Adaptations following chronic opioid treatment and withdrawal

长期阿片类药物治疗和戒断后的适应

• 批准号: 10359731
• 负责人: Sweta Adhikary
• 金额: $ 5.18万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10359731
• 关键词: Absence of pain sensation; Acute; Acute Pain; Address; Adenosine; Adenosine Monophosphate; Adenylate Cyclase; Agonist; Alanine; Analgesics; Body Regions; Brain; Brain region; Cells; Chronic; Clinical; Corpus striatum structure; Coupling; Cyclic AMP; Dependence; Development; Disease; Electrophysiology (science); Event; Fentanyl; Glutamates; Intake; Knock-in Mouse; Knock-out; Lead; Link; Measures; Mediating; Methods; Morphine; Mus; Mutation; Neuraxis; Neurons; Opioid; Pain; Patients; Periodicity; Perioperative; Pharmaceutical Preparations; Pharmacology; Phosphorylation; Play; Postoperative Pain; Presynaptic Terminals; Public Health; Purinergic P1 Receptors; 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; mu opioid receptors; neurotransmitter release; new therapeutic target; opioid exposure; opioid use; opioid use disorder; opioid withdrawal; optogenetics; physical symptom; receptor; receptor sensitivity; research study; response

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.

项目摘要 吗啡和芬太尼等阿片类药物有效地挽救急性和术后疼痛，但长期 由于滥用责任，使用是有问题的。长期使用阿片类药物会导致细胞和电路水平适应 这可能导致成瘾，但是确切的机制尚未完全理解。此外，退出 Opioids揭示了这些适应性变化，促进了药物摄入量增加并促进缓解。这 提案将使用光遗传学方法来分离阿片类药物敏感（丘脑）的谷氨酸投影 和不敏感的（皮质）末端进入小鼠的纹状体。全细胞电生理记录 在脑切片中，将用于研究慢性Ooid后介导适应性变化的机制 治疗和退出。 受体磷酸化是介导急性脱敏和长期的关键细胞事件 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 在突触前末端MORS中介导信号传导中。因此，AIM 1中的实验将阐明 介导急性敏感性和对吗啡和芬太尼的长期耐受性的磷酸化 终端慢性治疗。此外，慢性治疗后的适应超出了 受体水平并可能影响下游第二使者，例如腺苷酸环化酶。腺苷酸环化酶可以 在中枢神经系统突触中代谢为腺苷，以调节谷氨酸释放。实验 因此，在AIM 2中，将重点关注纹状体中腺苷的释放和调节的机制 突触，特别是MOR在慢性阿片类药物治疗后介导腺苷浓度的作用。 总体假设是，MOR磷酸化是一个关键信号事件，可以建立这两个急性 对阿片类药物的敏感性和长期耐受性，而MOR的激活在介导 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 并确定由慢性阿片类药物治疗和戒断导致的受体和细胞适应。经过 查看吗啡（部分激动剂）和芬太尼（完整激动剂）的影响，这是一种综合 了解慢性阿片类药物暴露后受体磷酸化对突触传播的作用 将建立。了解关键受体和细胞变化，使得介导突触活动后 慢性阿片类药物治疗是识别新型治疗靶标的治疗阿片类药物使用的至关重要的第一步 紊乱。