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

项目摘要 内源性阿片样物质系统调节疼痛敏感性，并且被临床中使用的阿片样物质药物靶向（例如， 吗啡）用于控制病理性（疾病或损伤引起的）疼痛。目前，阿片类药物 治疗产生显著的副作用（即反常的痛觉过敏、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）。内源性阿片系统由几种肽激动剂（包括 脑啡肽）和δ、κ和μ阿片受体（分别为DOR、KOR和莫尔）。的 已经通过以下方法探索了单个阿片受体和肽对疼痛处理的贡献： 药理学和基因敲除方法，但令人惊讶的是，很少有人知道的机制， 这些肽和受体之间的相互作用调节疼痛。 这项研究的目的是为了更好地了解脑啡肽和阿片类药物如何调节疼痛 在脊髓中的传递，在那里神经可塑性变化导致慢性疼痛发生，发展新的 治疗吗啡抵抗型慢性疼痛的治疗策略。 我们将首先探讨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。我们将检验这样一个假设，即由于DOR和 莫尔细胞生物学（例如，不同神经元的表达、不同运输特性或亚细胞生物学） 两种阿片受体的激活差异性地改变神经元活性。我们会调查 脊髓脑啡肽能回路，并确定神经元对脑啡肽和阿片样物质的反应 介导这些反应的受体（DOR和/或莫尔）。我们将检验一个假设， 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 脑啡肽能神经元自身（自身信号传导）。最后，我们将使用行为分析来测试 脑啡肽能神经元在慢性疼痛中对设定痛阈至关重要的假说。 拟议的研究将大大提高我们对内源性 阿片系统控制疼痛。此外，这些研究可能解释了 目前的治疗方法，并站在揭示新的阿片类药物为基础的战略，以管理慢性疼痛。此外，双方 在这个项目中开发的创新方法和获得的新信息预计将有广泛的 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 成瘾）。 导师艾米·麦克德莫特博士在以下方面的富有成效和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 受训人员将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高质量的环境， 研究计划。研究设施、教育机会和智力环境都很出色 并将大大有助于拟议活动的成功。

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.