Peripheral Neural Mechanisms of Itch

在之前的资助期间，我们发现局部皮内应用牛皮针可以诱导 由非组胺能机制引起的瘙痒。无髓鞘(C-纤维)和 外周神经的有髓(A-纤维)传入显示组胺和母牛的激活不同 外周通路。对于C纤维，机械不敏感传入(MIA)可被组胺激活，但不能 而机械敏感伤害性传入(MSA)对这两种传入都有反应，但 对同居的反应要大得多。类似地，组胺而不是母牛激活A纤维 MIA，而A纤维MSA对母牛血清和/或组胺有反应。再一次，对母牛捕杀的回应 明显大于对组胺的反应。这些发现表明，瘙痒的感觉 可以通过多个传入通路进行调节。拟议的电生理实验将 有助于确定这些不同类别的传入在传递不同感觉方面的相对作用 与瘙痒刺激有关。具体地说，我们建议：1)确定是否有瘙痒和/或 通过研究A和C纤维对MIA的反应，存在伤害性选择性类别的MIA 瘙痒和痛性刺激。2)研究瘙痒缓解的一种潜在的外周机制 或通过应用热刺激来止痒。我们将确定这种刺激的应用是否会导致 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对同种饲料的反应明显疲劳。3)调查 一种新型的痛觉和痛觉小径传入神经的化学敏感性差异 应用技术，即项目1中显示的热灭活的母牛针叶，用于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药，如半胱氨酸 蛋白酶。我们推测，不同群体的小的有髓和无髓MSA介导了 由这些刺激产生的瘙痒和疼痛的感觉。这些研究的结果将加强我们的 了解引起瘙痒和疼痛感觉的外周神经装置。 相关性(请参阅说明)： 抵抗治疗的瘙痒是一个主要的临床问题，例如用抗组胺药物治疗。建议数 研究将增加我们对瘙痒感觉是如何在大脑的神经纤维中传递的理解 皮肤。这些研究的结果可能会潜在地导致制定更好的战略 治疗瘙痒。

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.