Identification of Arginine-Vasopressin Receptor 1a (Avpr1a/Avpr1a) as a Novel Candidate Gene for Chronic Visceral Pain Sheds Light on the Potential Role of Enteric Neurons in the Development of Visceral Hypersensitivity.

Autor:	Kader L; Department of Anesthesiology, Pain, and Perioperative Medicine, KU Medical Center, Kansas City, Kansas; Neuroscience Graduate Program, KU Medical Center, Kansas City, Kansas., Willits AB; Department of Anesthesiology, Pain, and Perioperative Medicine, KU Medical Center, Kansas City, Kansas; Neuroscience Graduate Program, KU Medical Center, Kansas City, Kansas., Meriano S; Department of Anesthesiology, Pain, and Perioperative Medicine, KU Medical Center, Kansas City, Kansas; Department of Cell Biology and Physiology, KU Medical Center, Kansas City, Kansas., Christianson JA; Department of Cell Biology and Physiology, KU Medical Center, Kansas City, Kansas., La JH; Department of Neurobiology, University of University of Texas Medical Branch, Galveston, Texas., Feng B; Biomedical Engineering Department, University of Connecticut, Storrs, Connecticut., Knight B; Department of Neuroscience, University of Connecticut Health Center, Farmington, Connecticut., Kosova G; Division of Statistical Genetics,TenSixteen Bio, Suffolk, Massachusetts., Deberry JJ; Department of Anesthesiology & Perioperative Medicine, University of Alabama at Birmingham, Birmingham, Alabama., Coates MD; Department of Medicine, Division of Gastroenterology & Hepatology, Penn State College of Medicine, Hershey, Pennsylvania., Hyams JS; Department of Gastroenterology, Connecticut Children's Medical Center, Hartford, Connecticut., Baumbauer KM; Department of Anesthesiology, Pain, and Perioperative Medicine, KU Medical Center, Kansas City, Kansas; Department of Cell Biology and Physiology, KU Medical Center, Kansas City, Kansas., Young EE; Department of Anesthesiology, Pain, and Perioperative Medicine, KU Medical Center, Kansas City, Kansas; Neuroscience Graduate Program, KU Medical Center, Kansas City, Kansas; Department of Cell Biology and Physiology, KU Medical Center, Kansas City, Kansas. Electronic address: eyoung6@kumc.edu.
Jazyk:	angličtina
Zdroj:	The journal of pain [J Pain] 2024 Sep; Vol. 25 (9), pp. 104572. Date of Electronic Publication: 2024 May 18.
DOI:	10.1016/j.jpain.2024.104572
Abstrakt:	Chronic abdominal pain in the absence of ongoing disease is the hallmark of disorders of gut-brain interaction (DGBIs), including irritable bowel syndrome (IBS). While the etiology of DGBIs remains poorly understood, there is evidence that both genetic and environmental factors play a role. In this study, we report the identification and validation of arginine-vasopressin receptor 1A (Avpr1a) as a novel candidate gene for visceral hypersensitivity (VH), a primary peripheral mechanism underlying abdominal pain in DGBI/IBS. Comparing 2 C57BL/6 (BL/6) substrains (C57BL/6NTac and C57BL/6J) revealed differential susceptibility to the development of chronic VH following intrarectal zymosan instillation, a validated preclinical model for postinflammatory IBS. Using whole-genome sequencing, we identified a single-nucleotide polymorphism differentiating the 2 strains in the 5' intergenic region upstream of Avpr1a, encoding the protein Avpr1a. We used behavioral, histological, and molecular approaches to identify distal colon-specific gene expression and neuronal hyperresponsiveness covarying with Avpr1a genotype and VH susceptibility. While the 2 BL/6 substrains did not differ across other gastrointestinal phenotypes (eg, fecal water retention), VH-susceptible BL/6NTac mice had higher colonic Avpr1a mRNA and protein expression. These results parallel findings that patients' colonic Avpr1a mRNA expression corresponded to higher pain ratings. Moreover, neurons of the enteric nervous system were hyperresponsive to the Avpr1a agonist arginine-vasopressin, suggesting a role for enteric neurons in the pathology underlying VH. Taken together, these findings implicate differential regulation of Avpr1a as a novel mechanism of VH susceptibility as well as a potential therapeutic target specific to VH. PERSPECTIVE: This article presents evidence of Avpr1a as a novel candidate gene for VH in a mouse model of IBS. Avpr1a genotype and/or tissue-specific expression represents a potential biomarker for chronic abdominal pain susceptibility. (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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