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Roles of TRPA1 and TRPV1 in cutaneous injury-induced hypersensitivity.

机译：TRPA1和TRPV1在皮肤损伤引起的超敏反应中的作用。

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摘要

Cutaneous injuries are common and painful. Additionally, incision size during surgery has been correlated with the degree of postoperative pain. Ineffective management of cutaneous pain can lead to complications including poor wound healing. Postoperative pain in human patients and in rodent models exhibits aspects of heat and mechanical hypersensitivity and spontaneous, non-evoked pain. In rodents, skin incisions induce mechanical and heat hypersensitivity similar to levels observed with deeper incisions that include damage to fascia and muscle. Therefore, cutaneous injury might drive a majority of the mechanical and heat hypersensitivity. Understanding the molecular mechanisms that underlie cutaneous injuryinduced pain may lead to topical treatment options for lacerations, puncture wounds, and postoperative pain.;Transient Receptor Potential (TRP) channels are non-specific cation channels expressed in the plasma membrane of sensory neurons that innervate peripheral tissues, including skin. The TRP Ankyrin 1 (TRPA1) and TRP Vanilloid 1 (TRPV1) channels mediate mechanical and heat hyperalgesia, respectively, in nerve injury and inflammatory models. Therefore, in my dissertation, I investigated the contribution of TRPA1 and TRPV1 in cutaneous injury-induced mechanical and heat hypersensitivity.;In my dissertation work which utilized genetic ablation and pharmacological inhibition, I show that TRPA1 does not mediate behavioral mechanical hypersensitivity with cutaneous injury. While conducting functional calcium imaging, I found that TRPA1 agonists predominantly excite a subpopulation of small-diameter dorsal root ganglia (DRG) neurons that are non-peptidergic (lack neuropeptides and bind isolectin-B4, IB4). When I conducted retrograde labeling of cutaneously-innervating afferents, most neurons excited by TRPA1 agonists were also IB4-binding. Among neurons with mixed peripheral tissue targets or among cutaneous neurons, TRPA1 is not functionally upregulated in DRG neurons after skin incision injury.;The TRPV1 channel is also high expressed in cutaneous afferent nociceptors. I explored the role of TRPV1 in cutaneous injury-induced heat hypersensitivity. The results indicate that TRPV1 mediates thermal hypersensitivity induced by skin incision in mouse. Further, TRPV1 function was increased in DRG neurons, specifically in IB4-binding neurons. Together, these findings suggest that enhanced TRPV1 function, particularly in IB4-binding neurons, underlies heat hypersensitivity following skin incision injury.;In conclusion, my dissertation work provides evidence that TRPA1 is functionally expressed in the IB4-binding subpopulation of sensory neurons, which are thought to feed into a pathway involved in emotional, affective aspects of pain. Although TRPA1 is largely expressed in cutaneous sensory neurons, TRPA1 does not mediate cutaneous injury-induced mechanical hypersensitivity. However, my dissertation work provides evidence for a role of TRPV1 in skin incision-induced pain. Ultimately, this work suggests that IB4-binding neurons may serve an important role in postoperative pain and that TRPV1 antagonists may be used to alleviate cutaneous injury pain.
机译：皮肤受伤是常见且痛苦的。另外，手术期间的切口大小与术后疼痛的程度有关。皮肤疼痛的无效管理可导致并发症，包括伤口愈合不良。人类患者和啮齿动物模型的术后疼痛表现为热和机械超敏反应以及自发性，非诱发性疼痛。在啮齿动物中，皮肤切口会引起机械和热超敏反应，类似于在更深的切口（包括对筋膜和肌肉的损伤）中观察到的水平。因此，皮肤损伤可能会导致大多数机械和热超敏反应。了解皮肤损伤引起的疼痛的分子机制可能会导致撕裂伤，穿刺伤口和术后疼痛的局部治疗选择;瞬时受体电位（TRP）通道是表达于神经末梢的感觉神经元质膜中的非特异性阳离子通道包括皮肤在内的组织。在神经损伤和炎性模型中，TRP锚蛋白1（TRPA1）和TRP香草酸1（TRPV1）通道分别介导机械痛觉过敏和热痛觉过敏。因此，在本文中，我研究了TRPA1和TRPV1在皮肤损伤引起的机械性和热性超敏反应中的作用。 。在进行功能性钙成像时，我发现TRPA1激动剂主要激发了非肽能的小直径背根神经节（DRG）神经元的亚群（缺乏神经肽并结合isolectin-B4，IB4）。当我对受神经刺激的传入神经进行逆向标记时，大多数由TRPA1激动剂激发的神经元也都具有IB4结合作用。在具有混合的外周组织靶标的神经元中或在皮肤神经元中，TRPA1在皮肤切口损伤后在DRG神经元中没有功能上调。； TRPV1通道在皮肤传入伤害感受器中也高表达。我探讨了TRPV1在皮肤损伤引起的热超敏反应中的作用。结果表明TRPV1介导小鼠皮肤切口诱导的热超敏反应。此外，DRPV神经元，特别是在IB4结合神经元中TRPV1功能增加。在一起，这些发现表明，TRPV1功能的增强，尤其是在IB4结合神经元中，是皮肤切口损伤后热超敏性的基础。；总之，我的论文工作提供了TRPA1在感觉神经元的IB4结合亚群中功能性表达的证据，这被认为可以进入涉及疼痛的情感和情感方面的途径。尽管TRPA1在皮肤感觉神经元中大量表达，但TRPA1并不介导皮肤损伤引起的机械性超敏反应。但是，我的论文工作为TRPV1在皮肤切口引起的疼痛中的作用提供了证据。最终，这项工作表明结合IB4的神经元可能在术后疼痛中起重要作用，并且TRPV1拮抗剂可用于缓解皮肤损伤疼痛。

著录项

  • 作者

    Barabas, Marie-Elizabeth A.;

  • 作者单位

    The Medical College of Wisconsin.;

  • 授予单位 The Medical College of Wisconsin.;
  • 学科 Biology Neuroscience.;Health Sciences Surgery.;Biology Cell.
  • 学位 Ph.D.
  • 年度 2014
  • 页码 152 p.
  • 总页数 152
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 高分子化学（高聚物）;
  • 关键词

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