Investigating the Neural Circuits of Itch

研究瘙痒的神经回路

• 批准号: 10087888
• 负责人: Sarah Elizabeth Ross
• 金额: $ 65.25万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-11 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10087888
• 关键词: Acetone; Acids; Acute; Address; Alleles; Anatomy; Antipruritic Effect; Behavior; Behavioral; Behavioral Assay; Biological Assay; Cells; Chemicals; Contact Dermatitis; Data; Dermatologic; Development; Dynorphins; Esters; Ethers; Funding; Genetic; Goals; Health; Human; Immune; Interneurons; Intervention; Knock-in; Mechanics; Mediating; Modality; Modeling; Mus; Neural Pathways; Neurons; Opioid agonist; Pathologic; Peripheral; Pharmaceutical Preparations; Pharmacology; Physiological; Physiology; Population; Preparation; Pruritus; Quality of life; Receptor Signaling; Research; Role; Signal Transduction; Skin; Specificity; Spinal; Testing; Therapeutic; Translations; Visit; Water; cell type; clinically relevant; clinically translatable; dorsal horn; effective therapy; experimental study; inhibitory neuron; innovation; insight; kappa opioid receptors; keratinocyte; neural circuit; novel; novel therapeutics; programs; somatosensory; spontaneous pain; tool; transcription factor

PROJECT DESCRIPTION Persistent itch is an aversive condition that results in a severely diminished quality of life. Our approach to address this important health issue is to gain a better understanding of the underlying neural circuits and pathways. Specifically, we propose to investigate the mechanisms through which KOR signaling modulates itch. The long-term goal of our research program is aimed at the development of novel interventions for itch that are both safe and effective. We previously found that mice lacking the transcription factor Bhlhb5 show elevated itch, and that this effect is caused by the loss of a specific population spinal inhibitory interneurons that express the dynorphin. However, the neurons that respond to dynorphin — those that express KOR — remained unknown, and the neural circuits through which KOR agonists inhibit itch were unclear. To address these gaps, our lab developed novel tools (KOR-cre allele) and approaches (ex vivo preparation) to study this circuitry. We also discovered that in models of pathological itch there is abnormal bursting behavior in lamina I spinal neurons. Here we propose to elucidate the circuitry through which KOR agonists inhibit itch, combining anatomical (AIM 1), behavioral (AIM 2), physiological (AIM 3), and translational (AIM 4) approaches. Our overall hypothesis is that KOR signaling acts on both primary afferents and spinal neurons to inhibit acute pruritoception, and that KOR agonists will continue to be effective in the presence of persistent itch. Our proposal is innovative because it combines these state-of-the-art tools and approaches to elucidate the neural circuits through which KOR agonists inhibit pruritoception. The combination of conceptual advances and therapeutic insight into the neural circuitry through which KOR agonists inhibit itch makes this proposal highly significant to human health.

项目说明 持续性瘙痒是一种令人厌恶的情况，会导致生活质量严重下降。我们的方法是 解决这一重要的健康问题是为了更好地了解潜在的神经回路和 小路。具体地说，我们建议研究KOR信号调节的机制 很痒。我们研究计划的长期目标是开发治疗瘙痒的新方法。 既安全又有效。我们之前发现，缺乏转录因子Bhlhb5的小鼠表现出 这种效应是由特定数量的脊髓抑制性中间神经元的丧失引起的 表达强啡肽的基因。然而，对强啡肽做出反应的神经元--那些表达KOR的神经元-- 仍不清楚，KOR激动剂抑制瘙痒的神经回路也不清楚。致信地址 针对这些差距，我们实验室开发了新的工具(KOR-cre等位基因)和方法(体外准备)来研究这一问题 电路。我们还发现，在病理性瘙痒模型中，I层有异常的爆裂行为。 脊髓神经元。在这里，我们建议阐明KOR激动剂抑制瘙痒的回路，结合 解剖学(AIM 1)、行为学(AIM 2)、生理学(AIM 3)和翻译(AIM 4)方法。我们的 总体假设是KOR信号同时作用于初级传入神经元和脊髓神经元以抑制急性 KOR激动剂在持续瘙痒的情况下将继续有效。我们的 建议是创新的，因为它结合了这些最先进的工具和方法来阐明神经 KOR激动剂抑制瘙痒感觉的回路。概念上的进步和 对KOR激动剂抑制瘙痒的神经回路的治疗洞察力使这一提议变得非常重要 对人类健康意义重大。