The Role of Lumbar Splanchnic Innervations in Visceral Nociception and Pain

项目摘要/摘要 慢性内脏疼痛是肠易激综合征(IBS)患者的主要症状，影响多达 占美国人口的15%。有效和可靠的治疗干预仍然不可用，尽管 内脏疼痛造成的巨大经济负担。治疗内脏疼痛的药物影响外周 和中枢神经系统(PNS，CNS)由于相似的离子通道/调节剂组成，以及CNS相关 副作用通常超过止痛药的益处。内脏痛与其他类型的疼痛在以下方面有显著不同 伤害性刺激的“充分性”，谢林顿首先将其定义为引发痛苦和有害的反应。有害的 皮肤刺激(例如，割伤、挤压、灼伤)在应用于中空内脏时不是可靠的伤害性刺激 而机械的内脏器官扩张(拉伸/拉伸)是“充分的”伤害性的。此外 以前的研究揭示了盆腔神经(PN)传入在编码结直肠扩张和 导致结肠直肠超敏反应的因素，我们第一次揭示了更重要的参与 腰内脏神经(LSN)中编码结直肠扩张的传入比先前假设的： 约40%的LSN传入神经编码大肠轴向牵张，这也是结直肠扩张所产生的。我们也 结果发现：1)LSN神经分布密集的结直肠区域(靠近肠系膜)更具顺应性 2)结直肠黏膜下层有丰富的承载网络 胶原纤维。我们新的神经和机械数据表明，LSN传入在 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，这项建议的目的是揭示腰椎内脏传入神经编码的 结直肠扩张和伤害性在宏观和微观机械和分子水平。三个具体目标 都被提出了。目标1将量化腰部内脏传入神经编码的结直肠扩张和 结直肠伤害性感觉与延长的结直肠超敏反应。目标2将量化宏观和微观力学 腰椎内脏通路中结直肠传入末梢的差异机械神经编码。目标 3将确定与不同腰椎内脏的结直肠机械敏感性相关的分子图谱 延迟性大肠超敏反应的传入分类。生物力学影响因素的研究进展 结直肠机械敏感性和超敏反应将补充现有的神经生理学方法 协同推进我们对大肠传入神经编码和伤害性感受的机械理解， 尤其是在腰椎内脏通路。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时间结直肠高敏感性的伤害性。这 这项工作将为确定新的生物力学和潜在的可用药靶点来管理慢性病提供理论基础 IBS疼痛，同时最大限度地减少非靶点中枢神经系统影响。

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.