Transcriptomic single-cell profiling in breathing-specific parabrachial mu-opioid receptor neurons

呼吸特异性臂旁μ阿片受体神经元的转录组单细胞分析

• 批准号: 10512708
• 负责人: Sung Han
• 金额: $ 74.3万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-15 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10512708
• 关键词: Acute; Address; Affinity; Agonist; Amygdaloid structure; Analgesics; Anatomy; Animals; Antidotes; Attenuated; Behavioral; Binding; Brain Stem; Brain region; Breathing; Candidate Disease Gene; Cause of Death; Cell Nucleus; Cells; Centers for Disease Control and Prevention (U.S.); Color; Complex; Constipation; Coupled; Death Rate; Dependence; Development; Disadvantaged; Dissection; Dizziness; Economics; Emotions; Fluorescent in Situ Hybridization; G-Protein-Coupled Receptors; Gene Expression Profile; Genes; Genetic; Goals; Half-Life; Human; Imaging Techniques; Injections; Knockout Mice; Label; Lateral; Ligands; Mediating; Mediator of activation protein; Molecular; Monitor; Morphine; Mus; Naloxone; Nausea; Neurons; Opioid; Opioid Analgesics; Opioid Antagonist; Opioid Receptor; Pain; Pathogenesis; Persons; Pharmacology; Physiological; Play; Population; Procedures; Proteins; Public Health; Regulation; Research; Role; Sedation procedure; Techniques; Testing; United States; Ventilatory Depression; addiction; antagonist; cell type; druggable target; experience; illicit opioid; mRNA Differential Displays; misuse of prescription only drugs; morphine administration; mu opioid receptors; neural circuit; neuromechanism; neuronal circuitry; new therapeutic target; novel; novel therapeutic intervention; opioid mortality; opioid use; pain perception; pain processing; parabrachial nucleus; prescription opioid; rate of change; receptor; relating to nervous system; respiratory; side effect; single-cell RNA sequencing; social; therapeutic target; tool; transcriptome; transcriptomics; transmission process; treatment strategy; welfare

ABSTRACT Opioids are the most commonly used and most effective analgesics, and are the first line of defense against acute and severe pain. However, this dramatic ability to mitigate pain comes with many side effects. These include constipation, nausea, sedation, dizziness, respiratory depression, dependence, and addiction. Among these, respiratory depression is the major driver of death by opioid overdose. According to the Center for Disease Control (CDC), nearly 50,000 people died in 2019 by opioid-induced respiratory depression (OIRD) in the United States, and the death rate is rising rapidly due to increased misuse and addiction to both prescription and illicit opioids. Thus, the US is currently experiencing a serious national public health crisis that is also taking a toll on social economic welfare. Despite these dire numbers, research elucidating the neural mechanisms of OIRD, which could identify therapeutic targets, has not been rigorously investigated. Animal studies have shown that OIRD and opioid analgesia are both mediated by the µ-opioid receptor (MOR), however the neural circuits and brain regions responsible for OIRD and opioid analgesia are not fully understood. The proposed research aims to dissect the neural circuits that selectively mediate OIRD or opioid analgesia using cutting-edge molecular, physiological, behavioral, and imaging techniques. Projection-specific single-cell transcriptomic analysis will then be used to identify functional markers expressed in the MOR- expressing neurons that specifically mediate OIRD, not opioid analgesia. Successful completion of the proposed research will identify novel therapeutic targets that selectively rescue OIRD without altering analgesic effects of opioids.

抽象的 阿片类药物是最常用、最有效的镇痛药，是预防癌症的第一道防线 急性和剧烈的疼痛。然而，这种显着的减轻疼痛的能力也伴随着许多副作用。这些 包括便秘、恶心、镇静、头晕、呼吸抑制、依赖性和成瘾。之中 其中，呼吸抑制是阿片类药物过量死亡的主要原因。据该中心称 美国疾病控制与预防中心 (CDC) 表示，2019 年，美国有近 50,000 人死于阿片类药物引起的呼吸抑制 (OIRD) 在美国，由于滥用和成瘾的增加，死亡率正在迅速上升 处方和非法阿片类药物。因此，美国目前正在经历严重的全国公共卫生危机 也对社会经济福利造成损害。尽管有这些可怕的数字，但研究阐明了神经元 OIRD 的机制可以识别治疗靶点，但尚未得到严格研究。动物 研究表明 OIRD 和阿片类镇痛均由 µ-阿片受体 (MOR) 介导， 然而，负责 OIRD 和阿片类镇痛的神经回路和大脑区域并不完全 明白了。拟议的研究旨在剖析选择性介导 OIRD 或阿片类药物的神经回路 使用尖端的分子、生理、行为和成像技术进行镇痛。投影特定 然后，单细胞转录组分析将用于鉴定 MOR- 中表达的功能标记。 表达特异性介导 OIRD（而非阿片类镇痛）的神经元。圆满完成了 拟议的研究将确定新的治疗靶点，在不改变镇痛药的情况下选择性地挽救 OIRD 阿片类药物的影响。