Neural mechanisms of itch

瘙痒的神经机制

• 批准号: 8500209
• 负责人: EARL E CARSTENS
• 金额: $ 31.28万
• 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 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8500209
• 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.

瘙痒是一种与抓挠欲望相关的不愉快感觉。虽然急性瘙痒通常发生在 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症状， 许多皮肤病和全身性疾病。慢性瘙痒治疗不佳， 影响生活质量，并带来沉重的经济和社会负担。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。该提案将使用 抓挠行为评估，结合电生理学和神经解剖学 方法，研究在正常动物和动物模型中的瘙痒传播机制， 慢性瘙痒该项目包括五个具体目标。具体目标1将研究皮内（id） 微量注射瘙痒介质5-羟色胺，蛋白酶激活受体（PAR）亚型2的激动剂 和4以及组胺以与瘙痒感觉一致的方式引起小鼠的抓挠行为 在人类身上。我们将测试是否通过阿片类拮抗剂而不是吗啡来减少抓挠， 经常会引起瘙痒具体目标2旨在确定 小鼠背角浅层中促肾上腺素原激活的神经元。这将是完成 使用神经解剖学方法定位促分裂原敏感神经元， 的方法来记录这些位置的神经元的反应，以刺激和伤害性的刺激， 麻醉小鼠的皮肤。我们假设，在皮层浅层的神经元亚群， 小鼠腰背角对id瘙痒原的反应方式与信号传导作用一致 急性瘙痒。具体目标3将研究脊髓丘脑和脊髓臂旁通路的作用 使用神经解剖学双标记策略在小鼠和大鼠中介导瘙痒。具体目标4将 研究P物质和其他神经肽在脊髓瘙痒传递中的作用，使用神经毒素 表达NK-1受体的神经元的消融以及拮抗剂的脑池内递送。 具体目标5将研究慢性瘙痒小鼠模型中瘙痒信号通路的致敏作用。 我们假设实验性慢性瘙痒将导致由促炎原引起的抓挠增强 以及诸如辣椒素的致藻素。我们进一步假设实验性慢性瘙痒 背角浅层神经元，表现为Fos表达增加和功能性过度兴奋 表现为异常自发活动和对促炎原的反应增加。这些 将使用两种慢性瘙痒的鼠模型，NC "瘙痒"小鼠品系，和 实验性干性皮肤