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

基本信息

批准号：
10268988
负责人：
Michael R. Bruchas
金额：
$ 38.39万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
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/10268988
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 Wireless Technology 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

项目摘要

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.

项目概要 2019 年，滥用处方药和非法阿片类药物导致美国估计超过 47,000 人死亡。从治疗性用途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，但令人惊讶的是很少。人们了解阿片类药物如何在自由活动的动物体内调节大脑的空间和时间。部分原因是无法在亚秒级时间内检测和监测阿片类药物。这些问题凸显了“体内精准药理学”取得重大进展的必要性特别是在 RFA-DA-20-019 NIDA 计划公告中使用的最新进展。可光激活的阿片类化合物（光药理学）与新的光流控硬件设备一起展示令人兴奋的希望最终了解阿片类信号传导的时间特征然而，进一步。阿片类药物检测和激活方面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在这里，我们与生物化学家、神经科学家组成的多学科团队共同应对这一挑战。我们将利用一系列尖端方法来：1）开发新型阿片类药物传感器。体内，芬太尼、吗啡和美沙酮的亚秒测量，2) 证明了用于剖析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进行体内精密药理学实验以调节疼痛和奖励回路的方法与药物滥用有关。