Scaffolding Opiate Analgesia

摘要 该研究项目的长期目标是了解支架蛋白在调节 阿片受体。阿片样物质通常作为全身性镇痛剂施用，以治疗急性、慢性和全身性疼痛。 顽固性疼痛综合征然而，整个中枢神经系统的μ阿片受体（MOPr）的激活 系统产生负面的副作用，往往禁忌继续使用。目标外设MOPr 减少疼痛并避免全身副作用（Stein等，2003），但外周阿片受体的行为 与中枢神经系统中表达的不同，它们的调节机制知之甚少。这 这是一个巨大的知识差距和一个重要的未满足的需求，因为仔细确定了 外周阿片受体反应性的贡献者将提供新的外周治疗药物， 镇痛药物开发的目标。本申请的总体目标是确定 支架蛋白A-激酶调节蛋白79/150（AKAP）调节MOPr反应性。中央 本研究的假设是AKAP支持MOPr信号传导。这一假设将通过 两个具体目标：（1）确定AKAP对感觉神经元中MOPr信号传导的贡献，以及（2） 评估AKAP与MOPr的相关性。AKAP对MOPr下游信号通路的调节将是 通过药理学、生物化学和分子技术的组合进行研究。此外，委员会认为， 初级感觉神经元培养将用于增加与未来行为的翻译相关性。 问题研究这项研究的贡献是重大的，因为它是确定具体的第一步。 外周阿片受体信号系统的调节成分。加上初步数据， 研究结果将证明AKAP与MOPr的结合正向调节下游信号传导， 从而增加阿片类镇痛作用。

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.