Regulation of Kappa opioid receptor-mediated signaling and peripheral analgesia

摘要/概要 疼痛影响的美国人比糖尿病、心脏病和癌症加起来还要多。阿片类药物是关键 然而，用于疼痛治疗的药物类别存在显著的缺点（例如CNS不良反应、社会和 法律的问题）限制了它们用于有效管理疼痛。因此，小说的发展 改善疼痛控制的方法是一个至关重要的研究目标。为了消除不利的中枢神经系统- 衍生的影响，注意力已经转向靶向外周定位阿片受体表达的疼痛- 感知神经元重要的是，外周阿片受体系统的调节机制， 感觉神经元是独特的，从其他系统（CNS，异源表达）的研究中获得的结果 系统等）并不总是转化为外周感觉神经元。因此，为了了解阿片受体 在外周感觉神经元中的功能，必须用外周感觉神经元进行实验。 本项目的目的是研究kappa阿片受体（KOR）信号系统在大鼠脑内的调节作用。 外周感觉神经元，使用成年大鼠感觉神经元的原代培养物和 伤害感受我们的具体目标是：1）阐明ERK在外周血KOR功能调节中的作用， 2）阐明JNK在外周感觉神经元KOR功能调节中的作用; 3）阐明急性脱敏在调节KOR激动剂外周感觉效应中的作用 神经元 我们的总体目标是增加外周血限制性κ B的可靠性和治疗效果。 阿片类镇痛药通过了解参与调节细胞内蛋白质的细胞机制， κ阿片受体系统对外周感觉神经元的反应性，改善的治疗方法 可以产生具有改善的治疗功效并且没有CNS介导的衰弱的疼痛。 不良影响结合使用培养的初级感觉神经元的严格机制研究， 与行为研究的翻译价值提供了一个强大的方法来理解 调节卡帕阿片受体激动剂在生理相关系统中的功效，并可能导致新的 改善疼痛药物治疗的方法。

Abstract/Summary Pain affects more Americans than does diabetes, heart disease and cancer combined. Opioids are a key drug class for pain treatment, however, there are significant drawbacks (e.g. CNS adverse effects, social and legal issues) that limit their use for effective management of pain. Consequently, development of novel approaches for improved pain control is a critically important research objective. To eliminate adverse CNS- derived effects, attention has turned to targeting peripherally located opioid receptors expressed on the pain- sensing neurons themselves. Importantly, the regulatory mechanisms of opioid receptor systems in peripheral sensory neurons are unique, and results obtained from studies in other systems (CNS, heterologous expression systems, etc.) do not always translate to peripheral sensory neurons. Thus, to understand opioid receptor function in peripheral sensory neurons, experiments must be done with peripheral sensory neurons. The goal of this project is to study the regulation of kappa opioid receptor (KOR) signaling systems in peripheral sensory neurons, using primary cultures of adult rat sensory neurons and a behavioral model of nociception. Our specific aims are 1) To delineate the role of ERK in regulation of KOR function in peripheral sensory neurons; 2) To delineate the role of JNK in regulation of KOR function in peripheral sensory neurons; and 3) To delineate the role of acute desensitization in regulating KOR agonist efficacy in peripheral sensory neurons. Our overall goal is to increase the reliability and therapeutic efficacy of peripherally-restricted kappa opioid analgesic drugs. By understanding the cellular mechanisms that are involved in regulating the responsiveness of kappa opioid receptor systems on peripheral sensory neurons, improved approaches to treat pain can be developed that have improved therapeutic efficacy and are devoid of debilitaing CNS-mediated adverse effects. The combination of rigorous mechanistic studies using primary sensory neurons in culture with the translational value of behavioral studies provides a powerful approach to understanding the regulation kappa opioid receptor agonist efficacy in a physiologically relevant system and may lead to new approaches for improved pharmacotherapy for pain.