Neural mechanisms of itch

瘙痒的神经机制

• 批准号: 7891381
• 负责人: EARL E CARSTENS
• 金额: $ 34.09万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-10 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7891381
• 关键词: Ablation; Acute; Address; Agonist; Allergic Reaction; Animal Model; Animals; Attenuated; Behavior; Behavior assessment; Bombesin Receptor; Capsaicin; Chronic; Economics; Esthesia; Exhibits; Histamine; Human; Insect Bites; Label; Lead; Location; Mediating; Mediator of activation protein; Methods; Microinjections; Modeling; Morphine; Mouse Strains; Mus; Narcotic Antagonists; Neurons; Neuropeptides; PAR-2 Receptor; Pain; Pathway interactions; Plants; Population; Posterior Horn Cells; Property; Proteinase-Activated Receptors; Quality of life; Rattus; Role; Sensory; Serotonin; Serotonin Agonists; Signal Pathway; Signal Transduction; Skin; Spinal; Substance P; Substance P Receptor; Symptoms; Systemic disease; Testing; Thalamic structure; Tracer; dorsal horn; effective therapy; mouse model; neuromechanism; neurotoxic; neurotransmission; parabrachial nucleus; protease-activated receptor 4; receptor; response; seryl-leucyl-isoleucyl-glycyl--arginyl-leucinamide; social; transmission process

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.

瘙痒是与刮擦渴望相关的一种不愉快的感觉。而急性瘙痒通常发生 伴有昆虫叮咬，过敏反应或与某些植物接触，慢性瘙痒是 许多皮肤病学疾病和全身性疾病。慢性瘙痒治疗不佳，负面影响 影响生活质量，并带有繁重的经济和社会伯恩。非常需要 更好地了解瘙痒的机制，以开发更有效的治疗方法。该建议将使用 划痕的行为评估，与电生理和神经解剖学结合 方法，研究普通动物和动物模型中瘙痒传播的机制 慢性瘙痒。该项目由5个具体目标组成。特定目标1将调查是否在皮内（ID） 瘙痒介质5-羟色胺的显微注射，蛋白酶激活受体（PAR）亚型的激动剂2 和4和组胺，以与瘙痒感一致的方式引起小鼠的刮擦行为 在人类中。我们将测试是否通过 - 阿片类拮抗剂减少刮擦，而不是吗啡，这是 唤起瘙痒。特定目标2旨在确定的位置和功能特性 小鼠表面背角的瘙痒激活神经元。这将完成 使用神经解剖学方法来定位培养基敏感的神经元和电生理学 记录这些位置中神经元对核和有害刺激的反应的方法 麻醉小鼠的皮肤。我们假设神经元在浅表层中的亚群 鼠腰腰角对ID尿素的反应以与信号传导的作用一致的方式 急性瘙痒。特定的目标3将研究脊柱丘脑和脊柱旋转途径的作用 在使用神经解剖学双标签策略中介导小鼠和大鼠的瘙痒时。具体目标4将 使用神经毒性研究物质P和其他神经肽在脊柱瘙痒传播中的作用 表达NK-1受体的神经元的消融以及拮抗剂的内递送。 特定的目标5将研究慢性瘙痒小鼠模型中瘙痒信号途径的灵敏度。 我们假设实验性慢性瘙痒将导致prutritogens引起的刮擦增强 以及诸如辣椒素之类的算法。我们进一步假设实验性慢性瘙痒灵敏度 浅表背角神经元，表现为FOS表达增加和功能过度刺激性 由异常赞助商活性和对培养基的反应增加所示。这些 假设将使用两个慢性瘙痒的鼠模型，NC“瘙痒”小鼠菌株和 实验性干燥皮肤。