Impact of fentanyl dependence on a parabrachio-amygdalar opioid circuit

芬太尼依赖对臂旁杏仁核阿片类药物回路的影响

• 批准号: 10604569
• 负责人: Lisa Wooldridge
• 金额: $ 4.77万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10604569
• 关键词: Address; Affect; Amygdaloid structure; Analgesics; Animals; Anterior; Attenuated; Automobile Driving; Aversive Stimulus; Behavior; Behavior Control; Behavioral; Biological Assay; Brain; Calcium; Cells; Chronic; Clinical; Coupled; Dependence; Experimental Designs; FOS gene; Fentanyl; Fiber; Foundations; Functional disorder; Future; GTP-Binding Proteins; Genetic; Glutamates; Goals; Hyperactivity; Hyperalgesia; Image; Immediate-Early Genes; Investigation; Knowledge; Lateral; Life; Mediating; Mediator; Modeling; Molecular Target; Mus; Neurons; Neurosciences; Neurosciences Research; Nociception; Opiate Addiction; Opioid; Opioid Receptor; Opioid agonist; Pain; Pain Threshold; Pain management; Pathway interactions; Patients; Photometry; Physical Dependence; Pontine structure; Population; Predisposition; Process; Public Health; Recreation; Repression; Research Personnel; Rewards; Rodent; Role; Signal Transduction; Stimulus; Substance Withdrawal Syndrome; Techniques; Training; Viral; Viral Vector; Withdrawal; Work; antagonist; associated symptom; behavioral pharmacology; career; cell type; chronic pain management; drinking water; endogenous opioids; fentanyl exposure; genetic manipulation; in vivo; in vivo calcium imaging; mouse model; neural; neural circuit; neuroregulation; novel therapeutics; opioid exposure; opioid misuse; opioid use; opioid use disorder; opioid withdrawal; parabrachial nucleus; prescription opioid; protein kinase C-delta; response; side effect; statistics; synthetic opioid

Project Summary/Abstract Opioid Use Disorder remains a dire public health problem, but opioid agonists such as fentanyl remain a first- line therapy for several pain conditions. As in recreational use settings, prolonged use of opioid agonists in pain management can produce physical dependence and a paradoxical decrease in pain thresholds and tolerance, which increase patients’ reliance on opioids and increase the likelihood of transitioning to Opioid Use Disorder. Continual stimulation of the inhibitory µ-opioid receptor (MOR), the primary mediator of the analgesic and rewarding effects of opioid agonists, induces counter-adaptive excitatory processes and hyperexcitability in MOR-expressing neurons. To discover new treatments that leverage the benefits of opioids but mitigate aversive and life-threatening side effects of prolonged opioid use, it is critical to determine the specific cell-types and neural circuits in the brain that are susceptible to the opioid-induced cellular maladaptations that underlie dependence and OIH. MORs are densely expressed throughout ascending pain pathways, including in the parabrachial nucleus of the pons (PBNMOR). PBNMOR neurons project to the capsular region of the central amygdala (CeC), which itself contains a pronociceptive population of neurons expressing Protein Kinase C-δ (CeCPKCδ) Activation of the PBNMOR®CeC pathway decreases pain tolerance and increases aversion-related responses, but its role in driving OIH and withdrawal, and the contribution of CeCPKCδ neurons in particular, has not been investigated. The goal of the proposal is to determine the impact of fentanyl dependence on the neural activity in the PBNMOR®CeCPKCδ pathway and whether such activity drives withdrawal and OIH-related behaviors. Aim 1 will investigate the effects of fentanyl dependence on PBNMOR®CeC projections and their role in driving OIH and withdrawal behavior by using in vivo population calcium imaging and chemogenetic manipulations during nociceptive assays and withdrawal. Aim 2 will image and manipulate the CeCPKCδ population during behavior to determine its contribution to OIH and withdrawal. Successful completion of these Aims will lay the foundation for future investigations of the pathophysiology of opioid dependence. Ideally, results from this work will suggest novel therapeutic avenues for reducing dependence mechanisms within specific cell-types. Ms. Wooldridge will receive expert training in chemogenetics, in vivo calcium imaging and its analysis, viral-mediated genetic targeting, and rigorous experimental design and statistics. The addition of this training will facilitate the applicant’s current and future research goals and enable her to have continual impact on basic neuroscience research throughout a future career as an independent academic researcher.

项目概要/摘要 阿片类药物使用障碍仍然是一个可怕的公共卫生问题，但芬太尼等阿片类药物激动剂仍然是首要问题。 针对多种疼痛状况的线疗法。与在娱乐用途中一样，长期使用阿片类激动剂来缓解疼痛 管理可能会产生身体依赖性以及疼痛阈值和耐受性的矛盾下降， 这增加了患者对阿片类药物的依赖，并增加了转变为阿片类药物使用障碍的可能性。 持续刺激抑制性 µ-阿片受体 (MOR)，这是镇痛和镇痛的主要介质 阿片类激动剂的奖赏作用，诱导反适应性兴奋过程和过度兴奋 MOR 表达神经元。发现新的治疗方法，利用阿片类药物的好处，但减轻厌恶 和长期使用阿片类药物的危及生命的副作用，确定特定的细胞类型和 大脑中的神经回路容易受到阿片类药物引起的细胞适应不良的影响 依赖性和 OIH。 MOR 在整个上行疼痛通路中密集表达，包括在 脑桥臂旁核 (PBNMOR)。 PBNMOR 神经元投射到中央的被膜区域 杏仁核 (CeC)，其本身包含表达蛋白激酶 C-δ 的促痛神经元群 (CeCPKCδ) PBNMOR®CeC 通路的激活会降低疼痛耐受性并增加厌恶相关性 反应，但其在驱动 OIH 和戒断中的作用，特别是 CeCPKCδ 神经元的贡献，已经 没有被调查。该提案的目标是确定芬太尼依赖对神经系统的影响 PBNMOR®CeCPKCδ 通路中的活性以及此类活性是否会导致戒断和 OIH 相关行为。 目标 1 将研究芬太尼依赖对 PBNMOR®CeC 预测的影响及其在驾驶中的作用 使用体内群体钙成像和化学遗传学操作观察 OIH 和戒断行为 在伤害性测定和戒断期间。目标 2 将在期间对 CeCPKCδ 群体进行成像和操纵 行为来确定其对 OIH 和戒断的贡献。成功完成这些目标将奠定 为未来研究阿片类药物依赖的病理生理学奠定基础。理想情况下，这项工作的结果 将提出减少特定细胞类型内依赖性机制的新治疗途径。多发性硬化症。 伍德里奇将接受化学遗传学、体内钙成像及其分析、病毒介导的专家培训 基因靶向、严格的实验设计和统计。此次培训的增加将有助于 申请人当前和未来的研究目标，并使她能够对基础神经科学产生持续的影响 作为独立学术研究员的整个未来职业生涯的研究。