Spinal mechanisms of itch

瘙痒的脊柱机制

• 批准号: 9027080
• 负责人: EARL E CARSTENS
• 金额: $ 33.95万
• 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 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9027080
• 关键词: Acute; Address; Affect; Antipruritic Effect; Antipruritics; Area; Basic Science; Behavior; Brain; Brain Stem; Cells; Chloroquine; Chronic; Data; Development; Economic Burden; Electrophysiology (science); Excision; Fiber Optics; Funding; Funding Opportunities; Grant; Health; Histamine; Human; Implant; Interneurons; Light; Medical; Methods; Midbrain structure; Modeling; Mus; Neurons; Nociception; Optics; Pain; Pathway interactions; Pharmacology; Population; Pruritus; Quality of life; Rodent Model; Signal Transduction; Site; Skin; Spinal; Systemic disease; Testing; Time; Touch sensation; Transgenic Organisms; Translational Research; Withdrawal; Work; base; brain pathway; effective therapy; improved; intradermal injection; locus ceruleus structure; neuromechanism; noradrenergic; novel; optogenetics; pain behavior; pre-clinical; public health relevance; response; skin disorder; socioeconomics; transmission process

 DESCRIPTION (provided by applicant): The present proposal is a revised renewal of our RO1 grant investigating itch mechanisms, and is highly appropriate for the funding opportunity, PA-12-131, to improve translational and basic research to control itch in humans. Skin disease affects upwards of one-third of the US population at any given time and imposes a huge economic burden. Chronic itch frequently accompanies skin and systemic diseases, and is associated with scratching which can cause a vicious itch-scratch cycle that reduces the quality of life. Most types of chronic itch are poorly treated, establishing a compelling need to address the basis of chronic itch in order to develop more effective mechanisms-based treatments for this major medical and socioeconomic problem. During the funding period we developed models of itch using scratching behavior as a readout to investigate underlying neural mechanisms. The present proposal builds on these results, focusing on the poorly understood issue of descending modulation of itch. Specific Aim 1 uses an optogenetic approach to selectively transduce channelrhodopsin in noradrenergic neurons in the locus coeruleus/subcoeruleus of dbh-cre mice, and serotonergic neurons in the rostral ventromedial medulla of fev-cre mice. We will investigate the effects of optic activation of these brain areas on nocifensive (thermal paw withdrawal) and pruritogen-evoked scratching behaviors. We hypothesize that pain and itch behaviors are under opposing descending modulatory effects. Specific Aims 2 and 3 will use complementary electrophysiological methods to investigate brainstem mechanisms of descending modulation of spinal itch transmission. We will investigate how removal of descending influences from the brain affects the activity of spinal itch-signaling neurons. We will also investigate how conditions of acute itch or pain affect ON- and OFF-neurons in the rostral ventromedial medulla (RVM) that are thought to respectively facilitate or inhibit spinal nociceptive transmission (Specific Aim 2). We will also investigate spinal and supraspinal mechanisms by which scratching the skin inhibits itch (Specific Aim 3). These studies are expected to provide novel information regarding how descending pathways from the brain can modulate itch transmission. The results of this project have important translational significance for the development of new, mechanisms-based treatments for itch by enhancing inhibition and reducing facilitation of itch transmission.

 描述（由适用提供）：本提案是对我们的RO1拨款调查机制的修订续订，并且非常适合资助机会PA-12-131，以改善转化和基础研究以控制人类的瘙痒。在任何给定的时间，皮肤疾病都会影响美国三分之一以上的人口，不可能带来巨大的经济负担。慢性瘙痒经常涉及皮肤和全身性疾病，并且与刮擦有关，这可能会导致恶性瘙痒周期，从而降低生活质量。大多数类型的慢性瘙痒都受到治疗不佳，确定了解决慢性瘙痒基础的迫切需求，以便为这一主要的医学和社会经济问题开发基于机制的更有效的治疗方法。在资金期间，我们使用刮擦行为作为读数开发了瘙痒模型，以研究潜在的神经机制。目前的提案以这些结果为基础，重点是瘙痒下降调节的不良理解问题。特定目标1使用一种光遗传学方法在DBH-CRE小鼠的坐骨层/下层中有选择性地传播肾上腺素能神经元中的通道Ropopsin，以及FEV-CRE小鼠的Rostral腹膜内膜中的血清素能神经元。我们将研究这些大脑区域的视觉激活对鼻型（热爪戒断）和瘙痒诱发的刮擦行为的影响。我们假设疼痛和瘙痒行为在相反的下降调节作用下。具体目的2和3将使用完整的电生理方法研究脊柱瘙痒传播的降临调节的脑干机制。我们将研究从大脑中的下降影响的去除如何影响脊柱瘙痒信号神经元的活性。我们将 还要研究急性瘙痒或疼痛的条件如何影响腹侧腹膜髓质（RVM）中的鼻神经元和外神经元，这些状况被认为分别支持或抑制脊柱伤害感受性传播（特定的目标2）。我们还将研究脊柱和上脊柱上的机制，通过刮擦皮肤会抑制瘙痒（特定目标3）。预计这些研究将提供有关大脑下降途径如何调节瘙痒传播的新信息。该项目的结果通过增强瘙痒传播的抑制和减少设施来开发新的，基于机制的瘙痒的疗法具有重要的翻译意义。