Regulation of Kappa opioid receptor-mediated signaling and peripheral analgesia

描述(由申请者提供)：疼痛影响的美国人比糖尿病、心脏病和癌症加起来还要多。阿片类药物是治疗疼痛的关键药物类别；然而，存在重大缺陷(如中枢神经系统不良反应、社会和法律问题)，限制了其用于有效治疗疼痛。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。为了消除中枢神经系统产生的不利影响，人们的注意力转向了靶向表达在痛觉神经元本身上的外周阿片受体。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，从其他系统(中枢神经系统、异源表达系统等)的研究中获得的结果。并不总是转化为外周感觉神经元。因此，要了解外周感觉神经元中阿片受体的功能，必须对外周感觉神经元进行实验。本项目的目的是利用原代培养的成年大鼠感觉神经元和伤害性行为模型，研究kappa阿片受体(KOR)信号系统在外周感觉神经元中的调节。我们的具体目标是：1)阐明ERK在调节外周感觉神经元KOR功能中的作用；2)阐明JNK在调节外周感觉神经元KOR功能中的作用；3)阐明急性脱敏在调节外周感觉神经元KOR激动剂效应中的作用。我们的总体目标是增加外周限制性kappa阿片类止痛药的可靠性和治疗效果。通过了解调节外周感觉神经元上kappa阿片受体系统反应性的细胞机制，可以开发出更好的治疗疼痛的方法，从而提高治疗效果，并且没有削弱中枢神经系统介导的不良反应。使用培养的初级感觉神经元进行的严格的机制研究与行为研究的翻译价值相结合，为理解生理相关系统中kappa阿片受体激动剂疗效的调节提供了强有力的方法，并可能导致改进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.