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

项目总结 内源性阿片系统调节疼痛敏感性，是临床上使用的阿片类药物的靶点。 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 治疗会产生明显的副作用(如反常的痛觉过敏、药物滥用、呕吐、便秘、 呼吸抑制等)，对某些类型的慢性疼痛(即 神经病理性疼痛)。内源性阿片系统由几种多肽激动剂(包括 脑啡肽)和阿片受体(分别为DOR、KOR和MOR)。这个 个体阿片受体和多肽在疼痛处理中的作用已被探索 药理学和基因敲除方法，但令人惊讶的是，人们对其机制知之甚少 这些多肽和受体之间的哪些相互作用调节疼痛。 这项拟议的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。 脊髓中的传递，在那里发生神经可塑性变化导致慢性疼痛，以发展新的 治疗吗啡抵抗类型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。我们将检验假设，由于DOR和DOR之间的区别 MOR细胞生物学(例如，不同神经元、不同运输特性或亚细胞的表达 两种阿片受体的激活不同地改变了神经元的活动。然后我们将进行调查 脊髓脑啡肽能回路和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)。我们将检验这一假设，即释放 脑啡肽抑制邻近的已知对慢性疼痛至关重要的投射神经元，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测试 假设脑啡肽能神经元在慢性疼痛过程中对设定痛阈值至关重要。 拟议的研究应该会极大地提高我们对内源性 阿片系统控制疼痛。此外，这些研究可能会为有限的效率提供解释 目前的治疗方法，并有望发现新的阿片类药物为基础的战略，以管理慢性疼痛。此外，两者 在这个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 影响我们对阿片类药物作用机制的理解，超出疼痛领域(即药物 上瘾)。 导师艾米·麦克德莫特博士因在以下方面的富有成效和相关性的研究而享有盛誉 脊椎痛觉回路的电生理学研究。此外，她还拥有很强的监督记录。 受训人员继续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都很好。 并将为拟议活动的成功作出巨大贡献。

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.