Vagal nociceptive pathway mediating pain from the esophagus

介导食道疼痛的迷走神经伤害感受通路

基本信息

批准号：
10132315
负责人：
Thomas Edward Taylor-Clark
金额：
$ 18.69万
依托单位：
UNIVERSITY OF SOUTH FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-25 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10132315
关键词：
Acids Address Adult Afferent Pathways Agonist Anatomy Area Brain Stem C Fiber Capsaicin Cells Central Nervous System Agents Chronic Clozapine Conscious Data Detection Direct Costs Embryo Esophageal mucous membrane Esophagus Esthesia Exposure to Facial Expression Fiber Ganglia Gastroesophageal reflux disease Goals Heartburn Human Infusion procedures Knowledge Label Location Lung Mechanics Mechanoreceptors Mediating Mucous Membrane Mus Nerve Neural Crest Neurons Neuropeptide Gene Nociception Nociceptors Nodose Ganglion Office Visits Oxides Pain Pain management Pathway interactions Patients Perception Peripheral Peripheral Nerves Preparation Property Proton Pump Inhibitors Purinoceptor Rattus Reporter Resistance Resort Role Sensory Spinal Stimulus Symptoms TAC1 gene TRPV1 gene Time United States Vagus nerve structure Validation Viscera Visceral Visceral pain adeno-associated viral vector afferent nerve base designer receptors exclusively activated by designer drugs effective therapy genetic approach innovation irritation nerve supply novel novel strategies novel therapeutic intervention pain sensation patient population receptor recombinase response selective expression therapeutic target vector

项目摘要

Heartburn is the main symptom of gastroesophageal reflux disease (GERD) which accounts for > 5.5 million office visits/year and its burden is >$9 billion/year in the United States. While in a majority of GERD patients, acid suppression is an effective therapy for this pain, in fully 20-30% of patients’ heartburn is not relieved; these people often resort to centrally acting drugs for relief. Our long-term goal is to fill a major gap in the understanding of the afferent pathways mediating heartburn to enable novel strategies to relieve acid suppression-resistant pain. We will address our novel hypothesis that heartburn is mediated by a relatively unstudied nociceptor subtype, namely the vagal jugular afferent C-fibers. Our hypothesis is based on two premises: Firstly, there are two distinguishable but overlapping types of painful esophageal sensations in humans: the heartburn, which is reliably evoked by esophageal acid infusion, and esophageal pain (more similar to other types of visceral pain), which is reliably evoked by esophageal distention. Simultaneously, there are two subtypes of of esophageal C- fiber nociceptors (vagal jugular and spinal DRG) with afferent properties that favor preferential detection of acid (vagal jugular nociceptors innervating the mucosa) and mechanical distention (distention-sensitive DRG nociceptors). In Aim 1 (discovery of novel target) we will determine which vagal afferent nerve subtype(s) has peripheral nerve terminals in the esophageal mucosa such that it is likely to be exposed to luminal acid, is activated by acid, and has central terminals in the brainstem areas implicated in perceptions of visceral noxious stimuli. Vagal esophageal afferent nerves can be divided into 4 major subtypes: P2X2+/TRPV1- nodose mechanoreceptors, P2X2+/TRPV1+ nodose C-fibers acid-, Tac1+/TRPV1+ jugular nociceptors, and poorly characterized capsaicin-insensitive jugular fibers Tac1+/TRPV1-. We have developed innovative approaches to selectively express reporters in these subtypes including TRPV1-Flp crossed with P2X2-Cre or Tac1-Cre to obtained mice in which nodose or jugular subtypes can be selectively targeted by appropriate dual Flp-/Cre- sensitive AAV-vectors. In Aim 2 (validation of novel target) we will begin to evaluate the role of selective activation of only vagal jugular C-fibers (Tac1+/TRPV1+ subtype) in initiating painful sensations from the esophagus in the mouse and rat by selectively expressing the DREADD receptor hM3Dq in esophageal jugular C-fiber (Tac1+/TRPV1+) neurons and evaluating the pain-induced responses to systemic administration of hM3Dq agonist clozapine N -oxide (CNO).

胃灼热是胃食管反射疾病（GERD）的主要症状，占550万在美国，办公室访问/年及其烧伤> 90亿美元。在大多数GERD患者中，抑制酸是治疗这种疼痛的有效疗法，在20-30％的患者的胃灼热中没有缓解；这些人们经常诉诸于中央表演药物以缓解。我们的长期目标是填补理解的重大空白介导心灼热的传入途径，以实现新的策略来挽救抗酸抑制作用疼痛。我们将解决我们的新颖假设，即胃灼热是由一个相对未研究的伤害感受器介导的亚型，即迷走神经传入C纤维。我们的假设基于两个前提：首先，有人类中两种独特但重叠的痛苦的食管感觉：胃灼热，就是食管酸输注和食管疼痛（与其他类型的内脏疼痛更相似）可靠地引起食管扩张可靠地唤起。同时，有两个亚型的食管C- 具有传入特性的纤维伤害感受器（迷走神经和脊柱DRG）优先检测酸（神经化粘膜的迷走神经伤害感受器）和机械距离（扩张敏感的DRG 伤害感受器）。在AIM 1（发现新目标）中，我们将确定哪种迷走神经亚型具有食道粘膜中的外周神经末端，使其可能暴露于腔内，被酸激活，并在内脏有害的感知中实施的脑干地区中央终端刺激。迷走性食管传入神经可以分为4个主要亚型：p2x2+/trpv1- nodose 机械感受器，p2x2+/trpv1+ nodose c纤维酸 - tac1+/trpv1+颈伤害者，较差表征辣椒素不敏感的颈纤维纤维Tac1+/trpv1-。我们已经开发了创新的方法在这些亚型中有选择地表达记者，包括与p2x2-cre或tac1-cre交叉的TRPV1-FLP 可以通过适当的双FLP/CRE-选择淋巴结或颈亚型的小鼠。敏感的AAV向量。在AIM 2（新目标的验证）中，我们将开始评估选择性激活的作用仅迷走神经C纤维（TAC1+/TRPV1+亚型），从而引发了食管中痛苦的感觉小鼠和大鼠通过在食管颈C纤维中选择性地表达Dreadd接收器HM3DQ （TAC1+/TRPV1+）神经元并评估疼痛引起的对HM3DQ的全身施用的反应激动剂氯氮平N-氧化物（CNO）。