Peripheral Neural Mechanisms of Itch

在上一个资助期，我们发现，局部，皮内应用牛骨针诱导 由非组胺能机制引起的瘙痒。无髓鞘（C纤维）和 周围神经中的有髓鞘（A-纤维）传入揭示了组胺和cowhage激活不同的 外周通路对于C纤维，机械不敏感传入（MIA）被组胺激活，但不被组胺激活。 而机械敏感性伤害性传入（MSA）对两者都有反应，但 对牧牛的反应要大得多。同样地，组胺而不是牛皮激活A纤维， MIA，而A-纤维MSAs对牛皮或组胺或两者都有反应。再一次，对牧牛的反应 比对组胺的反应要大得多。这些发现表明瘙痒的感觉 可以通过多个传入通路来介导。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传递不同感觉信号中的相对作用 与过敏性刺激有关。具体而言，我们建议：1）确定是否具有免疫性和/或 通过研究A-和C-纤维MIA对以下物质的反应性，存在MIA的伤害性选择性类别： 疼痛和痛觉刺激。2)研究划痕诱导瘙痒缓解的潜在外周机制 或通过施加热刺激缓解瘙痒。我们将确定这种刺激的应用是否会导致 A-纤维和C-纤维MSAs对刺激的反应减少。初步结果表明 机械刺激后，C-MSA对牛的反应明显疲劳。3)探讨 伤害性和伤害性小直径传入神经的化学敏感性差异 施用技术，即项目1中所示的热灭活的牛骨针， 含有辣椒素、组胺和非组胺能抗炎剂，如半胱氨酸 蛋白酶我们假设不同的有髓和无髓的小MSA群体介导了这些细胞的增殖。 由这些刺激引起的痒和痛的感觉。这些研究的结果将提高我们的 理解瘙痒和疼痛感觉背后的外周神经元装置。 相关性（见说明）： 对治疗（例如用抗组胺药）有抗性的瘙痒是主要的临床问题。拟议 研究将增加我们对瘙痒感觉如何在神经纤维中介导的理解。 皮肤这些研究的结果可能会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.