Role of NK-1 receptors in descending modulation and ascending transmission of itch

NK-1 受体在瘙痒的下行调节和上行传播中的作用

• 批准号: 10227960
• 负责人: EARL E CARSTENS
• 金额: $ 32.69万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-05 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10227960
• 关键词: Acute; Affect; Antipruritics; Atopic Dermatitis; Behavior; Behavioral; Brain Stem; Cells; Cervical; Clozapine; Development; Drug Targeting; Electrophysiology (science); Fiber Optics; Fire - disasters; Health; Light; Mechanics; Mediating; Microinjections; Modeling; Mus; Neurons; Optics; Pain; Pharmacology; Population; Posterior Horn Cells; Presynaptic Terminals; Pruritus; Psoriasis; Role; Sensory; Signal Transduction; Site; Skin; Spinal; Spinal Cord; Stimulus; Substance P; Substance P Receptor; Testing; Thalamic structure; Touch sensation; Withdrawal; base; behavioral response; chronic itch; cost; designer receptors exclusively activated by designer drugs; dorsal horn; effective therapy; in vivo; intradermal injection; mouse model; novel; optogenetics; pain behavior; parabrachial nucleus; pre-clinical; response; socioeconomics; somatosensory; transmission process

Project Summary Itchy skin conditions affect a substantial portion of the US population at annual costs exceeding $100 billion. Most types of chronic itch are poorly managed, establishing a compelling need to develop more effective mechanisms-based treatments for these debilitating conditions. The present proposal will investigate the role of neurons located in the rostral ventromedial medulla (RVM) that express the receptor for substance P (i.e., NK-1R) in descending modulation of itch, as well as the role of NK-1R-expressing neurons in the superficial spinal and medullary dorsal horn in the ascending transmission of itch. The proposal has two overarching aims. Specific Aim 1 hypothesizes that NK-1R-expressing neurons, and specifically ON-cells in the RVM (i.e., those that fire just prior to a noxious stimulus-evoked withdrawal response), are critically involved in descending inhibition of spinal itch transmission. We will employ chemogenetic and intracranial microinjection approaches to test if activation of NK-1R-expressing RVM neurons suppresses acute pruritogen-evoked itch behavior, or manifestations of chronic itch (spontaneous and touch-evoked scratching) in mouse models of psoriasis and atopic dermatitis itch. We will also investigate NK- 1R-mediated descending inhibition of spinal itch-transmitting neurons. Finally, we will record from optogenetically identified NK-1R-expressing neurons in RVM and functionally establish if they are ON cells. Specific Aim 2 hypothesizes that NK-1R-expressing neurons in the superficial spinal/ medullary dorsal horn give rise to ascending projections to the somatosensory thalamus and parabrachial nucleus that are critically involved in transmitting itch-related signals. We will use an optogenetic approach to determine if NK-1R- expressing neurons in the spinal/medullary dorsal horn are activated by pruritogenic stimuli, and opto- and chemogenetic approaches to investigate if the activation of such neurons elicits behavioral signs of itch (and/or pain). A better understanding of central itch modulation and ascending sensory transmission has translational significance for developing novel antipruritic treatments targeting NK-1 receptors to increase descending inhibition of itch and reduce ascending itch-related signals. Page 1

项目摘要 发痒的皮肤状况会以超过100美元的年成本影响美国人口的很大一部分 十亿。大多数类型的慢性瘙痒管理不善，建立了迫切需要发展的需求 针对这些令人衰弱的条件的有效机制治疗。本提案将调查 位于延髓腹侧髓质（RVM）中的神经元的作用，表达物质P的受体 （即NK-1R）在瘙痒的降序调制中，以及表达NK-1R的神经元在 瘙痒的上升传播中的脊柱和髓质背角。 该提案具有两个总体目标。特定目标1假设表达NK-1R的神经元， 特别是在RVM中的元素（即，在有害刺激诱发的戒断之前发射的那些 反应），至关重要地参与抑制脊柱瘙痒传播的抑制。我们将雇用 化学发生和颅内微注射方法，用于测试表达NK-1R的RVM的激活 神经元抑制急性瘙痒症的瘙痒行为，或慢性瘙痒的表现（自发和 牛皮癣小鼠模型和特应性皮炎的小鼠模型中的接触式刮擦。我们还将调查NK- 1R介导的脊柱瘙痒转移神经元的下降抑制。最后，我们将从 光遗传学鉴定在RVM中表达NK-1R的神经元，并在功能上确定它们是否在细胞上。 特定目标2假设表面脊柱/髓质角中表达NK-1R的神经元 引起对体感的丘脑和副核的上升投影，这些核心非常重要 涉及传输与瘙痒相关的信号。我们将使用光遗传学方法来确定NK-1R-是否是否 在脊柱/髓质背角中表达神经元，通过培养基刺激激活，光和光。 研究这种神经元的激活是否引起瘙痒的行为迹象（和/或 疼痛）。更好地理解中央瘙痒调制和上升感官传播具有翻译 开发靶向NK-1受体以增加下降的新型抗尿素治疗的重要性 抑制瘙痒并减少上升瘙痒相关的信号。 第1页