9(-/-) mice. These data demonstrate that P2Y receptor activation stimulates mouse and human visceral nociceptors, highlighting P2Y-dependent mechanisms in the generation of visceral pain during gastrointestinal disease.
dc.description.sponsorshipThis work was supported by The Medical Research Council (D.C.B.), a Wellcome Trust University Award (L.A.B.), Neusentis (D.C.B.), The Royal College of Surgeons of England (G.B.), The Biotechnology and Biological Sciences Research Council (J.R.F.H.), Bowel & Cancer Research (M.A.T.), Pain Relief Foundation and Crohn's in Childhood Research Association (V.C.-G.), and The Dr Hadwen Trust for Humane Research (C.M.).
dc.languageeng
dc.publisherSociety for Neuroscience
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectATP
dc.subjectNav1.9
dc.subjectP2Y receptors
dc.subjectnociceptor
dc.subjectpurinergic signaling
dc.subjectvisceral pain
dc.subjectAdolescent
dc.subjectAdult
dc.subjectAged
dc.subjectAged, 80 and over
dc.subjectAnimals
dc.subjectCells, Cultured
dc.subjectColon
dc.subjectFemale
dc.subjectGanglia, Spinal
dc.subjectHumans
dc.subjectMale
dc.subjectMice
dc.subjectMice, Inbred C57BL
dc.subjectMice, Knockout
dc.subjectMiddle Aged
dc.subjectNAV1.9 Voltage-Gated Sodium Channel
dc.subjectNociceptors
dc.subjectPurine Nucleotides
dc.subjectPyrimidine Nucleotides
dc.subjectReceptors, Purinergic P2Y
dc.subjectSpecies Specificity
dc.titleP2Y Receptors Sensitize Mouse and Human Colonic Nociceptors.
dc.typeArticle
prism.endingPage2376
prism.issueIdentifier8
prism.publicationDate2016
prism.publicationNameJournal of Neuroscience
prism.startingPage2364
prism.volume36
dc.identifier.doi10.17863/CAM.31573
dcterms.dateAccepted2015-12-30
rioxxterms.versionofrecord10.1523/JNEUROSCI.3369-15.2016
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/
rioxxterms.licenseref.startdate2016-02-24
dc.contributor.orcidHockley, James [0000-0002-9578-6071]
dc.contributor.orcidBulmer, David [0000-0002-4703-7877]
dc.identifier.eissn1529-2401
rioxxterms.typeJournal Article/Review
cam.issuedOnline2016-02-24


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