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，每年的费用超过100美元 十亿美元。大多数类型的慢性瘙痒都管理不善，迫切需要开发更多 针对这些衰弱状况的有效的基于机制的治疗。本提案将调查 延髓头端腹内侧区神经元表达P物质受体的作用 (即NK-1R)在瘙痒下行调节中的作用，以及表达NK-1R的神经元在 脊髓浅层和延髓背角在瘙痒的上行传递。 该提案有两个首要目标。特定目的1假设表达NK-1R的神经元， 特别是RVM中的ON细胞(即，在有害刺激诱发的戒断之前激发的那些细胞 反应)，在下行抑制脊髓瘙痒传递中起关键作用。我们将聘用 化学发生和颅内微量注射方法检测NK-1R表达的RVM是否激活 神经元抑制急性瘙痒诱发的瘙痒行为，或慢性瘙痒的表现(自发性和 在牛皮癣和特应性皮炎瘙痒的小鼠模型中)。我们还将调查NK- 1R介导的脊髓瘙痒传递神经元下行抑制作用。最后，我们将从 光遗传学鉴定RVM中表达NK-1R的神经元，并从功能上确定它们是否在细胞上。 特定目的2假设在脊髓/延髓背角浅层有NK-1R表达的神经元 引起对躯体感觉丘脑和臂旁核的上行投射，这是至关重要的 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-1R- 在脊髓/延髓背角表达的神经元被瘙痒刺激激活，而光和 研究这些神经元的激活是否会引起瘙痒(和/或)的行为迹象的化学发生方法 疼痛)。更好地理解中枢瘙痒调制和上行感觉传递具有翻译意义 开发针对NK-1受体的新型止痒药物以增加降幅的意义 抑制瘙痒，减少上行瘙痒相关信号。 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