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（由申请人提供）：本提案是对研究瘙痒机制的 RO1 拨款的修订更新，非常适合资助机会 PA-12-131，以改进控制人类瘙痒的转化和基础研究。在任何特定时间，皮肤病都会影响超过三分之一的美国人口，并造成巨大的经济负担。慢性瘙痒经常伴随皮肤和全身疾病，并且与抓挠有关，这可能导致恶性瘙痒-抓挠循环，从而降低生活质量。大多数类型的慢性瘙痒治疗效果不佳，因此迫切需要解决慢性瘙痒的基础问题，以便为这一重大医学和社会经济问题开发更有效的基于机制的治疗方法。在资助期间，我们开发了瘙痒模型，使用抓挠行为作为读数来研究潜在的神经机制。目前的提议建立在这些结果的基础上，重点关注人们知之甚少的瘙痒递减调节问题。具体目标 1 使用光遗传学方法选择性地转导 dbh-cre 小鼠蓝斑/蓝下层去甲肾上腺素能神经元和 fev-cre 小鼠头端腹内侧延髓中血清素能神经元中的通道视紫红质。我们将研究这些大脑区域的视神经激活对伤害（热缩爪）和瘙痒引起的抓挠行为的影响。我们假设疼痛和瘙痒行为受到相反的下降调节作用。具体目标 2 和 3 将使用互补的电生理学方法来研究脊髓痒传播的下行调节的脑干机制。我们将研究消除大脑的下行影响如何影响脊髓瘙痒信号神经元的活动。我们将 还研究了急性瘙痒或疼痛的情况如何影响头端腹内侧髓质（RVM）中的开和关神经元，这些神经元被认为分别促进或抑制脊髓伤害性传递（具体目标 2）。我们还将研究抓挠皮肤抑制瘙痒的脊柱和脊柱上机制（具体目标 3）。这些研究有望提供有关大脑下行通路如何调节瘙痒传播的新信息。该项目的结果通过增强抑制和减少瘙痒传播的促进作用，对于开发新的基于机制的瘙痒治疗方法具有重要的转化意义。