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

描述(由申请人提供)：内源性阿片系统调节疼痛敏感性，是临床上用于治疗病理性(疾病或损伤引起的)疼痛的阿片类药物(如吗啡)的靶点。然而，目前的阿片类药物治疗会产生严重的副作用(如反常的痛觉过敏、药物滥用、呕吐、便秘、呼吸抑制等)，并且对某些类型的慢性疼痛(即神经性疼痛)的疗效有限。内源性阿片系统由几种多肽激动剂(包括脑啡肽)和Delta、Kappa和Mu阿片受体(分别为DOR、KOR和MOR)组成。通过药理学和基因敲除的方法已经探讨了单个阿片受体和多肽在疼痛处理中的作用，但令人惊讶的是，人们对这些多肽和受体之间相互作用调节疼痛的机制知之甚少。这项拟议的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，在脊髓中发生神经可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脊髓神经元活动的细胞机制，已知的脊髓神经元是慢性疼痛的关键。我们将检验这一假设，即由于DOR和MOR细胞生物学上的差异(例如，不同神经元的表达、不同的转运特性或亚细胞定位)，两种阿片受体的激活会不同地改变神经元的活动。然后，我们将研究脊髓脑啡肽能回路，并确定对脑啡肽有反应的神经元和介导这些反应的阿片受体(DOR和/或MOR)。我们将检验这一假设，即脑啡肽的释放抑制了已知的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(自身信号)。最后，我们将使用行为分析来检验脑啡肽能神经元在慢性疼痛期间设定痛阈值的关键这一假设。拟议的研究将极大地提高我们对内源性阿片系统控制疼痛的机制的理解。此外，这些研究可能会为目前治疗效果有限的原因提供解释，并有望发现新的基于阿片类药物的策略来管理慢性疼痛。此外，该项目开发的创新方法和获得的新信息预计都将对我们理解阿片类药物的作用机制产生广泛影响，超越疼痛领域(即药物成瘾)。导师艾米·麦克德莫特博士在脊髓痛觉回路的电生理学研究方面富有成效和相关研究方面享有盛誉。此外，她在监督受训人员方面有着良好的记录，这些受训人员后来成为多产的独立研究人员。哥伦比亚大学为谢勒博士的职业发展和研究计划提供了高质量的环境。研究设施、教育机会和智力环境都很出色，将极大地促进拟议活动的成功。 公共卫生相关性：吗啡等阿片类药物被广泛用于治疗剧烈疼痛，尽管会产生显著的副作用(呕吐、便秘、呼吸抑制、药物滥用等)，而且对某些类型的慢性疼痛(神经性疼痛)的疗效有限。拟议研究的目的是了解阿片类药物缓解疼痛和产生副作用的机制，以开发更有效和更安全的治疗疼痛的药物。

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.