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

• 批准号: 9976825
• 负责人: Thomas Edward Taylor-Clark
• 金额: $ 22.43万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-25 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9976825
• 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 therapeutics; pain sensation; patient population; receptor; recombinase; response; selective expression; therapeutic target; vector

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).

烧心是胃食道反流病(GERD)的主要症状，占550万 办公室访问量/年，它在美国的负担是90亿美元/年。而在大多数GERD患者中， 抑酸是治疗这种疼痛的有效疗法，足足有20%-30%的患者的胃灼热没有缓解；这些 人们经常求助于集中作用的药物来缓解症状。我们的长期目标是填补认识上的一个重大空白 介导胃灼热的传入通路使缓解酸抑制抵抗的新策略成为可能 疼痛。我们将阐述我们的新假设，即胃灼热是由一种相对未被研究过的伤害性感受器介导的。 亚型，即迷走神经传入C纤维。我们的假设基于两个前提：第一，有 人类有两种可区分但重叠的食道痛感：烧心，这是 可靠地由食管酸注入引起，以及食道疼痛(更类似于其他类型的内脏疼痛)， 它是由食道扩张可靠地引起的。同时，有两种亚型的食道C- 纤维伤害性感受器(迷走神经颈静脉和脊髓背根神经节)，其传入特性有利于优先检测酸 (迷走颈静脉伤害性感受器支配粘膜)和机械扩张(对扩张敏感的背根节) 痛觉感受器)。在目标1(新靶点的发现)中，我们将确定迷走神经传入神经的哪一亚型(S 周围神经末梢在食道粘膜中，使其很可能暴露于鲁米酸，是 被酸激活，在脑干区有中央终末，与内脏有害物质的感觉有关 刺激物。迷走神经可分为4个主要亚型：P2X2+/TRPV1-结节 机械感受器，P2X2+/TRPV1+结状C纤维酸性，Tac1+/TRPV1+颈静脉伤害性感受器 表征了辣椒素不敏感的颈静脉纤维TAC1+/TRPV1-。我们开发了创新的方法来 在这些亚型中选择性地表达报告，包括TRPV1-FLP与P2X2-Cre或Tac1-Cre杂交以 获得结节或颈静脉亚型可被适当的双重FLP-/Cre-选择性靶向的小鼠 敏感的AAV载体。在目标2(新靶点的确认)中，我们将开始评估选择性激活的作用 只有迷走神经C纤维(Tac1+/TRPV1+亚型)在食道引起痛感中起作用 食道颈静脉C纤维选择性表达DREADD受体hM3Dq (Tac1+/TRPV1+)神经元及全身应用hM3Dq对疼痛反应的评估 激动剂氯氮平N-氧化物(CNO)。