Optopharmacology and Sensors for Dissecting Opioid Action In Vivo

项目总结 2019年，处方和非法阿片类药物的滥用导致美国估计有超过4.7万人死亡。 从治疗性使用到破坏性阿片使用障碍的转变是通过不适应激活发生的。 大脑中皮质边缘环路。尽管几十年的研究将这些途径与阿片类药物联系在一起，但令人惊讶的是，几乎没有 了解阿片类药物如何在自由活动的动物体内在空间和时间上调节大脑。这是, 部分原因是无法在亚秒时间尺度上检测和监测阿片类药物。加在一起，这些 这些问题突出了“体内精确药理学”取得重大进展的必要性。 特别是在这份RFA-DA-20-019 NIDA计划公告中。最近的发展，使用 可光激活阿片类化合物(光学药理学)与新的光流控硬件设备一起展示 为最终了解阿片类药物信号的时间特征带来了令人兴奋的前景。然而，进一步 阿片类药物检测和激活的进展对于完全破译阿片类药物如何调制神经回路是必要的 在活体内。在这里，我们与生物化学家、神经科学家组成的多学科团队正面应对这一挑战 和生物工程师。我们将利用一系列尖端方法：1)开发用于IN的新型阿片传感器 芬太尼、吗啡和美沙酮的活体、亚秒级测量，2)证明了 研究阿片类药物作用的光学药理学方法，以及3)传感器和光学药理学的应用 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.