Nociceptive Afferent Topographical Innervation of the Heart and Stomach

心脏和胃的伤害性传入地形神经支配

• 批准号: 10021470
• 负责人: ZIXI Jack CHENG
• 金额: $ 45.97万
• 依托单位: UNIVERSITY OF CENTRAL FLORIDA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-19 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10021470
• 关键词: 3-Dimensional; Abdomen; Abdominal Pain; Afferent Neurons; American; Anatomy; Animals; Atlases; Axon; Cardiac; Celiac ganglion; Cell Nucleus; Chest; Chest Pain; Complex; Coronary heart disease; Data; Development; Female; Future; Ganglia; Gastrointestinal tract structure; Heart; Heart Atrium; Heart failure; Incidence; Individual; Injections; Label; Left; Location; Mammals; Maps; Mediating; Molecular; Motor; Nerve; Nociception; Nodose Ganglion; Organ; Organ Specificity; Pain; Pain Measurement; Pain management; Peripheral; Persons; Physiological; Physiological Processes; Presynaptic Terminals; Prevalence; Process; Rattus; Resources; Sex Differences; Side; Spinal; Spinal Ganglia; Stomach; Structure; TRPV1 gene; Taxonomy; Techniques; Therapeutic Intervention; Tracer; Visceral; Visceral pain; Work; afferent nerve; chronic abdominal pain; chronic pain; heart innervation; improved; male; microscopic imaging; nerve supply; neural circuit; non-opioid analgesic; receptive field; reconstruction; scaffold; sex

More than 50 million Americans suffer from chronic pain. Of those, 25 million live with daily chronic pain and lack effective and safe non-opioid options for pain management. In particular, the new incidence of chest pain is 15.5 per 1000 person-years, which is highly related to coronary heart disease and heart failure. In addition, the prevalence of chronic abdominal pain is around 22.9 per 1,000 person-years. A large percentage of abdominal pain is related to the gastrointestinal tract (GI). However, the anatomical and physiological mechanisms of peripheral nociceptive processes have not been well studied. In this study, we aim to perform a comprehensive anatomical mapping of pain-related neural circuitry in two visceral organs: heart (Aim 1) and stomach (Aim 2). Nociception, from these organs in mammals, is mainly mediated by sensory neurons in the spinal dorsal root ganglia (DRG) and to a lesser extent in the vagal nodose-jugular ganglion complex (for short: nodose ganglion, seen below). Previously, Dr. Powley’s group and Dr. Cheng’s group have studied vagal afferent and efferent as well as sympathetic efferent innervations of the heart and stomach, and their different types of terminal structures (taxonomy) in whole mounts of atria and the stomach. To do so, we used a combination of techniques, including tracer injections, anterograde tracing of axon distributions and terminal structures, and microscopic imaging. However, the study of specific nociceptive nerve topographical innervation in the heart and stomach is not well studied because such elegant, powerful, and challenging techniques above have not yet been well applied in the spinal DRG. In this study, we will inject different tracers into the DRG (left or right: C7-T5 for Heart; left or right: T6-T12 for Stomach) and into the vagal nodose ganglia (left or right: for both Heart and Stomach) for anterograde labeling of sensory nerve innervation. In addition, we will also use immunohistochemical (IHC) labeling of CGRP, SP, and TRPV1 (the three nociceptive nerve markers) in tracer-injected animals that will specifically identify the nociceptive afferent innervation of these organs from distinct origins (spinal, vagal, or left/right side). The topographical innervation map will be annotated and presented in the 3D reconstructed heart and stomach, and then their 3D scaffolds of these organs (Aim 3). We will also assess for organ specificity (nociceptive innervation that distinguishes the heart and stomach from each other), left or right sidedness of ganglia, and sex differences. Comprehensive and topographical mapping of nociceptive afferent innervation of these organs will substantially improve the understanding of physiological processes in relation to nociception. This mapping data will also aid to develop new selective interventional therapies/stimulations for visceral pain of these organs.

超过5000万美国人患有慢性疼痛。其中，有2500万人每天都有慢性疼痛 并且缺乏疼痛管理的有效和安全的非阿片类药物选择。特别是新事件的胸部事件 疼痛为每1000人年15.5人，这与冠心病和心力衰竭高度相关。 此外，慢性腹痛的患病率约为每1000人年22.​​9。很大的比例 腹痛与胃肠道（GI）有关。但是，解剖学和生理 周围伤害性过程的机制尚未得到很好的研究。在这项研究中，我们旨在执行 两个内脏器官中与疼痛相关的神经回路的全面解剖图：心脏（AIM 1）和 胃（目标2）。来自哺乳动物的这些器官的伤害吸引力主要是由感觉神经元介导的 脊柱背根神经节（DRG）和迷走神经结节 - 朱古牙神经节复合物的程度较小（简而言之： nodose神经节，下面看到）。以前，Powley博士的小组和Cheng博士的小组有Studiod迷走神经 传入，有效的，以及心脏和胃的同情有效神经，它们的不同 终端结构（分类法）的类型（分类法）和船尾的整个山脉。为此，我们使用了 技术的组合，包括示踪剂注射，轴突分布和终端的顺行示踪 结构和微观成像。但是，对特定伤害性神经地形的研究 在心脏和胃中的神经无法很好地研究，因为如此优雅，强大和挑战 上面的技术尚未在脊柱DRG中得到很好的应用。在这项研究中，我们将注入不同的示踪剂 进入DRG（左或右：心脏的C7-T5；左或右：胃T6-T12）并进入迷走神经淋巴结 神经节（左或右：对心脏和胃）进行感觉神经神经的顺行标记。在 此外，我们还将使用CGRP，SP和TRPV1的免疫组织化学（IHC）标记（三个伤害感受器 神经标记）在注射示踪剂的动物中，这些动物将明确识别伤害性传入的神经支配 这些器官来自不同的起源（脊柱，迷走神经或左/右侧）。地形神经图将是 在3D重建的心脏和摊位中注释并呈现，然后是它们的3D脚手架 器官（目标3）。我们还将评估器官特异性（伤害性神经支配，区分心脏 彼此失望），神经节的左或右侧以及性别差异。全面和 这些器官的伤害感受传入神经神经的地形映射将显着改善 了解与伤害感受有关的物理过程。这些映射数据也将有助于开发 这些器官内脏疼痛的新的选择性介入疗法/刺激。