The Role of Lumbar Splanchnic Innervations in Visceral Nociception and Pain

腰椎内脏神经支配在内脏伤害感受和疼痛中的作用

• 批准号: 10163182
• 负责人: Bin Feng
• 金额: $ 39.72万
• 依托单位: UNIVERSITY OF CONNECTICUT STORRS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10163182
• 关键词: Action Potentials; Adverse effects; Affect; Afferent Neurons; Analgesics; Axon; Biological Assay; Biomechanics; Cells; Cellular biology; Chronic; Clinical; Collagen; Collagen Fiber; Colon; Colorectal; Complement; Cre-LoxP; Cutaneous; Data; Distal; Drug Targeting; Economic Burden; Electrophysiology (science); Elements; Fiber; Gastrointestinal Diseases; Gene Expression; Generations; Goals; Harvest; Histology; Hypersensitivity; Image; Individual; Intracolonic; Ion Channel; Irritable Bowel Syndrome; Label; Measures; Mechanics; Mesentery; Modeling; Molecular; Molecular Biology; Molecular Profiling; Multimodal Imaging; Mus; Nerve; Nerve Endings; Neuraxis; Nociception; Nociceptive Stimulus; Optics; Organ; Pain; Pathway interactions; Patients; Pelvis; Peripheral; Persons; Pharmaceutical Preparations; Population; Reaction; Rectum; Research; Research Personnel; Risk; Rodent; Role; Sensory Nerve Endings; Spinal Ganglia; Splanchnic Nerves; Stimulus; Stretching; Structure; Submucosa; Symptoms; Tamoxifen; Testing; Therapeutic Intervention; Time; Tissues; Visceral; Visceral pain; Weight-Bearing state; Work; Zymosan; afferent nerve; colorectal distension; cost; mechanical properties; mechanotransduction; mouse model; nerve supply; neuronal cell body; neurophysiology; novel; relating to nervous system; response; second harmonic; side effect; simulation; soft tissue; transcriptome

Project Summary/Abstract Chronic visceral pain is the cardinal symptom of patients with irritable bowel syndrome (IBS) affecting up to 15% of the U.S. population. Efficacious and reliable therapeutic intervention is still unavailable despite the tremendous economic burden imposed by visceral pain. Drugs to treat visceral pain impact both the peripheral and central nervous systems (PNS, CNS) due to similar ion channel/modulator composition, and CNS-related side effects usually outweigh analgesic benefits. Visceral pain differs significantly from other types of pain in the `adequacy' of nociceptive stimuli, defined first by Sherrington as triggering painful and noxious reactions. Noxious cutaneous stimuli (e.g., cutting, pinching, burning) are not reliably nociceptive when applied to hollow visceral organs, whereas mechanical visceral organ distension (stretch/tension) is `adequately' nociceptive. In addition to previous studies that reveal the role of pelvic nerve (PN) afferents in encoding colorectal distension and contributing to prolonged colorectal hypersensitivity, we reveal, for the first time, a more significant participation of afferents in the lumbar splanchnic nerves (LSN) in encoding colorectal distension than previously assumed: ~40% of LSN afferents encode axial colorectal stretch, which is also produced by colorectal distension. We also found that: 1) the colorectal region with dense LSN innervation (next to the mesentery) is more compliant mechanically than the adjacent region, and 2) the colorectal submucosa has a rich network of load-bearing collagen fibers. Our new neural and mechanical data suggest an underappreciated role for LSN afferents in encoding colorectal distension, an `adequate,' noxious stimulus that evokes visceral pain in IBS patients. Accordingly, the objective of this proposal is to reveal lumbar splanchnic afferent neural encoding of colorectal distension and nociception at macro- and micro-mechanical, and molecular levels. Three specific aims are proposed. Aim 1 will quantify lumbar splanchnic afferent neural encoding of colorectal distension and colorectal nociception in prolonged colorectal hypersensitivity. Aim 2 will quantify macro- and micro-mechanics of differential mechanical neural encoding of colorectal afferent endings in the lumbar splanchnic pathway. Aim 3 will define the molecular profiles relevant to colorectal mechanosensitivity of different lumbar splanchnic afferent classes in prolonged colorectal hypersensitivity. The proposed study of the biomechanical factors in colorectal mechanosensitivity and hypersensitivity will complement existing neurophysiological approaches to synergistically advance our mechanistic understanding of colorectal afferent neural encoding and nociception, especially in the lumbar splanchnic pathway. Through this proposed research, we will establish the influence of biomechanics in colorectal mechanosensitivity and nociception in prolonged colorectal hypersensitivity. This work will provide a rationale to identify novel biomechanical and potential `drugable' targets for managing chronic IBS pain while minimizing off-target CNS effects.

项目概要/摘要 慢性内脏疼痛是肠易激综合征（IBS）患者的主要症状，影响最多 占美国人口的 15%。尽管目前仍缺乏有效、可靠的治疗干预措施 内脏疼痛造成巨大的经济负担。治疗内脏疼痛的药物会影响外周神经 和中枢神经系统（PNS、CNS）由于相似的离子通道/调节剂成分，以及 CNS 相关 副作用通常超过镇痛效果。内脏痛与其他类型的疼痛有很大不同 伤害性刺激的“充分性”，首先由谢林顿定义为引发痛苦和有害的反应。有毒的 当应用于中空内脏时，皮肤刺激（例如，切割、捏、烧）并不可靠地产生伤害性 器官，而机械性内脏器官扩张（拉伸/张力）是“充分”伤害性的。此外 先前的研究揭示了盆腔神经（PN）传入在编码结直肠扩张和 导致长期结直肠过敏的原因是，我们首次揭示了更重要的参与 编码结直肠扩张的腰内脏神经 (LSN) 传入神经数量比之前假设的要多： 约 40% 的 LSN 传入编码轴向结直肠拉伸，这也是由结直肠扩张产生的。我们也 发现：1）具有密集 LSN 神经支配的结直肠区域（靠近肠系膜）更顺应 机械强度高于邻近区域，2）结直肠粘膜下层具有丰富的承重网络 胶原纤维。我们新的神经和机械数据表明，LSN 传入神经的作用被低估了 编码结直肠扩张，这是一种“足够的”有害刺激，会引起 IBS 患者的内脏疼痛。 因此，该提案的目的是揭示腰内脏传入神经编码 宏观和微观机械以及分子水平上的结直肠扩张和伤害感受。三个具体目标 被提议。目标 1 将量化结直肠扩张的腰椎内脏传入神经编码和 长期结直肠超敏反应中的结直肠伤害感受。目标 2 将量化宏观和微观力学 腰内脏通路中结直肠传入末梢的差异机械神经编码的研究。目的 图3将定义与不同腰内脏的结直肠机械敏感性相关的分子谱 长期结直肠过敏的传入类别。生物力学因素的拟议研究 结直肠机械敏感性和超敏感性将补充现有的神经生理学方法 协同推进我们对结直肠传入神经编码和伤害感受的机制理解， 尤其是在腰椎内脏通路中。通过这项拟议的研究，我们将确定 结直肠机械敏感性的生物力学和长期结直肠超敏反应的伤害感受。这 这项工作将为确定新的生物力学和潜在的“可药物”目标来管理慢性病提供依据。 IBS 疼痛，同时最大限度地减少脱靶中枢神经系统的影响。