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: 10263240
• 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 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10263240
• 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2500万人每天都有慢性疼痛 缺乏有效和安全的非阿片类药物治疗疼痛的选择。特别是，胸部新发病率 疼痛为15.5/1000人-年，与冠心病和心力衰竭高度相关。在 此外，慢性腹痛的患病率约为每1 000人年22.9例。很大比例 腹痛与胃肠道（GI）有关。然而，解剖学和生理学 外周伤害感受过程的机制尚未得到很好的研究。在这项研究中，我们的目标是执行一个 在两个内脏器官中与疼痛相关的神经回路的全面解剖映射：心脏（目标1）和 胃（目标2）。来自哺乳动物这些器官的伤害感受主要由皮层中的感觉神经元介导。 脊髓背根神经节（DRG）和迷走神经结-颈静脉神经节复合体（简称： 结状神经节，见下文）。此前，Powley博士的小组和Cheng博士的小组研究了迷走神经 心脏和胃的传入和传出以及交感传出神经支配，以及它们的不同 心房和胃的整个安装中的终端结构类型（分类学）。为此，我们使用了 结合技术，包括示踪剂注射，轴突分布的顺行追踪和终端 结构和显微成像。然而，特定伤害性神经地形图的研究 心脏和胃的神经支配没有得到很好的研究，因为这种优雅，强大，具有挑战性的 上述技术尚未很好地应用于脊柱DRG。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：胃的T6-T12）并进入迷走神经结 神经节（左侧或右侧：心脏和胃），用于感觉神经支配的顺行标记。在 此外，我们还将使用CGRP，SP和TRPV 1（三种伤害性感受因子）的免疫组织化学（IHC）标记， 神经标记物），这将特异性地识别 这些器官来自不同的起源（脊髓、迷走神经或左/右侧）。地形神经分布图将 注释并在3D重建的心脏和胃中呈现，然后它们的3D支架 器官（目标3）。我们还将评估器官特异性（区分心脏的伤害性神经支配 和胃），神经节的左侧或右侧，以及性别差异。全面和 这些器官的伤害性传入神经支配的地形图将显著改善 了解与伤害感受有关的生理过程。这些地图数据也将有助于开发 新的选择性介入治疗/刺激这些器官的内脏疼痛。