The Role of Lumbar Splanchnic Innervations in Visceral Nociception and Pain

项目概要/摘要 慢性内脏痛是肠易激综合征（IBS）患者的主要症状， 占美国人口的15%。有效和可靠的治疗干预仍然不可用，尽管 内脏疼痛带来的巨大经济负担。治疗内脏疼痛的药物既影响外周神经， 和中枢神经系统（PNS，CNS），由于相似的离子通道/调节剂组成，和CNS相关 副作用通常超过止痛效果。内脏疼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Sherrington定义为引发疼痛和有害反应。有毒 皮肤刺激（例如，切割、挤压、烧灼）在应用于中空内脏时不可靠地具有伤害性 器官，而机械内脏器官扩张（拉伸/张力）是“充分的”伤害性感受。此外 先前的研究揭示了盆神经（PN）传入在编码结直肠扩张中的作用， 我们首次揭示，在结肠直肠超敏反应的延长中， 腰内脏神经（LSN）的传入神经编码结直肠扩张比以前假设的： 约40%的LSN传入编码轴向结肠直肠牵拉，其也由结肠直肠扩张产生。我们也 发现：1）结直肠区域与密集的LSN神经支配（肠系膜旁）更顺应 机械比邻近区域，和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，在神经元的活动中， 编码结直肠扩张，一种“适当的”有害刺激，引起IBS患者的内脏疼痛。 因此，本研究的目的是揭示腰椎内脏传入神经编码的机制， 在宏观和微观机械和分子水平上的结肠直肠扩张和伤害感受。三个具体目标 被提议。目的1将量化结直肠扩张的腰内脏传入神经编码， 结直肠伤害性感受在延长的结直肠超敏反应中的作用目标2将量化宏观和微观力学 的差异机械神经编码的结直肠传入末梢在腰内脏通路。目的 3将定义与不同腰内脏器官的结直肠机械敏感性相关的分子谱， 长期结肠直肠超敏反应的传入类。建议的生物力学因素的研究， 结直肠机械敏感性和超敏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机制理解， 尤其是在腰内脏神经通路中。通过这项研究，我们将建立的影响， 结直肠机械敏感性的生物力学和长期结直肠超敏性的伤害感受。这 这项工作将为确定新的生物力学和潜在的“可用药”靶点提供理论基础， IBS疼痛，同时最大限度地减少脱靶CNS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.