Adaptations following chronic opioid treatment and withdrawal

长期阿片类药物治疗和戒断后的适应

基本信息

批准号：
10554400
负责人：
Sweta Adhikary
金额：
$ 0.15万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-01 至 2023-03-02
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10554400
关键词：
Absence of pain sensation Acute Address Adenosine Adenylate Cyclase Agonist Alanine Analgesics Body Regions Brain Brain region Cells Central Nervous System Chronic Clinical Corpus striatum structure Coupling Cyclic AMP Dependence Development Disease Electric Stimulation Electrophysiology (science)Event Fentanyl Glutamates Intake Knock-in Mouse Knock-out Link Measures Mediating Methods Morphine Mus Mutation Neurons Opioid Opioid Receptor Pain Patients Perioperative Pharmaceutical Preparations Phosphorylation Play Postoperative Pain Presynaptic Terminals Public Health Purinergic P1 Receptors Receptor Signaling Regulation Relapse Reporting Rewards Role Second Messenger Systems Serine Signal Transduction Site Slice Source Synapses Synaptic Transmission Thalamic structure Threonine Up-Regulation Wild Type Mouse Withdrawal Work abuse liability addiction antagonist bird song curative treatments desensitization emotional symptom experimental study extracellular neurotransmitter release new therapeutic target opioid exposure opioid use opioid use disorder opioid withdrawal optogenetics pharmacologic physical symptom receptor receptor sensitivity research study response

项目摘要

Project Summary Opioids such as morphine and fentanyl effectively relieve acute and post-operative pain but long-term use is problematic due to their abuse liability. Long-term opioid use causes cellular and circuit level adaptations that can lead to addiction, but the precise mechanisms are not fully understood. Furthermore, withdrawal from opioids unmasks these adaptive changes facilitating increased drug intake and promoting relapse. This proposal will use an optogenetic approach to isolate glutamate projection from both opioid sensitive (thalamic) and insensitive (cortical) terminals coming into the striatum in mice. Whole-cell electrophysiological recordings in brain slices will be used to investigate the mechanisms mediating adaptive changes following chronic opioid treatment and withdrawal. Receptor phosphorylation is a key cellular event mediating acute desensitization and long-term tolerance in cell-body specific µ-opioid receptors (MORs), but little is known about the role of phosphorylation in mediating signaling in presynaptic terminal MORs. Experiments in Aim 1 will therefore elucidate the role of phosphorylation in mediating acute sensitivity and long-term tolerance to both morphine and fentanyl after chronic treatment in terminal MORs. Furthermore, adaptations following chronic treatment go beyond the receptor level and can influence downstream second messengers like adenylyl cyclase. Adenylyl cyclase can be metabolized to adenosine in central nervous system synapses to modulate glutamate release. Experiments in Aim 2 will therefore focus on the mechanisms underlying release and regulation of adenosine in striatal synapses, specifically the role of MORs in mediating adenosine concentration after chronic opioid treatment. The overall hypothesis is that MOR phosphorylation is a key signaling event that establishes both acute sensitivity and long-term tolerance to opioids, and activation of MORs plays a critical role in mediating the concentration of adenosine in striatal synapses. Ultimately, the results from this study will address the role of phosphorylation in terminal MOR signaling and determine receptor and cellular adaptations that result from chronic opioid treatment and withdrawal. By looking at the effects of both morphine (a partial agonist) and fentanyl (a full agonist), a comprehensive understanding of the role of receptor phosphorylation on synaptic transmission after chronic opioid exposure will be established. Understanding the key receptor and cellular changes that mediate synaptic activity after chronic opioid treatment is a crucial first step in identifying novel therapeutic targets to treat opioid use disorder.

项目概要吗啡和芬太尼等阿片类药物可有效缓解急性和术后疼痛，但长期效果不佳由于长期使用阿片类药物会导致细胞和电路水平的适应，因此使用存在问题。这可能会导致成瘾，但其确切机制尚不完全清楚。阿片类药物揭示了这些适应性变化，促进药物摄入量增加并促进复发。该提案将使用光遗传学方法将谷氨酸投射与阿片类药物敏感（丘脑）分离和进入小鼠纹状体的不敏感（皮质）末端。脑切片将用于研究慢性阿片类药物后介导适应性变化的机制治疗和停药。受体磷酸化是介导急性脱敏和长期作用的关键细胞事件细胞体特异性μ阿片受体（MOR）的耐受性，但对磷酸化的作用知之甚少因此，目标 1 中的实验将阐明突触前末端 MOR 中介导信号传导的作用。磷酸化介导对吗啡和芬太尼的急性敏感性和长期耐受性终末期 MOR 的长期治疗此外，长期治疗后的适应超出了治疗范围。受体水平并可以影响下游第二信使，如腺苷酸环化酶。在中枢神经系统突触中代谢为腺苷以调节谷氨酸释放。因此，目标 2 将重点关注纹状体中腺苷释放和调节的机制。突触，特别是长期阿片类药物治疗后 MOR 在介导腺苷浓度中的作用。总体假设是 MOR 磷酸化是一个关键的信号传导事件，它建立了急性对阿片类药物的敏感性和长期耐受性，MOR 的激活在介导阿片类药物的敏感性和长期耐受性方面发挥着关键作用纹状体突触中腺苷的浓度。最终，这项研究的结果将解决磷酸化在末端 MOR 信号传导中的作用并确定长期阿片类药物治疗和戒断导致的受体和细胞适应。观察吗啡（部分激动剂）和芬太尼（完全激动剂）的作用，综合了解慢性阿片类药物暴露后受体磷酸化对突触传递的作用将建立了解介导突触活动的关键受体和细胞变化。慢性阿片类药物治疗是确定治疗阿片类药物使用的新治疗靶点的关键第一步紊乱。