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: 10418733
• 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/10418733
• 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; 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.

项目摘要/摘要 慢性内脏疼痛是肠易激综合征（IB）患者的主要症状，影响到 15％的美国人口。有效可靠的治疗干预措施仍然无法 内脏疼痛施加的巨大经济负担。治疗内脏疼痛的药物会影响周围 由于类似的离子通道/调节剂组成以及与CNS相关的中枢神经系统（PNS，CNS） 副作用通常超过镇痛益处。内脏疼痛与其他类型的疼痛明显不同 伤害性刺激的“充分性”，首先是由Sherrington定义为引发痛苦和有害的反应。有害 当应用于空心内脏时，皮肤刺激（例如切割，捏，燃烧）并不可靠地伤害感受 器官，而机械内脏器官的延伸（拉伸/张力）是“充分的”伤害感。此外 对揭示骨盆神经（PN）传入在编码结直肠扩张和的作用的研究 我们首次揭示了更重要的参与，从而有助于长期结肠直肠过敏 编码结直肠扩张的腰椎神经（LSN）中的传入量比先前假设的： 〜40％的LSN传入编码轴向结直肠伸展，这也是通过结直肠扩张产生的。我们也是 发现以下 机械地比相邻区域，2）结直肠粘膜蛋白粘膜具有丰富的负载网络 胶原纤维。我们的新神经和机械数据表明，LSN传入在 编码结直肠延伸，一种“足够”的有害刺激，引起了IBS患者内脏疼痛的刺激。 因此，该提议的目的是揭示腰部诊断传入神经编码 宏观机械和分子水平的结直肠升高和伤害感受。三个具体目标 提出了。 AIM 1将量化结直肠扩张和 长时间结直肠超敏反应的结直肠伤害感受。 AIM 2将量化宏观力学和微力学 腰界途径中结直肠传入末端的差异机械神经编码。目的 3将定义与不同腰部鼻子的结直肠机械敏感性相关的分子曲线 长期结直肠过敏的传入类别。提出的对生物力学因子的研究 结直肠机械强度和超敏反应将补充现有的神经生理方法 协同促进我们对结直肠传入神经编码和伤害感受的机械理解， 尤其是在腰部闪烁的途径中。通过这项拟议的研究，我们将建立 长时间结直肠过敏的结直肠机械效率和伤害感受的生物力学。这 工作将提供一个理由，以识别新型的生物力学和潜在的“吸毒”目标来管理慢性 IBS疼痛，同时最大程度地减少脱靶中枢神经系统效果。