Please use this identifier to cite or link to this item:
https://hdl.handle.net/2440/122479
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Type: | Journal article |
Title: | Activation of pruritogenic TGR5, MRGPRA3, and MRGPRC11 on colon-innervating afferents induces visceral hypersensitivity |
Author: | Castro, J. Harrington, A.M. Lieu, T. Garcia Caraballo, S. Maddern, J. Schober, G. O'Donnell, T. Grundy, L. Lumsden, A.L. Miller, P.E. Ghetti, A. Steinhoff, M.S. Poole, D.P. Dong, X. Chang, L. Bunnett, N.W. Brierley, S.M. |
Citation: | JCI Insight, 2019; 4(20):e131712-1-e131712-24 |
Publisher: | AMER SOC CLINICAL INVESTIGATION INC |
Issue Date: | 2019 |
ISSN: | 2379-3708 2379-3708 |
Statement of Responsibility: | Joel Castro, Andrea M. Harrington, TinaMarie Lieu, Sonia Garcia-Caraballo, Jessica Maddern, Gudrun Schober, Tracey O, Donnell, Luke Grundy, Amanda L. Lumsden, Paul Miller, Andre Ghetti, Martin S. Steinhoff, Daniel P. Poole, Xinzhong Dong, Lin Chang, Nigel W. Bunnett, Stuart M. Brierley |
Abstract: | Itch induces scratching that removes irritants from the skin, whereas pain initiates withdrawal or avoidance of tissue damage. Whilst pain arises from both the skin and viscera, we investigated whether pruritogenic irritant mechanisms also function within visceral pathways. We show that subsets of colon-innervating sensory neurons in mice express, either individually or in combination, the pruritogenic receptors Tgr5 and the Mas-gene-related G protein-coupled receptors, Mrgpra3 and Mrgpra11. Agonists of these receptors activated subsets of colonic sensory neurons and evoked colonic afferent mechanical hypersensitivity via a TRPA1-dependent mechanism. In vivo intra-colonic administration of individual TGR5, MRGPRA3, or MRGPRC11 agonists induced pronounced visceral hypersensitivity to colorectal distension. Co-administration of these agonists as an 'itch cocktail' augmented hypersensitivity to colorectal distension and changed mouse behaviour. These irritant mechanisms were maintained and enhanced in a model of chronic visceral hypersensitivity relevant to irritable bowel syndrome. Neurons from human dorsal root ganglia also expressed TGR5 as well as the human ortholog MRGPRX1 and showed increased responsiveness to pruritogenic agonists in pathological states. These data support the existence of an irritant-sensing system in the colon that is a visceral representation of the itch pathways found in skin, thereby contributing to sensory disturbances accompanying common intestinal disorders. |
Keywords: | Intestinal Mucosa Colon Ganglia, Spinal Animals Humans Mice Irritable Bowel Syndrome Disease Models, Animal Abdominal Pain Trinitrobenzenesulfonic Acid Receptors, G-Protein-Coupled Adolescent Adult Middle Aged Female Male Sensory Receptor Cells Young Adult Nociception Healthy Volunteers |
Rights: | © 2019, Castro et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License. |
DOI: | 10.1172/jci.insight.131712 |
Grant ID: | http://purl.org/au-research/grants/nhmrc/1083480 http://purl.org/au-research/grants/nhmrc/1126378 http://purl.org/au-research/grants/arc/DE130100223 |
Published version: | http://dx.doi.org/10.1172/jci.insight.131712 |
Appears in Collections: | Aurora harvest 4 Medicine publications |
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hdl_122479.pdf | Published version | 36.14 MB | Adobe PDF | View/Open |
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