Regulation of Kappa opioid receptor-mediated signaling and peripheral analgesia

描述（由申请人提供）：疼痛影响更多的美国人比糖尿病，心脏病和癌症的总和。阿片类药物是疼痛治疗的关键药物类别;然而，存在显著的缺点（例如CNS不良反应、社会和法律的问题），限制了其用于有效管理疼痛。因此，开发新的方法来改善疼痛控制是一个至关重要的研究目标。为了消除CNS衍生的不良作用，人们的注意力转向靶向外周定位的阿片受体表达的疼痛感觉神经元本身。重要的是，阿片受体系统在外周感觉神经元中的调节机制是独特的，并且从其他系统（CNS、异源表达系统等）中的研究获得的结果也是独特的。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。 本研究的目的是利用成年大鼠感觉神经元的原代培养和伤害感受的行为模型，研究外周感觉神经元中κ阿片受体（KOR）信号系统的调节。我们的具体目标是：1）阐明ERK在外周感觉神经元中调节KOR功能的作用; 2）阐明JNK在外周感觉神经元中调节KOR功能的作用; 3）阐明急性脱敏在外周感觉神经元中调节KOR激动剂功效的作用。 我们的总体目标是提高外周限制性κ阿片类镇痛药物的可靠性和疗效。通过了解参与调节κ阿片受体系统对外周感觉神经元的反应性的细胞机制，可以开发具有改善的治疗功效并且没有使CNS介导的不良反应的治疗疼痛的改进方法。使用初级感觉神经元培养的严格机制研究与行为研究的转化价值相结合，提供了一种强有力的方法来理解κ阿片受体激动剂在生理相关系统中的调节作用，并可能导致改善疼痛药物治疗的新方法。

DESCRIPTION (provided by applicant): 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 debilitating 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 of kappa opioid receptor agonist efficacy in a physiologically relevant system and may lead to new approaches for improved pharmacotherapy for pain.