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 2500 万每天都患有慢性疼痛。 缺乏有效且安全的非阿片类药物治疗疼痛的选择，特别是胸部疼痛的新发病率。 疼痛为每1000人年15.5次，与冠心病、心力衰竭高度相关。 此外，腹部慢性疼痛的患病率约为每1000人年22.​​9%。 腹痛与胃肠道（GI）有关，但与解剖学和生理学有关。 外周伤害感受过程的机制尚未得到充分研究，在这项研究中，我们的目标是进行一项研究。 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（目标 1）和 哺乳动物这些器官的伤害感受主要由胃部的感觉神经元介导。 脊髓背根神经节 (DRG) 以及较小程度的迷走神经结节-颈静脉神经节复合体（简称： 结节神经节，见下图）此前，Powley 博士团队和 Cheng 博士团队曾研究过迷走神经。 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 整个心房和胃的末端结构类型（分类）为此，我们使用了一个。 技术的组合，包括示踪剂注射、轴突分布的顺行追踪和末端 然而，特定伤害性神经拓扑的研究。 心脏和胃的神经支配尚未得到充分研究，因为这种优雅、强大且具有挑战性 上述技术尚未在脊柱 DRG 中得到很好的应用。在本研究中，我们将注射不同的示踪剂。 进入 DRG（左或右：C7-T5 代表心脏；左或右：T6-T12 代表胃）和迷走神经结 神经节（左或右：心脏和胃）用于顺行标记感觉神经支配。 此外，我们还将使用 CGRP、SP 和 TRPV1（三种伤害性感受器）的免疫组织化学 (IHC) 标记 神经标记）在注射示踪剂的动物中，将特异性识别伤害性传入神经支配 这些器官来自不同的起源（脊髓、迷走神经或左/右侧）。地形神经支配图将是。 在 3D 重建的心脏和胃中进行注释和呈现，然后是这些的 3D 支架 我们还将评估器官特异性（区分心脏的伤害性神经支配）。 和胃彼此），神经节的左侧或右侧，以及性别差异。 这些器官的伤害性传入神经支配的地形图将大大改善 了解与伤害感受相关的生理过程也将有助于发展。 针对这些器官内脏疼痛的新选择性介入疗法/刺激。