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: 10665580
• 负责人: EARL E CARSTENS
• 金额: $ 33.52万
• 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/10665580
• 关键词: Acute; Affect; Atopic Dermatitis; Behavior; Behavioral; Brain Stem; Cells; Cervical; Clozapine; Development; Economic Burden; Electrophysiology (science); Fiber Optics; Fire - disasters; Genetic; Light; Mechanics; Mediating; Microinjections; Modeling; Mus; Neurons; Optics; Pain; Pathway interactions; Population; Posterior Horn Cells; Presynaptic Terminals; Pruritus; Psoriasis; Role; Sensory; Signal Transduction; Site; Skin; Spinal; Spinal Cord; Stimulus; Substance P; TACR1 gene; Testing; Thalamic structure; Touch sensation; Vertebral column; Withdrawal; behavioral response; chronic itch; cost; designer receptors exclusively activated by designer drugs; dorsal horn; effective therapy; genetic approach; health economics; in vivo; intradermal injection; mouse model; neurotransmission; novel; optical fiber; optogenetics; pain behavior; parabrachial nucleus; pharmacologic; 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 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 化学遗传学方法来研究此类神经元的激活是否会引发瘙痒的行为迹象（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 开发针对NK-1受体的新型止痒治疗方法以增加下降的意义 抑制瘙痒并降低瘙痒相关信号上升。 第1页

项目成果

Thermal Hyperalgesia and Mechanical Allodynia Elicited by Histamine and Non-histaminergic Itch Mediators: Respective Involvement of TRPV1 and TRPA1.

由组胺和非希斯明素能瘙痒介质引起的热痛觉过敏和机械性异常性症：TRPV1和TRPA1的各自参与。

• DOI: 10.1016/j.neuroscience.2020.09.048
• 发表时间: 2020-11-21
• 期刊: Neuroscience
• 影响因子: 3.3
• 作者: Tsagareli MG;Nozadze I;Tsiklauri N;Carstens MI;Gurtskaia G;Carstens E
• 通讯作者: Carstens E

Role of 5-HT1A and 5-HT3 receptors in serotonergic activation of sensory neurons in relation to itch and pain behavior in the rat.

• DOI: 10.1002/jnr.24633
• 发表时间: 2020-10
• 期刊: Journal of neuroscience research
• 影响因子: 4.2
• 作者: Domocos D;Selescu T;Ceafalan LC;Iodi Carstens M;Carstens E;Babes A
• 通讯作者: Babes A

Characterization of the expression of gastrin-releasing peptide and its receptor in the trigeminal and spinal somatosensory systems of Japanese macaque monkeys: Insight into humans.

• DOI: 10.1002/cne.25376
• 发表时间: 2022-11
• 期刊: JOURNAL OF COMPARATIVE NEUROLOGY
• 影响因子: 2.5
• 作者: Takanami, Keiko;Oti, Takumi;Kobayashi, Yasuhisa;Hasegawa, Koki;Ito, Takashi;Tsutsui, Naoaki;Ueda, Yasumasa;Carstens, Earl;Sakamoto, Tatsuya;Sakamoto, Hirotaka
• 通讯作者: Sakamoto, Hirotaka

Estrogens influence female itch sensitivity via the spinal gastrin-releasing peptide receptor neurons.

• DOI: 10.1073/pnas.2103536118
• 发表时间: 2021-08-03
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Takanami K;Uta D;Matsuda KI;Kawata M;Carstens E;Sakamoto T;Sakamoto H
• 通讯作者: Sakamoto H

Opposing effects of cervical spinal cold block on spinal itch and pain transmission.

颈椎冷阻滞对脊髓瘙痒和疼痛传递的相反作用。

• DOI: 10.1097/itx.0000000000000016
• 发表时间: 2018
• 期刊: Itch (Philadelphia, Pa.)
• 作者: Carstens,Earl;Carstens,MirelaIodi;Akiyama,Tasuku;Davoodi,Auva;Nagamine,Masaki
• 通讯作者: Nagamine,Masaki