Investigating the Neural Circuits of Itch

描述(由申请人提供)：慢性瘙痒(脓疱炎)是一种严重的疾病，导致严重的生活质量下降。此外，这种情况比人们通常认为的要普遍得多，这是人们去看皮肤科医生的最常见原因，尽管治疗通常无效。然而，虽然瘙痒是从皮肤开始的，但我不仅仅是一种皮肤状况。相反，瘙痒是一种复杂且知之甚少的感觉，由外周、脊髓和大脑的神经回路调节。因此，从长远来看， 我们研究的目的是为了更好地了解介导瘙痒的神经回路，从而开发出更有效的治疗紫癜炎的方法。我们之前发现，转录因子Bhlhb5是脊髓中一组抑制性中间神经元(这里称为B5-I神经元)生存所必需的，这些神经元是正常瘙痒感觉所必需的；缺乏这些脊髓中间神经元的小鼠会遭受持续性病理性瘙痒。由于B5-I神经元是第一个被基因标记的瘙痒回路的组成部分，研究这些神经元为我们提供了一个独特的机会来解开瘙痒的神经基础。重要的是，我们最近发现B5-I神经元是表达强啡肽的脊髓中间神经元的一个特殊子集。这一发现很重要，因为强啡肽是一种kappa阿片受体(KOR)激动剂，而KOR激动剂最近被证明可以缓解啮齿动物和人类的瘙痒。因此，我们假设B5-I神经元具有抑制瘙痒的功能，并且它们部分通过在脊髓中释放强啡肽来实现这一功能。在这里，我们建议通过三个具体的目标来检验这一假设：目标1：确定B5-I神经元对瘙痒调节的特异性程度。目的2：以B5-I神经元为分子柄，解剖大鼠背角的神经回路。目的3：明确脊髓强啡肽在瘙痒中的作用。这些实验的结果可能对患有慢性瘙痒的人有重大的临床意义。 因为我们的发现将为未来止痒疗法的发展确定一个关键的细胞靶点，并将为KOR介导的止痒机制提供重要的见解。

DESCRIPTION (provided by applicant): Chronic itch (puritis) is a severe condition that results in severely diminished quality of life. Moreover, this condition is much more widespread than generally appreciated, representing the most common reason to visit a dermatologist, despite the fact that treatments are generally ineffective. However, while itch is initiated in the skin, i is more than just a skin condition. Rather, itch is a complex and poorly understood sensation that is mediated by neural circuits in the periphery, the spinal cord and the brain. Thus, the long-term goal of our research is to gain a better understanding of the neural circuits that mediate itch wit the view of developing more effective therapies for puritis. We previously discovered that the transcription factor Bhlhb5 is required for the survival of a subset of inhibitory interneurons in he spinal cord (which are here termed B5-I neurons) that are required for normal itch sensation; mice lacking these spinal interneurons suffer from persistent pathological itch. Since B5-I neurons are the first component of an itch circuit to be labeled genetically, studying these neurons provides us with a unique opportunity to unravel the neural basis of itch. Importantly, we have recently discovered that B5-I neurons are a specific subset of spinal interneurons that express dynorphin. This finding is important because dynorphin is a kappa opioid receptor (KOR) agonist, and KOR agonists have recently been shown to relieve itch in rodents and man. We therefore hypothesize that B5-I neurons function to inhibit itch, and that they do so in part through the release of dynorphin in the spinal cord. Here we propose to test this hypothesis in through 3 specific aims: Aim 1: Determine the degree to which B5-I neurons are specific to the regulation of itch. Aim 2: Dissect neural circuits in the dorsal horn using B5-I neurons as a molecular handle. Aim 3: Define the role of spinal dynorphin in itch. Results from these experiments are likely to have major clinical implications for people that suffer from chronic itch because our findings will define a key cellular target for the development of future anti-itch therapies and they will provide important insight into the mechanism of KOR-mediated inhibition of itch.