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

项目摘要 皮肤瘙痒影响了相当一部分美国人口，每年的费用超过100美元 亿大多数类型的慢性瘙痒是管理不善，建立一个迫切需要开发更多的 有效的机制为基础的治疗这些衰弱的条件。本提案将调查 位于延髓头端腹内侧（RVM）表达P物质受体的神经元的作用 (i.e., NK-1 R）在瘙痒下行调节中的作用，以及NK-1 R表达神经元在瘙痒下行调节中的作用。 浅脊髓和延髓背角在瘙痒的上行传递。 该提案有两个首要目标。特异性目的1假设NK-1 R表达神经元， 并且特别是RVM中的ON单元（即，那些在有害刺激诱发的戒断反应之前 反应），关键地参与脊髓瘙痒传递的下行抑制。我们会委聘 化学发生学和颅内显微注射方法，以测试表达NK-1 R的RVM是否活化 神经元抑制急性致敏原诱发的瘙痒行为，或慢性瘙痒的表现（自发和 触摸诱发的抓挠）。我们也会调查NK- 1 R介导的脊髓瘙痒传递神经元的下行抑制。最后，我们将记录从 光遗传学鉴定RVM中的NK-1 R表达神经元，并在功能上确定它们是否是ON细胞。 特异性目的2假设脊髓/延髓背角浅层NK-1 R表达神经元 引起向躯体感觉丘脑和臂旁核的上行投射， 参与传递瘙痒相关信号。我们将使用光遗传学方法来确定NK-1 R- 脊髓/延髓背角中的表达神经元被致炎性刺激激活，并且光和 研究这些神经元的激活是否诱发瘙痒的行为体征（和/或 疼痛）。更好地理解中枢瘙痒调制和上行感觉传递具有翻译 开发靶向NK-1受体的新型抗炎治疗方法以增加降血糖的意义 抑制瘙痒并降低瘙痒相关信号上升。 第1页

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