Optopharmacology and Sensors for Dissecting Opioid Action In Vivo

用于剖析阿片类药物体内作用的光药理学和传感器

• 批准号: 10471283
• 负责人: Michael R. Bruchas
• 金额: $ 37.77万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10471283
• 关键词: Absence of pain sensation; Acute; Address; Affect; Animals; Behavior; Biomedical Engineering; Biosensor; Brain; Brain region; Cell membrane; Cells; Cessation of life; Characteristics; Chemicals; Coupled; Detection; Development; Devices; Dimerization; Drug abuse; Endoplasmic Reticulum; Ensure; Fentanyl; Fiber; Fluorescence; Golgi Apparatus; Head; Image; Implant; In Vitro; Infusion procedures; Ligands; Link; Measures; Mediating; Methadone; Methods; Microdialysis; Monitor; Morphine; Motivation; Mus; NIH Program Announcements; Naloxone; National Institute of Drug Abuse; Needles; Neurons; Nucleus Accumbens; Opiate Addiction; Opioid; Opioid Analgesics; Opioid Receptor; Optics; Oral; Overdose; Pathway interactions; Peptide Signal Sequences; Pharmaceutical Preparations; Pharmacology; Photometry; Proteins; Reporter; Research; Resolution; Rewards; Saline; Self Administration; Series; Signal Transduction; Site; System; Testing; Therapeutic Uses; Time; Training; United States; Ventral Tegmental Area; Viral Vector; abuse liability; calcium indicator; combinatorial; design; experimental study; extracellular; illicit opioid; in vivo; in vivo imaging; lens; midbrain central gray substance; multidisciplinary; nanobodies; neural circuit; neurotransmission; novel; opioid use disorder; prescription opioid abuse; prescription opioid addiction; prescription opioid misuse; relating to nervous system; response; scaffold; sensor; spatiotemporal; tool; two-photon; wireless

PROJECT SUMMARY In 2019, abuse of prescription and illicit opioids resulted in an estimated over 47,000 deaths in the United States. The transition from therapeutic use to destructive opioid use disorder occurs through the maladaptive activation of mesocorticolimbic circuits. Despite decades of research linking these pathways with opioids, surprisingly little is understood about how opioids modulate the brain in vivo in space and time in freely moving animals. This is, in part, driven by the inability to detect and monitor opioids at sub-second timescales. Together, these issues highlight the need for significant advancements for “in vivo precision pharmacology” as indicated specifically in this RFA-DA-20-019 NIDA program announcement. Recent developments using photoactivatable opioid compounds (optopharmacology) together with new optofluidic hardware devices show exciting promise for finally understanding the temporal characteristics of opioid signaling. However, further advances in opioid detection and activation are necessary for fully decoding how opioids modulate neural circuits in vivo. Here we address this challenge head on with a multi-disciplinary team of biochemists, neuroscientists and bioengineers. We will utilize a series of cutting-edge approaches to: 1) develop novel opioid sensors for in vivo, sub-second measures of fentanyl, morphine, and methadone, 2) demonstrate the utility of optopharmacological approaches for dissecting opioid action, and 3) apply the sensors and optopharmacological approaches to perform in vivo precision pharmacological experiments to modulate pain and reward circuits related to drug abuse.

项目摘要 2019年，处方和非法阿片类药物的滥用导致美国估计有47,000多人死亡。 从热使用到破坏性阿片类药物使用障碍的过渡是通过适应不良激活发生的 中质粒圆圈。尽管数十年的研究将这些途径与阿片类药物联系起来，但令人惊讶的 关于阿片类药物如何在自由移动动物的空间和时间上调节大脑的大脑如何理解。这是， 在某种程度上，由于无法检测和监测亚秒时间标准的阿片类药物的驱动。在一起，这些 问题突出了对“体内精度药理学”的重大进步的必要性 特别是在此RFA-DA-20-019 NIDA计划公告中。最新的发展使用 光活化阿片化合物（光药学）以及新的OptoFluidic硬件设备显示 最终了解阿片类药物信号传导的暂时特征的令人兴奋的前途。但是，进一步 阿片类药物检测和激活的进步对于完全解码阿片类药物如何调节神经回路是必要的 体内。在这里，我们与一个多学科的生物化学家，神经科学家一起解决了这一挑战领域 和生物工程师。我们将利用一系列尖端方法来：1）开发新颖的阿片类药物传感器 体内，芬太尼，吗啡和Metagadone的次秒测量，2）证明了效用 剖析选项作用的光药学方法，以及3）应用传感器和光药学 执行体内精度药物实验的方法，以调节疼痛和奖励电路 与药物滥用有关。