Nociceptive Afferent Topographical Innervation of the Heart and Stomach

超过5000万美国人患有慢性疼痛。其中，2500万人生活在每天的慢性疼痛中 缺乏有效和安全的非阿片类药物止痛选择。尤其是胸腔积液的新发病率 疼痛是每1000人年15.5次，与冠心病和心力衰竭高度相关。在……里面 此外，慢性腹痛的患病率约为每1000人年22.9人。很大的百分比 腹痛与胃肠道(GI)有关。然而，解剖和生理上的 外周伤害性过程的机制还没有得到很好的研究。在这项研究中，我们的目标是执行一项 两个内脏器官疼痛相关神经回路的全面解剖标测：心脏(目标1)和 胃部(目标2)。在哺乳动物中，来自这些器官的伤害性感受主要由 脊髓背根神经节(DRG)，迷走神经结状-颈静脉神经节复合体(简称： 结状神经节，见下图)。此前，鲍威尔博士的团队和程博士的团队都研究过迷走神经 心脏和胃的传入和传出以及交感传出神经及其不同 整个心房和胃的末端结构类型(分类学)。为此，我们使用了 技术组合，包括示踪剂注射、轴突分布和终末的顺行追踪 结构和显微成像。然而，对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，因为如此优雅、强大和具有挑战性 上述技术在脊柱DRG中尚未得到很好的应用。在这项研究中，我们将注入不同的示踪剂 进入背根节(左或右：心脏：C7-T5；左或右：T6-T12，胃)和迷走神经结节 感觉神经顺行标记的神经节(左或右：心和胃)。在……里面 此外，我们还将使用免疫组织化学(IHC)标记CGRP、SP和TRPV1(三种伤害性感受器 在注射示踪剂的动物中，可以特异性地识别伤害性传入神经 这些器官来自不同的来源(脊髓、迷走神经或左/右)。地形图上的神经图将是 在3D重建的心脏和胃中进行注释和展示，然后他们的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 和彼此的胃)、神经节的左侧或右侧以及性别差异。全面和 对这些器官的伤害性传入神经的地形图将大大改善 对与伤害有关的生理过程的理解。这些测绘数据也将有助于开发 针对这些器官的内脏疼痛的新的选择性介入疗法/刺激。

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.