Scaffolding Opiate Analgesia

摘要 这一研究项目的长期目标是了解支架蛋白在调节 阿片受体。阿片类药物通常作为全身镇痛剂用于治疗急性、慢性和 顽固性疼痛综合征。然而，Mu阿片受体(MOPr)的激活遍及中枢神经 该系统会产生负面副作用，通常不利于继续使用。瞄准外设MOPr 减轻疼痛和规避全身副作用(Stein等人，2003)，但外周阿片受体表现 不同于在中枢神经系统中表达的那些基因，它们的调控机制尚不清楚。这 代表着知识上的巨大差距和一个重要的未得到满足的需求，因为仔细确定 外周阿片受体反应性的贡献者将提供新的外周治疗 止痛药开发的目标。此应用程序的总体目标是确定 支架蛋白A-激酶锚定蛋白79/150(AKAP)调节MOPr的反应性。中环 这项研究的假设是AKAP支持MOPr信号。这一假说将通过 两个特定的目标：(1)确定AKAP在感觉神经元MOPr信号中的作用；(2) 评估AKAP与MOPr的关联性。对MOPr下游信号通路的AKAP调节将是 通过药理学、生化和分子技术的组合进行研究。此外， 原代感觉神经元培养将被用来增加与未来行为的翻译相关性 学习。这项研究的贡献是重大的，因为它是朝着确定特定的 外周阿片受体信号系统的调节组件。连同初步数据， 研究结果将证明，AKAP与MOPr的关联正向调节下游信号 从而增加阿片类药物的止痛作用。

ABSTRACT The long-term goal of this research project is to understand the role of scaffolding proteins in the regulation of opioid receptors. Opioids are commonly administered as systemic analgesics to treat acute, chronic, and intractable pain syndromes. However, activation of mu opioid receptors (MOPr) throughout the central nervous system produces negative side effects that often contraindicate continued use. Targeting peripheral MOPr reduces pain and circumvents systemic side effects (Stein et al., 2003), yet peripheral opioid receptors behave differently than those expressed in the central nervous system, and their regulation is poorly understood. This represents a large gap in knowledge and an important unmet need, since the careful identification of contributors to opioid receptor responsiveness in the periphery would provide new, peripheral therapeutic targets for analgesic drug development. The overall objective of this application is to determine whether the scaffolding protein A-Kinase Anchoring Protein 79/150 (AKAP) regulates MOPr responsiveness. The central hypothesis for this study is that AKAP supports MOPr signaling. This hypothesis will be addressed through two specific aims that (1) determine the contribution of AKAP to MOPr signaling in sensory neurons and (2) evaluate AKAP association with MOPr. AKAP regulation of signaling pathways downstream of MOPr will be investigated through a combination of pharmacological, biochemical, and molecular techniques. Furthermore, primary sensory neuron cultures will be utilized to increase translational relevance with future behavioral studies. The contribution of this research is significant because it is the first step towards identifying specific regulatory components of the peripheral opioid receptor signaling system. Together with preliminary data, research results will demonstrate that AKAP association with MOPr positively regulates signaling downstream of the receptor, thereby increasing opioid analgesia.