Kappa opioid signaling in somatosensation

体感中的 Kappa 阿片类信号传导

• 批准号: 9258102
• 负责人: Marissa Stearns Kuzirian
• 金额: $ 1.03万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-01 至 2017-02-10
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9258102
• 关键词: Address; Afferent Neurons; Agonist; Alleles; Anatomy; Attenuated; Behavioral; Calcium; Cell Nucleus; Cells; Clinical; Clinical Trials; Complement; Depressed mood; Drug Targeting; Dynorphins; Electrophysiology (science); Enterobacteria phage P1 Cre recombinase; G-substrate; GTP-Binding Proteins; Genetic; Glutamates; Hair; Hair follicle structure; Human; Immunohistochemistry; Ion Channel; Knock-in Mouse; Knowledge; Label; Ligands; Light; Measures; Mechanics; Mechanoreceptors; Modality; Mus; Nerve; Nervous system structure; Neurons; Opioid; Opioid Receptor; Pain; Pain management; Peripheral; Physiologic pulse; Physiological; Population; Preparation; Probability; Pruritus; Receptor Signaling; Refractory; Role; Sensory; Signal Transduction; Skin; Spinal; Spinal Cord; Synaptic Transmission; Testing; Time; Touch sensation; allodynia; cellular targeting; delta opioid receptor; dorsal column; dorsal horn; experimental study; insight; kappa opioid receptors; mu opioid receptors; neurochemistry; neurotransmission; novel; optogenetics; presynaptic; response; somatosensory; voltage

Project Summary/Abstract Opioids — mu, kappa, and delta—are important regulators of somatosensation, including pain, itch, and touch (1). In particular, recent studies suggest that heat-sensitive primary afferents express the mu opioid receptor (MOR), whereas mechanically sensitive primary afferents express the delta opioid receptor (DOR) (2, 3). In contrast, the primary afferent subtypes that express the kappa opioid receptor (KOR) are completely unknown. Addressing this gap in knowledge is important because peripherally selective kappa agonists are currently being tested in clinical trials, yet the cellular targets of these drugs have not been defined (4). To address this issue, we recently generated a KOR-Cre knock-in mouse to define the primary afferents that express KOR and investigate their function in somatosensation (5). Surprisingly, we discovered KOR-Cre expression in an unexpected population of primary afferents: low-threshold mechanoreceptors that form either lanceolate or circumferential endings around hair follicles. These findings raise the possibility that kappa opioid signaling within primary afferents modulates light touch. Here, I propose to elucidate the role of KOR signaling in primary sensory afferent function using a combination of immunohistochemistry, optogenetics, and electrophysiology. In particular, I will test the hypothesis that kappa opioid signaling inhibits the activity of low-threshold mechanoreceptors. Specifically, I will 1) define the primary afferents that express KOR; 2) test the function of KOR signaling in these cells; and 3) test the role of KOR signaling on synaptic transmission into the dorsal horn. Understanding the population(s) of primary afferents that express KOR may have important clinical implications for the treatment of allydonia, a type of pain that is refractory to current therapies.

项目总结/摘要 阿片类物质--μ、κ和δ--是躯体感觉（包括疼痛、瘙痒和触觉）的重要调节剂 （一）.特别是，最近的研究表明，热敏初级传入表达μ阿片受体 (MOR)而机械敏感的初级传入神经表达δ阿片受体（DOR）（2，3）。在 相反，表达κ阿片受体（KOR）的初级传入亚型完全未知。 解决这一知识差距很重要，因为外周选择性κ激动剂目前 正在临床试验中进行测试，但这些药物的细胞靶点尚未确定（4）。为了解决这个 问题，我们最近产生了一个KOR-Cre基因敲入小鼠来定义表达KOR的初级传入， 探讨它们在躯体感觉中的功能（5）。令人惊讶的是，我们发现KOR-Cre表达在一个 初级传入的意外群体：低阈值机械感受器， 披针形或环绕毛囊的末端。这些发现提出了kappa 初级传入内的阿片样物质信号传导调节轻触。在此，我建议澄清大韩民国的角色 使用免疫组织化学、光遗传学和 电生理学特别是，我将测试的假设，κ阿片信号抑制的活动， 低阈值机械感受器具体来说，我将1）定义表达KOR的主要传入; 2）测试 KOR信号在这些细胞中的功能;和3）测试KOR信号在突触传递中的作用， 背角了解表达KOR的初级传入神经的群体可能具有重要的意义。 临床意义的治疗allydonia，一种类型的疼痛，是难治性的目前的治疗。