Optopharmacology and Sensors for Dissecting Opioid Action In Vivo

项目摘要 2019年，滥用处方和非法阿片类药物导致美国估计超过47，000人死亡。 从治疗性使用到破坏性阿片类药物使用障碍的转变是通过适应不良激活发生的 中皮层边缘回路的一部分尽管数十年的研究将这些途径与阿片类药物联系起来，但令人惊讶的是， 了解阿片类药物如何在空间和时间上调节自由移动动物的体内大脑。这是， 部分原因是无法在亚秒的时间尺度上检测和监测阿片类药物。所有这些 这些问题突出表明，需要在“体内精确药理学”方面取得重大进展， 特别是在RFA-DA-20-019 NIDA计划公告中。最近的事态发展， 光活化阿片类化合物（光药理学）与新的光流体硬件设备一起显示， 令人兴奋的承诺，最终了解阿片信号的时间特征。但进一步 阿片类药物检测和激活方面的进展对于充分解码阿片类药物如何调节神经回路是必要的 in vivo.在这里，我们与生物化学家，神经科学家， 和生物工程师我们将利用一系列尖端的方法：1）开发新型阿片类药物传感器， 芬太尼、吗啡和美沙酮的体内亚秒测量，2）证明了 解剖阿片类药物作用的光学药理学方法，以及3）应用传感器和光学药理学方法， 进行体内精确药理学实验以调节疼痛和奖赏回路的方法 与药物滥用有关。

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.