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Activation of pruritogenic TGR5, MrgprA3, and MrgprC11 on colon-innervating afferents induces visceral hypersensitivity
Joel Castro, … , Nigel W. Bunnett, Stuart M. Brierley
Joel Castro, … , Nigel W. Bunnett, Stuart M. Brierley
Published September 19, 2019
Citation Information: JCI Insight. 2019;4(20):e131712. https://doi.org/10.1172/jci.insight.131712.
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Research Article Gastroenterology Neuroscience

Activation of pruritogenic TGR5, MrgprA3, and MrgprC11 on colon-innervating afferents induces visceral hypersensitivity

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Abstract

Itch induces scratching that removes irritants from the skin, whereas pain initiates withdrawal or avoidance of tissue damage. While 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 GPCRs Mrgpra3 and Mrgprc11. Agonists of these receptors activated subsets of colonic sensory neurons and evoked colonic afferent mechanical hypersensitivity via a TRPA1-dependent mechanism. In vivo intracolonic administration of individual TGR5, MrgprA3, or MrgprC11 agonists induced pronounced visceral hypersensitivity to colorectal distension. Coadministration of these agonists as an “itch cocktail” augmented hypersensitivity to colorectal distension and changed mouse behavior. 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.

Authors

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

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Figure 5

In vivo intracolonic administration of the TGR5 agonist CCDC enhances colorectal distension–induced signaling within the dorsal horn of the spinal cord.

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In vivo intracolonic administration of the TGR5 agonist CCDC enhances co...
(A) Colorectal distension (CRD) at a pressure of 40 mmHg in healthy mice results in activation of dorsal horn (DH) neurons within the thoracolumbar (T10-L1) spinal cord, as indicated by phospho–MAP-kinase-ERK-1/2 immunoreactivity (pERK-IR, yellow arrows). pERK-IR neurons within the thoracolumbar DH, activated in response to 40 mmHg CRD, were predominantly located in laminae I–IV. (B) Group data showing that mice pretreated with intracolonic CCDC (100 μM) displayed significantly more pERK-IR DH neurons within the thoracolumbar spinal cord following 40 mmHg CRD compared with 40 mmHg CRD alone (*P < 0.05; dots indicate individual counts in spinal cord sections from CRD mice [N = 7] vs. CCDC + CRD mice [N = 7]). (C and D) Similarly, intracolonic pretreatment with CCDC in mice overexpressing TGR5 (Tgr5-Tg) increased the number of pERK-IR–activated neurons following 40 mmHg CRD, compared with 40 mmHg CRD alone (*P < 0.05; Tgr5-Tg CRD mice [N = 4] vs. Tgr5-Tg CCDC + CRD mice [N = 4]). (E and F) In contrast, intracolonic pretreatment with CCDC in Tgr5–/– mice did not result in an increase in pERK-IR–activated neurons following 40 mmHg CRD, compared with 40 mmHg CRD alone (P > 0.05, Tgr5–/– CRD mice [N = 4] vs.Tgr5–/– CCDC + CRD mice [N = 4]). (G and H) Trpa1–/– mice administered an intracolonic pretreatment with CCDC did not display increased numbers of pERK-IR neurons following 40 mmHg CRD, compared with 40 mmHg CRD alone (P > 0.05, CRD mice [N = 4] vs. CCDC + CRD mice [N = 4]). Data presented are mean ± SEM. P values determined by unpaired t tests (B, D, F, and H). Dots represent data from individual sections of spinal cord from N = 4–7 mice. Scale bars: 100μm (A, C, E, and G).

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