Peripheral Neural Mechanisms of Itch

瘙痒的周围神经机制

• 批准号: 7762399
• 负责人: Matthias Ringkamp
• 金额: $ 29.35万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7762399
• 关键词: Abbreviations; Accounting; Action Potentials; Address; Afferent Pathways; Antihistamines; Atopic Dermatitis; Attenuated; Burn injury; C Fiber; Caliber; Capsaicin; Cathepsins; Chemicals; Cholestasis; Clinical; Cutaneous; Cysteine Protease; Development; Disease; Esthesia; Fatigue; Fiber; Funding; Goals; Grant; HIV Infections; Heating; Histamine; Hodgkin Disease; Human; Instruction; Lead; Maps; Mechanical Stimulation; Mechanics; Mediating; Monkeys; Nerve Fibers; Neurons; Nociception; Pain; Pathway interactions; Patients; Perception; Peripheral; Peripheral Nerves; Polycythemia Vera; Population; Principal Investigator; Psychophysiology; Relative (related person); Resistance; Role; Signal Transduction; Skin; Stimulus; Techniques; Testing; Unmyelinated Nerve Fibers; Uremia; attenuation; dorsal horn; heat stimulus; human subject; neuromechanism; nonhuman primate; novel; receptive field; research study; response; tool; treatment strategy

During the previous grant period, we found that topical, intradermal application of cowhage spicules induces itch by non-histaminergic mechanisms. Electrophysiological recordings from unmyelinated (C-fiber) and myelinated (A-fiber) afferents in peripheral nerves revealed that histamine and cowhage activate different peripheral pathways. For C-fibers, mechano-insensitive afferents (MIAs) were activated by histamine but not cowhage, whereas mechanosensitive nociceptive afferents (MSAs) were responsive to both, but the responses to cowhage were substantially greater. Similarly, histamine but not cowhage activated A-fiber MIAs, whereas A-fiber MSAs responded to cowhage or histamine or both. Again, the responses to cowhage were significantly greater than the responses to histamine. These findings indicate that the sensation of itch can be mediated through multiple afferent pathways. The proposed electrophysiological experiments will help to determine the relative roles of these different classes of afferents in signaling the different sensations associated with the pruritic stimuli. Specifically, we propose: 1) To determine whether pruriceptive and/or nociceptive selective classes of MIAs exist by investigating the responsiveness of A- and C-fiber MIAs to pruritic and algesic stimuli. 2) To investigate a potential peripheral mechanism for scratch induced itch relief or itch relieve by application of thermal stimuli. We will determine if application of such stimuli leads to a decrement in the response to pruritic stimuli of A-fiber and C-fiber MSAs. Preliminary results reveal significant fatigue in the responses of C-MSAs to cowhage after mechanical stimulation. 3) To investigate the differential chemosensitivity of nociceptive and pruriceptive small-diameter afferents using a novel application technique, i.e. heat-inactivated, cowhage-spicules shown in project 1 to cause itch and pain when loaded with chemicals including capsaicin, histamine and non-histaminergic pruritic agents such as cysteine proteases. We postulate that different populations of small myelinated and unmyelinated MSAs mediate the sensation of itch and pain produced by these stimuli. The results from these studies will enhance our understanding of the peripheral neuronal apparatus underlying the sensation of itch and pain. RELEVANCE (See Instructions): Itch that is resistant to treatment, for example with antihistamines, is a major clinical problem. The proposed studies will increase our understanding about how the sensation of itch is mediated in the nerve fibers of the skin. The findings of these studies may potentially lead to the development of better strategies for the treatment of itch.

在上一个资助期间，我们发现局部皮内应用牛骨针会诱导 通过非组胺能机制引起瘙痒。无髓鞘（C 纤维）和 周围神经中的有髓鞘（A 纤维）传入神经显示组胺和牛能激活不同的 外周通路。对于 C 纤维，机械不敏感传入神经 (MIA) 被组胺激活，但不被组胺激活。 牛，而机械敏感伤害性传入神经 (MSA) 对两者都有反应，但 对母牛的反应要大得多。同样，组胺激活 A 纤维，但牛不激活 MIA，而 A 纤维 MSA 对牛或组胺或两者都有反应。再次，对牛的反应 明显大于对组胺的反应。这些发现表明瘙痒感 可以通过多种传入途径介导。拟议的电生理学实验将 有助于确定这些不同类别的传入神经在发出不同感觉信号时的相对作用 与瘙痒刺激有关。具体来说，我们建议：1) 确定是否有瘙痒和/或 通过研究 A 纤维和 C 纤维 MIA 的反应性，存在伤害性选择性 MIA 类别 瘙痒和痛觉刺激。 2) 研究缓解抓挠引起的瘙痒的潜在外周机制 或通过热刺激缓解瘙痒。我们将确定应用此类刺激是否会导致 A 纤维和 C 纤维 MSA 对瘙痒刺激的反应减弱。初步结果显示 机械刺激后 C-MSA 对牛的反应显着疲劳。 3）调查 使用一种新颖的方法研究伤害性和瘙痒性小直径传入神经的化学敏感性差异 应用技术，即项目 1 中所示的热灭活牛针，在以下情况下引起瘙痒和疼痛 含有辣椒素、组胺和非组胺能瘙痒剂（例如半胱氨酸）等化学物质 蛋白酶。我们假设不同群体的小有髓鞘和无髓鞘 MSA 介导 这些刺激产生的瘙痒和疼痛的感觉。这些研究的结果将增强我们的 了解引起瘙痒和疼痛感觉的周围神经元装置。 相关性（参见说明）： 对治疗（例如抗组胺药）有抵抗力的瘙痒是一个主要的临床问题。拟议的 研究将增加我们对瘙痒感是如何在神经纤维中介导的了解。 皮肤。这些研究的结果可能会导致制定更好的策略 治疗瘙痒。