Cellular basis for morphine-induced itch

吗啡引起的瘙痒的细胞基础

• 批准号: 9756018
• 负责人: Eileen Nguyen
• 金额: $ 5万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9756018
• 关键词: Adverse effects; Affect; Alleles; Anatomy; Anesthesiology; Automobile Driving; Behavior; Behavioral; Cells; Clinical; Complement; Data; Development; Disinhibition; Dynorphins; Electrophysiology (science); Excision; Fellowship; Fluorescent in Situ Hybridization; Functional disorder; Genes; Goals; Immunohistochemistry; Interneurons; Investigation; Lead; Mediating; Mentors; Molecular; Morphine; Mus; Neurons; Opioid; Pain; Pain management; Patients; Pharmacology; Physicians; Physiological; Physiology; Population; Process; Pruritus; Reporter; Research Training; Scientist; Sensory; Slice; Spinal; Spinal Cord; Spinal cord posterior horn; Symptoms; Testing; Therapeutic; Time; Training; Work; base; cell type; dorsal horn; effective therapy; experience; experimental study; improved; inhibitory neuron; insight; interest; leadership development; morphine administration; mu opioid receptors; neural circuit; neurochemistry; pain relief; patch clamp; receptor; side effect; skills; training opportunity

Project Summary/Abstract Itch is a prevalent and debilitating side effect that follows neuraxial (intrathecal and epidural) morphine administration and has limited the therapeutic potential of opioids for pain. Nevertheless, the cellular basis of morphine-induced itch remains unclear. Morphine acts at the mu opioid receptor (MOR) to inhibit neuronal activity. Thus, it follows that morphine can cause itch through inhibition of inhibitory neurons that gate itch. I seek to test the hypothesis that neuraxial morphine causes itch through disinhibition. I propose to determine which subtype(s) of spinal interneurons is/are responsible for morphine-induced itch. There are five distinct subtypes of inhibitory neurons in the spinal cord dorsal horn that can be distinguished using distinct neurochemical markers and targeted with specific Cre alleles. Of these, two have previously been implicated in the inhibition of itch and are, therefore, ideal candidates. I propose to identify which of these five populations is responsible for morphine-induced itch using a combination of behavioral, anatomical, and physiological approaches. My proposal comprises the following aims: Aim 1: Determine whether the expression of MOR in spinal inhibitory neurons is required for morphine-induced itch. Aim 2: Determine which cell types express MOR. Aim 3: Determine which cell types are inhibited by morphine. Together, these experiments could reveal the cellular basis for morphine-induced itch for the first time. This information is critically important because a better understanding of how morphine causes itch in the spinal cord can lead to improved treatments for pain that do not cause itch. Thus, this work integrates closely with my clinical interest in anesthesiology. In this proposal, I outline a combination of rigorous mentored research training, longitudinal clinical experiences, coursework, and professional and leadership development activities. The intellectual, technical, and professional skills refined during this fellowship training period will be instrumental in my development as an aspiring physician scientist in the clinical field of academic anesthesiology.

项目摘要/摘要 瘙痒是遵循神经（鞘内和硬膜外）吗啡的普遍且令人衰弱的副作用 给药，并限制阿片类药物对疼痛的治疗潜力。然而， 吗啡引起的瘙痒尚不清楚。吗啡作用于mu阿片受体（MOR）以抑制神经元 活动。因此，得出的是吗啡可以通过抑制止痒的抑制性神经元引起瘙痒。我 试图检验神经吗啡通过抑制引起瘙痒的假设。我建议确定 哪种亚型的脊柱中间神经元的亚型是/负责吗啡诱导的瘙痒。有五个不同的 脊髓背角中抑制性神经元的亚型，可以使用不同的区分 神经化学标记，并以特定的CRE等位基因靶向。其中，两个以前涉及 因此，瘙痒的抑制作用，因此是理想的候选者。我建议确定这五个人群中的哪个是 使用行为，解剖学和生理学的组合负责吗啡诱导的瘙痒 方法。我的提议包括以下目的：目标1：确定MOR的表达是否在 吗啡诱导的瘙痒需要脊柱抑制性神经元。目标2：确定哪些细胞类型表达 莫AIM 3：确定吗啡抑制了哪些细胞类型。这些实验在一起可以揭示 吗啡诱导的瘙痒的细胞基础首次。此信息至关重要，因为 更好地理解吗啡在脊髓中如何引起瘙痒会导致改善疼痛的治疗方法 不会引起痒。因此，这项工作与我对麻醉学的临床兴趣紧密融合。在这个 提案，我概述了严格的指导研究培训，纵向临床经验， 课程以及专业和领导力发展活动。智力，技术和 在此奖学金培训期间，专业技能将在我的发展中发挥作用 学术麻醉学临床领域的有抱负的医师科学家。