Activation of pruritogenic TGR5, MRGPRA3, and MRGPRC11 on colon-innervating afferents induces visceral hypersensitivity

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 Bunnett, Stuart M Brierley

Research output: Contribution to journalArticleResearchpeer-review

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.
Original languageEnglish
Number of pages42
JournalJCI Insight
Volume4
Issue number18
DOIs
Publication statusPublished - 19 Sep 2019

Cite this

Castro, J., Harrington, A. M., Lieu, T., Garcia-Caraballo, S., Maddern, J., Schober, G., ... Brierley, S. M. (2019). Activation of pruritogenic TGR5, MRGPRA3, and MRGPRC11 on colon-innervating afferents induces visceral hypersensitivity. JCI Insight, 4(18). https://doi.org/10.1172/jci.insight.131712
Castro, Joel ; Harrington, Andrea M ; Lieu, TinaMarie ; Garcia-Caraballo, Sonia ; Maddern, Jessica ; Schober, Gudrun ; O’Donnell, Tracey ; Grundy, Luke ; Lumsden, Amanda L ; Miller, Paul ; Ghetti, Andre ; Steinhoff, Martin S ; Poole, Daniel P. ; Dong, Xinzhong ; Chang, Lin ; Bunnett, Nigel ; Brierley, Stuart M. / Activation of pruritogenic TGR5, MRGPRA3, and MRGPRC11 on colon-innervating afferents induces visceral hypersensitivity. In: JCI Insight. 2019 ; Vol. 4, No. 18.
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title = "Activation of pruritogenic TGR5, MRGPRA3, and MRGPRC11 on colon-innervating afferents induces visceral hypersensitivity",
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.",
author = "Joel Castro and Harrington, {Andrea M} and TinaMarie Lieu and Sonia Garcia-Caraballo and Jessica Maddern and Gudrun Schober and Tracey O’Donnell and Luke Grundy and Lumsden, {Amanda L} and Paul Miller and Andre Ghetti and Steinhoff, {Martin S} and Poole, {Daniel P.} and Xinzhong Dong and Lin Chang and Nigel Bunnett and Brierley, {Stuart M}",
year = "2019",
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Castro, J, Harrington, AM, Lieu, T, Garcia-Caraballo, S, Maddern, J, Schober, G, O’Donnell, T, Grundy, L, Lumsden, AL, Miller, P, Ghetti, A, Steinhoff, MS, Poole, DP, Dong, X, Chang, L, Bunnett, N & Brierley, SM 2019, 'Activation of pruritogenic TGR5, MRGPRA3, and MRGPRC11 on colon-innervating afferents induces visceral hypersensitivity', JCI Insight, vol. 4, no. 18. https://doi.org/10.1172/jci.insight.131712

Activation of pruritogenic TGR5, MRGPRA3, and MRGPRC11 on colon-innervating afferents induces visceral hypersensitivity. / Castro, Joel; Harrington, Andrea M; Lieu, TinaMarie; Garcia-Caraballo, Sonia; Maddern, Jessica; Schober, Gudrun; O’Donnell, Tracey; Grundy, Luke ; Lumsden, Amanda L; Miller, Paul; Ghetti, Andre; Steinhoff, Martin S; Poole, Daniel P.; Dong, Xinzhong; Chang, Lin; Bunnett, Nigel; Brierley, Stuart M.

In: JCI Insight, Vol. 4, No. 18, 19.09.2019.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Activation of pruritogenic TGR5, MRGPRA3, and MRGPRC11 on colon-innervating afferents induces visceral hypersensitivity

AU - Castro, Joel

AU - Harrington, Andrea M

AU - Lieu, TinaMarie

AU - Garcia-Caraballo, Sonia

AU - Maddern, Jessica

AU - Schober, Gudrun

AU - O’Donnell, Tracey

AU - Grundy, Luke

AU - Lumsden, Amanda L

AU - Miller, Paul

AU - Ghetti, Andre

AU - Steinhoff, Martin S

AU - Poole, Daniel P.

AU - Dong, Xinzhong

AU - Chang, Lin

AU - Bunnett, Nigel

AU - Brierley, Stuart M

PY - 2019/9/19

Y1 - 2019/9/19

N2 - 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.

AB - 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.

U2 - 10.1172/jci.insight.131712

DO - 10.1172/jci.insight.131712

M3 - Article

VL - 4

JO - JCI Insight

JF - JCI Insight

SN - 2379-3708

IS - 18

ER -