Spinal mechanisms of itch

 描述（由申请人提供）：本提案是我们研究瘙痒机制的RO 1赠款的修订更新，非常适合资助机会PA-12-131，以改善控制人类瘙痒的转化和基础研究。皮肤病在任何时候都影响着超过三分之一的美国人口，并造成了巨大的经济负担。慢性瘙痒经常伴随皮肤和全身性疾病，并与抓挠有关，抓挠可导致恶性瘙痒-抓挠循环，降低生活质量。大多数类型的慢性瘙痒治疗效果不佳，迫切需要解决慢性瘙痒的基础，以便为这一主要的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，我们开发了使用抓挠行为作为读数的瘙痒模型，以研究潜在的神经机制。目前的建议建立在这些结果的基础上，重点是对瘙痒的下行调制知之甚少的问题。具体目标1使用光遗传学方法选择性地在dbh-cre小鼠的蓝斑/蓝斑下的去甲肾上腺素能神经元和fev-cre小鼠的延髓头端腹内侧的肾上腺素能神经元中选择性地调节视紫红质通道。我们将研究这些脑区的视觉激活对疼痛反应（热缩爪）和促分裂素诱发的抓挠行为的影响。我们假设疼痛和瘙痒行为受到相反的下行调节作用。具体目标2和3将使用互补的电生理学方法来研究脊髓瘙痒传递的下行调制的脑干机制。我们将研究从大脑中移除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如何影响延髓头端腹内侧（RVM）的ON和OFF神经元，它们被认为分别促进或抑制脊髓伤害性传递（具体目标2）。我们还将研究通过抓挠皮肤抑制瘙痒的脊髓和脊髓上机制（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。该项目的结果对于通过增强抑制和减少瘙痒传播的促进来开发新的基于机制的瘙痒治疗具有重要的转化意义。

 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.