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: 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
• 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

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).

胃灼热是胃食管反流病 (GERD) 的主要症状，胃食管反流病患者人数超过 550 万 每年办公室访问次数，其负担在美国每年超过 90 亿美元。虽然在大多数 GERD 患者中， 抑酸是治疗这种疼痛的有效疗法，足有20-30%的患者胃灼热未缓解；这些 人们经常求助于中枢作用药物来缓解症状。我们的长期目标是填补理解上的重大空白 调节胃灼热的传入途径，以实现缓解酸抑制抵抗的新策略 疼痛。我们将提出我们的新假设，即胃灼热是由相对未经研究的伤害感受器介导的 亚型，即迷走神经颈静脉传入 C 纤维。我们的假设基于两个前提：首先，有 人类食管疼痛的两种可区分但重叠的类型：胃灼热，这是 由食管酸输注可靠引起，以及食管疼痛（更类似于其他类型的内脏疼痛）， 这是由食管扩张可靠引起的。同时，食管癌有两种亚型： 纤维伤害感受器（迷走神经颈静脉和脊髓 DRG）具有有利于优先检测酸的传入特性 （支配粘膜的迷走颈静脉伤害感受器）和机械扩张（扩张敏感的 DRG） 伤害感受器）。在目标 1（发现新目标）中，我们将确定哪种迷走传入神经亚型具有 食管粘膜的周围神经末梢很可能暴露于鲁米那酸， 被酸激活，并在脑干区域有中央终端，与内脏有害物质的感知有关 刺激。迷走食管传入神经可分为 4 个主要亚型： P2X2+/TRPV1- 结节型 机械感受器、P2X2+/TRPV1+ 结节 C 纤维酸、Tac1+/TRPV1+ 颈静脉伤害感受器，并且较差 表征了对辣椒素不敏感的颈静脉纤维 Tac1+/TRPV1-。我们开发了创新方法 选择性表达这些亚型中的报告基因，包括与 P2X2-Cre 或 Tac1-Cre 杂交的 TRPV1-Flp 获得的小鼠，其中结节或颈静脉亚型可以通过适当的双 Flp-/Cre- 选择性靶向 敏感的 AAV 载体。在目标 2（新目标的验证）中，我们将开始评估选择性激活的作用 仅迷走神经颈静脉 C 纤维（Tac1+/TRPV1+ 亚型）在引发食道疼痛感时 小鼠和大鼠通过在食管颈静脉 C 纤维中选择性表达 DREADD 受体 hM3Dq (Tac1+/TRPV1+) 神经元并评估全身给予 hM3Dq 引起的疼痛反应 激动剂氯氮平 N-氧化物 (CNO)。