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

摘要 阿片类药物是最常用和最有效的止痛药，是预防 剧烈的疼痛。然而，这种戏剧性的缓解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、依赖和上瘾。其中 这些，呼吸抑制是阿片类药物过量死亡的主要驱动因素。根据该中心的数据 疾病控制中心(CDC)，2019年有近5万人死于阿片类药物引起的呼吸抑制(OIRD) 在美国，由于滥用和对两者上瘾的增加，死亡率正在迅速上升 处方和非法阿片类药物。因此，美国目前正在经历一场严重的国家公共卫生危机， 也对社会经济福利造成了影响。尽管有这些可怕的数字，但研究阐明了神经 OIRD的机制可以识别治疗靶点，但尚未得到严格的研究。动物 研究表明，OIRD和阿片类药物的镇痛都是由µ-阿片受体(MOR)介导的， 然而，负责OIRD和阿片类药物镇痛的神经回路和大脑区域并不完全 明白了。这项拟议的研究旨在剖析选择性地调节OIRD或阿片类药物的神经回路 使用尖端分子、生理、行为和成像技术的止痛。投影特定 然后，单细胞转录分析将被用来鉴定在MOR-1中表达的功能标记。 表达特异性介导OIRD的神经元，而不是阿片类止痛。圆满完成 拟议的研究将确定新的治疗靶点，在不改变止痛剂的情况下选择性地拯救OIRD 阿片类药物的影响。

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.