Activation of pruritogenic TGR5, MrgprA3, and MrgprC11 on colon-innervating afferents induces visceral hypersensitivity
| Autor: | Joel Castro, Paul Miller, Tracey A. O'Donnell, Lin Chang, Xinzhong Dong, Daniel P. Poole, Gudrun Schober, Nigel W. Bunnett, Andrea Ghetti, Jessica Maddern, Andrea M. Harrington, Stuart M. Brierley, Amanda L. Lumsden, Tina Marie Lieu, Sonia Garcia-Caraballo, Luke Grundy, Martin Steinhoff |
|---|---|
| Přispěvatelé: | 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 W, Brierley, Stuart M |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Male Nociception Pharmacology Receptors G-Protein-Coupled Irritable Bowel Syndrome Mice 0302 clinical medicine Itch sensation Ganglia Spinal Medicine Mrgpra3 gene Intestinal Mucosa Receptor Irritable bowel syndrome Gastroenterology General Medicine Middle Aged G protein-coupled bile acid receptor Healthy Volunteers 3. Good health sensory receptor cells G-protein coupled receptors 030220 oncology & carcinogenesis Ion channels Female Research Article Adult mice G-protein-coupled receptor Adolescent Sensory Receptor Cells Colon Pain Sensory system Dermatitis Atopic 03 medical and health sciences Young Adult chronic visceral hypersensitivity In vivo Animals Humans G protein-coupled receptor business.industry animal model Pruritus Scratching medicine.disease Abdominal Pain Disease Models Animal 030104 developmental biology Trinitrobenzenesulfonic Acid Mrgprc11 gene Intestinal Disorder business Neuroscience |
| Zdroj: | JCI Insight |
| ISSN: | 2379-3708 |
| Popis: | 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. TGR5, MrgprA3, and MrgprC11, receptors normally associated with pruritis, are expressed by colonic afferents and, when activated, induce visceral hypersensitivity relevant to irritable bowel syndrome. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|