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

• 批准号: 8164450
• 负责人: Gregory Scherrer
• 金额: $ 16.08万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8164450
• 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; 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

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Opioid drugs such as morphine are widely used for the treatment of severe pain despite generating significant side effects (vomiting, constipation, respiratory depression, drug abuse, etc) and having limited efficacy for the management of certain types of chronic pain (neuropathic pain). The goal of the proposed studies is to understand the mechanisms by which opioid drugs relieve pain and generate side effects to develop more efficient and safer drugs to treat pain.

描述（由申请人提供）：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（例如吗啡）的目标，用于治疗病理性（疾病或损伤引起的）疼痛。然而，目前的阿片类药物疗法会产生显着的副作用（即反常痛觉过敏、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）疗效有限。内源性阿片系统由多种肽激动剂（包括脑啡肽）和 delta、kappa 和 mu 阿片受体（分别为 DOR、KOR 和 MOR）组成。单个阿片受体和肽对疼痛处理的贡献已通过药理学和基因敲除方法进行了探讨，但令人惊讶的是，人们对这些肽和受体之间相互作用调节疼痛的机制知之甚少。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脊髓中的疼痛传递（在脊髓中发生神经塑性变化导致慢性疼痛），以开发新的治疗策略来治疗吗啡耐药类型的慢性疼痛。我们将首先研究脑啡肽调节已知对慢性疼痛至关重要的脊髓神经元活动的细胞机制。我们将测试以下假设：由于 DOR 和 MOR 细胞生物学之间的差异（例如不同神经元的表达、不同的运输特性或亚细胞定位），两种阿片受体的激活会不同地改变神经元活性。然后，我们将研究脊髓脑啡肽能回路，并识别对脑啡肽做出反应的神经元和介导这些反应的阿片受体（DOR 和/或 MOR）。我们将测试这样的假设：脑啡肽的释放会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检验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的假设。拟议的研究将大大提高我们对内源性阿片类药物系统控制疼痛机制的理解。此外，这些研究可能为当前疗法的有限效率提供解释，并有望发现新的基于阿片类药物的治疗慢性疼痛的策略。此外，该项目开发的创新方法和获得的新信息预计将对我们对阿片类药物作用机制的理解产生广泛的影响，超越疼痛领域（即药物成瘾）。导师艾米·麦克德莫特 (Amy MacDermott) 博士在脊髓疼痛回路电生理学研究方面富有成效且相关的研究方面享有盛誉。此外，她在监督实习生方面拥有良好的记录，这些实习生后来成为富有成效的独立研究人员。哥伦比亚大学为Scherrer博士的职业生涯和研究计划的发展提供了优质的环境。研究设施、教育机会和智力环境非常出色，将为拟议活动的成功做出巨大贡献。 公共健康相关性：吗啡等阿片类药物被广泛用于治疗严重疼痛，尽管会产生明显的副作用（呕吐、便秘、呼吸抑制、药物滥用等），并且对治疗某些类型的慢性疼痛（神经性疼痛）疗效有限。拟议研究的目标是了解阿片类药物缓解疼痛和产生副作用的机制，以开发更有效、更安全的药物来治疗疼痛。

项目成果

GINIP, a Gαi-interacting protein, functions as a key modulator of peripheral GABAB receptor-mediated analgesia.

• DOI: 10.1016/j.neuron.2014.08.056
• 发表时间: 2014-10-01
• 期刊: Neuron
• 影响因子: 16.2
• 作者: Gaillard S;Lo Re L;Mantilleri A;Hepp R;Urien L;Malapert P;Alonso S;Deage M;Kambrun C;Landry M;Low SA;Alloui A;Lambolez B;Scherrer G;Le Feuvre Y;Bourinet E;Moqrich A
• 通讯作者: Moqrich A