Rapid and sensitive in vivo detection of opioid peptides

快速、灵敏的阿片肽体内检测

• 批准号: 9767373
• 负责人: Ream Al-Hasani
• 金额: $ 24.32万
• 依托单位: ST. LOUIS COLLEGE OF PHARMACY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9767373
• 关键词: Absence of pain sensation; Abstinence; Acute; Address; Affective; Amino Acid Sequence; Amyloid beta-Protein; Anatomy; Anecdotes; Antibodies; Anxiety; Automobile Driving; Behavioral; Binding; Biological Assay; Biology; Brain region; Chronic; Cleaved cell; Collection; Complex; Conflict (Psychology); Cysteine; Data; Detection; Development; Dialysis procedure; Disease; Dynorphins; Ensure; Epidemic; Epitopes; Exposure to; Fentanyl; Goals; Health; Heroin; Incidence; Kinetics; Knowledge; Lead; Length; Measurement; Measures; Mental Depression; Mental Health; Methionine; Methods; Microdialysis; Missouri; Morphine; Mus; Naloxone; Narcan; Neurons; Neuropeptides; Neurotransmitters; Nucleus Accumbens; Opioid; Opioid Peptide; Overdose; Oxides; Pain; Peptide Hydrolases; Peptide Receptor; Peptides; Post-Translational Protein Processing; Process; Relapse; Research; Resolution; Risk; Role; Sampling; Sensitivity and Specificity; Severities; Stress; Symptoms; System; Techniques; Technology; Time; Tyrosine; United States; Virus; Withdrawal; Withdrawal Symptom; addiction; anxiety-like behavior; base; brain circuitry; carbon fiber; cohesion; disorder later incidence prevention; drug of abuse; drug withdrawal; economic cost; effective therapy; endogenous opioids; experience; improved; in vivo; innovation; kappa opioid receptors; liquid chromatography mass spectrometry; millisecond; negative affect; neurotransmitter release; novel; novel strategies; opioid epidemic; opioid use disorder; opioid withdrawal; optogenetics; overdose prevention; physical symptom; response; reward processing; spatiotemporal; temporal measurement

Project Summary The goals of this research are two fold: to better understand the role of dynorphin during fentanyl withdrawal and to develop innovative, novel approaches to allow in vivo detection of endogenously release opioids. The ability to better understand how dynorphin drives negative affect associated with drug withdrawal will be critical in reducing the incidence of relapse and overdose and allow us to consider alternative more affective long-term treatments for addiction. The US Department of Health states that 42,249 people died from overdosing on opioids in 2016, 2.1 million people had an opioid use disorder and the economic cost of this epidemic was $504 billion, but is still rising along with the number of people afflicted. The reasons for this are multifaceted, but include a deep lack of understanding of how opioids alter brain circuitry to cause analgesia- which is good, but also what happens to brain circuitry to drive addiction- which is bad. We also know that pain and addiction are co-morbid with other mental health diseases such as anxiety, depression and stress, which makes cohesive research challenging. The first aim of this proposal will directly measure in vivo changes in dynorphin levels in the nucleus accumbens during withdrawal from Fentanyl. Fentanyl is 80 times more potent than morphine in vivo; its rapid onset of action not only increases the risk of addiction but likely increases the severity of withdrawal symptoms. We will use liquid chromatography/mass spectrometry which will allow detection in sub-fmol range. The second aim focuses on the development of micro-immunoelectrodes to allow more spatiotemporally controlled detection of opioid peptide release in vivo. This technology will allow us to detect peptides changes on a second to minute timescale. The combination of these techniques will, for the first time, allow us to detect dynamic changes in opioid peptides in vivo. Importantly, this will facilitate our knowledge and ability to better treat addiction, but is also very much applicable to multiple disease states and neuropeptides biology in general.

项目摘要 这项研究的目的有两个：更好地了解强啡肽在芬太尼戒断过程中的作用， 开发创新的新方法，以允许在体内检测内源性释放的阿片类药物。的能力 为了更好地了解强啡肽如何导致与戒毒相关的负面影响， 减少复发和过量的发生率，并使我们能够考虑替代更有效的长期 治疗成瘾。美国卫生部指出，42，249人死于过量服用阿片类药物 2016年，210万人患有阿片类药物使用障碍，这一流行病造成的经济损失为5040亿美元， 但仍在沿着患病人数的上升。其原因是多方面的，但包括 对阿片类药物如何改变大脑回路以引起镇痛的理解严重缺乏-这是好的，但也是什么 大脑回路中发生了什么来驱动成瘾-这是不好的。我们还知道疼痛和成瘾是共存的 与其他心理健康疾病，如焦虑，抑郁和压力，这使得连贯的研究 挑战性该建议的第一个目的是直接测量细胞核中强啡肽水平的体内变化 芬太尼戒断期间的镇静剂。芬太尼在体内的效力是吗啡的80倍;其快速 作用的开始不仅增加了成瘾的风险，而且可能增加戒断症状的严重性。 我们将使用液相色谱/质谱法，这将允许在亚fmol范围内进行检测。第二 aim专注于开发微免疫电极，以实现更多的时空控制检测 阿片肽的释放。这项技术将使我们能够在一秒到一分钟内检测到肽的变化 时间尺度。这些技术的结合将首次使我们能够检测 体内阿片肽。重要的是，这将促进我们更好地治疗成瘾的知识和能力，但事实上， 一般也非常适用于多种疾病状态和神经肽生物学。