Analgesic Mechanism of Action of Endogenous Opioid Peptides Enkephalins with a Fo

内源性阿片肽脑啡肽的镇痛作用机制

基本信息

批准号：
8723142
负责人：
Gregory Scherrer
金额：
$ 24.9万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-30 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8723142
关键词：
Ablation Acute Pain Adverse effects Affinity Agonist Analgesics Behavioral Assay Behavioral Genetics Cellular biology Clinic Constipation Dendrites Development Disease Drug Addiction Drug abuse Drug usage Enkephalins Environment G-Protein-Coupled Receptors Genes Goals Health Hyperalgesia Individual Injury Interneurons Mediating Mentors Methods Morphine Neurons Opioid Opioid Peptide Opioid Receptor Pain Pain Threshold Pain management Peptide Receptor Peptides Pharmaceutical Preparations Process Property Recruitment Activity Research Research Personnel Resistance Signal Transduction Spinal Spinal Cord System Testing Treatment Efficacy Universities Ventilatory Depression Vomiting base career chronic pain dorsal horn endogenous opioids improved innovation knockout gene mu opioid receptors neuronal cell body neurotransmission novel therapeutics painful neuropathy preproenkephalin receptor research facility response success trafficking transmission process

项目摘要

PROJECT SUMMARY The endogenous opioid system regulates pain sensitivity and is targeted by opioid drugs used in the clinic (e.g. morphine) for the management of pathological (disease- or injury-induced) pain. However, current opioid therapies generate significant side effects (i.e. paradoxical hyperalgesia, drug abuse, vomiting, constipation, respiratory depression, etc) and have limited efficacy for the treatment of certain types of chronic pain (i.e neuropathic pain). The endogenous opioid system is composed of several peptide agonists (including enkephalins) and of the delta, kappa and mu opioid receptors (DOR, KOR and MOR, respectively). The contribution of individual opioid receptors and peptides to pain processing has been probed by pharmacological and gene knockout approaches, but surprisingly little is known about the mechanisms by which interactions between these peptides and receptors regulate pain. The objective of the proposed research is to better understand how enkephalins and opioid drugs regulate pain transmission in the spinal cord, where neuroplastic changes leading to chronic pain occur, to develop new therapeutic strategies to treat morphine-resistant types of chronic pain. We will first investigate the cellular mechanisms by which enkephalins regulate activity of spinal neurons known to be critical to chronic pain. We will test the hypothesis that because of distinctions between DOR and MOR cellular biology (e.g. expression by different neurons, different trafficking properties or subcellular localization) activation of the two opioid receptors differentially alters neuronal activity. We will then investigate spinal enkephalinergic circuits and identify both the neurons responding to enkephalins and the opioid receptors mediating these responses (DOR and/or MOR). We will test the hypothesis that release of enkephalins inhibits neighboring projection neurons known to be critical to chronic pain, as well as enkephalinergic neurons themselves (autosignaling). Finally, we will use behavioral assays to test the hypothesis that enkephalinergic neurons are critical to setting pain threshold during chronic pain. The proposed studies should greatly improve our understanding of the mechanisms by which the endogenous opioid system controls pain. In addition, these studies might provide an explanation for the limited efficiency of current therapies and stand to uncover new opioid-based strategies to manage chronic pain. Additionally, both the innovative methods developed in this project and the new information obtained is expected to have a broad impact on our understanding of the mechanism of action of opioid drugs, beyond the pain field (i.e. drug addiction). The mentor, Dr. Amy MacDermott, has a distinguished reputation for productive and relevant research on electrophysiological studies of the spinal pain circuitry. In addition, she has a strong track record of supervising trainees who go on to become productive, independent researchers. Columbia University provides a high-quality environment for the development of Dr. Scherrer's career and research plans. The research facilities, educational opportunities, and intellectual environment are outstanding and will contribute greatly to the success of the proposed activities.

项目概要内源性阿片类药物系统调节疼痛敏感性，是临床使用的阿片类药物的目标（例如阿片类药物）。吗啡）用于治疗病理性（疾病或损伤引起的）疼痛。然而，目前的阿片类药物治疗会产生显着的副作用（即矛盾的痛觉过敏、药物滥用、呕吐、便秘、呼吸抑制等），并且对于治疗某些类型的慢性疼痛（即神经性疼痛）。内源性阿片系统由多种肽激动剂组成（包括脑啡肽）以及 delta、kappa 和 mu 阿片受体（分别为 DOR、KOR 和 MOR）。这个体阿片受体和肽对疼痛处理的贡献已被探索药理学和基因敲除方法，但令人惊讶的是对其机制知之甚少这些肽和受体之间的相互作用调节疼痛。拟议研究的目的是更好地了解脑啡肽和阿片类药物如何调节疼痛脊髓中的传播，其中发生导致慢性疼痛的神经塑性变化，以开发新的治疗吗啡耐药类型的慢性疼痛的治疗策略。我们将首先研究脑啡肽调节脊髓神经元活动的细胞机制已知对慢性疼痛至关重要。我们将检验以下假设：由于 DOR 和 MOR 细胞生物学（例如不同神经元的表达、不同的运输特性或亚细胞两种阿片受体的激活会不同程度地改变神经元活动。我们随后将进行调查脊髓脑啡肽能回路并识别对脑啡肽和阿片类药物有反应的神经元介导这些反应的受体（DOR 和/或 MOR）。我们将测试释放的假设脑啡肽抑制已知对慢性疼痛至关重要的邻近投射神经元，以及脑啡肽能神经元本身（自动信号传导）。最后，我们将使用行为分析来测试假设脑啡肽能神经元对于慢性疼痛期间设定疼痛阈值至关重要。拟议的研究应该极大地提高我们对内源性机制的理解阿片类药物系统控制疼痛。此外，这些研究可能为有限的效率提供解释。目前的疗法，并有望发现新的基于阿片类药物的策略来治疗慢性疼痛。此外，两者该项目中开发的创新方法和获得的新信息预计将具有广泛的影响影响我们对阿片类药物作用机制的理解，超越疼痛领域（即药物瘾）。导师艾米·麦克德莫特 (Amy MacDermott) 博士在富有成效的相关研究方面享有盛誉。脊髓疼痛回路的电生理学研究。此外，她在监督方面有着良好的记录受训者将继续成为富有成效的独立研究人员。哥伦比亚大学为Scherrer博士的职业发展提供了优质的环境，研究计划。研究设施、教育机会和智力环境非常出色并将为拟议活动的成功做出巨大贡献。