Neural mechanisms of itch

瘙痒是一种与抓挠的欲望有关的不舒服的感觉。而急性瘙痒通常发生在 由于被昆虫叮咬、过敏反应或接触某些植物，慢性瘙痒是一种常见的 许多皮肤病和全身性疾病。慢性瘙痒治疗不佳，消极 影响生活质量，并带来沉重的经济和社会负担。有很大的需要 更好地了解瘙痒的机制，以开发更有效的治疗方法。这项提案将使用 结合电生理和神经解剖学的抓挠行为评估 方法，研究瘙痒在正常动物和动物模型中的传播机制。 慢性瘙痒。该项目由5个具体目标组成。特定目标1将调查皮内(Id) 微量注射瘙痒介质5-羟色胺和蛋白水解酶激活受体(PAR)亚型激动剂2 和4，以及组胺，以与瘙痒感觉一致的方式诱导小鼠的抓挠行为 在人类身上。我们将测试阿片类拮抗剂是否能减少抓挠，但吗啡不能。 经常会引起瘙痒。具体目标2试图确定位置和功能特性 瘙痒原激活的小鼠背角浅层神经元。这将会实现的 使用神经解剖学方法定位瘙痒原敏感神经元，以及电生理 记录这些部位神经元对瘙痒和伤害性刺激的反应的方法 麻醉小鼠的皮肤。我们假设大脑皮质浅层中的一个神经元亚群 小鼠腰椎背角对id瘙痒原的反应与信号转导的作用一致 急性瘙痒。特异靶3将研究脊髓丘脑和脊髓臂神经通路的作用 使用神经解剖学双标记策略调节小鼠和大鼠的瘙痒。具体目标4将 使用神经毒素研究P物质和其他神经肽在脊髓瘙痒传递中的作用 消融表达NK-1受体的神经元以及脑池内注射拮抗剂。 具体目标5将在慢性瘙痒的小鼠模型中研究瘙痒信号通路的敏化。 我们假设实验性慢性瘙痒将导致瘙痒原引起的更强的抓挠。 还有辣椒素等变应原。我们进一步假设，实验性慢性瘙痒会使 浅层背角神经元，表现为Fos表达增加和功能性超兴奋性 表现为异常的自发活动和对瘙痒原反应的增加。这些 假说将使用两种慢性瘙痒小鼠模型，NC“瘙痒”小鼠品系，以及 实验性干性皮肤。

Itch is an unpleasant sensation associated with the desire to scratch. While acute itch commonly occurs with insect bites, allergic reactions or contact with certain plants, chronic itch is a common symptom of many dermatological conditions and systemic disease. Chronic itch is poorly-treated, negatively impacts the quality of life, and carries a heavy economic and social burden. There is a great need to better understand mechanisms of itch to develop more effective treatments. This proposal will use behavioral assessment of scratching, combined with electrophysiological and neuroanatomical approaches, to investigate mechanisms of itch transmission in normal animals and in animal models of chronic itch. The project consists of 5 Specific Aims. Specific Aim 1 will investigate if intradermal (id) microinjection of the itch mediators serotonin, agonists of protease-activated receptor (PAR) subtypes 2 and 4, and histamine, elicit scratching behavior in mice in a manner that is consistent with itch sensation in humans. We will test if scratching is reduced by ¿-opioid antagonists but not by morphine, which often evokes itch. Specific Aim 2 seeks to identify the locations and functional properties of pruritogen-activated neurons in the superficial dorsal horn of the mouse. This will be accomplished using a neuroanatomical approach to localize pruritogen-sensitive neurons, and an electrophysiological approach to record the responses of neurons in these locations to pruritic and noxious stimulation of the skin in anesthetized mice. We hypothesize that a sub-population of neurons in superficial laminae of the murine lumbar dorsal horn responds to id pruritogens in a manner consistent with a role in signaling acute itch. Specific Aim 3 will investigate the role of the spinothalamic and spinoparabrachial pathways in mediating itch in mice and rats using a neuroanatomical double-label strategy. Specific Aim 4 will investigate a role for substance P and other neuropeptides in spinal itch transmission, using neurotoxic ablation of neurons expressing the NK-1 receptor as well as intracisternal delivery of antagonists. Specific Aim 5 will investigate sensitization of itch-signaling pathways in mouse models of chronic itch. We hypothesize that experimental chronic itch will lead to enhanced scratching elicited by pruritogens and also algogens such as capsaicin. We further hypothesize that experimental chronic itch sensitizes superficial dorsal horn neurons, manifested by increased Fos expression and functional hyperexcitability as exhibited by abnormal spontaneous activity and increased responses to pruritogens. These hypotheses will be addressed using two murine models of chronic itch, the NC "itchy" mouse strain, and experimental dry skin.