Regulation of Kappa opioid receptor-mediated signaling and peripheral analgesia

描述（由申请人提供）：疼痛对美国人的影响超过了糖尿病、心脏病和癌症的总和。阿片类药物是治疗疼痛的关键药物；然而，有明显的缺点（例如中枢神经系统的不良反应，社会和法律问题）限制了它们用于有效治疗疼痛的使用。因此，开发改善疼痛控制的新方法是一个至关重要的研究目标。为了消除中枢神经系统衍生的不良影响，人们的注意力已经转向靶向外周位于痛觉神经元上表达的阿片受体。重要的是，外周感觉神经元中阿片受体系统的调节机制是独特的，其他系统（中枢神经系统、异源表达系统等）的研究结果并不总是适用于外周感觉神经元。因此，要了解阿片受体在外周感觉神经元中的作用，必须对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）信号系统在外周感觉神经元中的调控，利用成年大鼠感觉神经元的原代培养和伤害感觉的行为模型。我们的具体目标是：1)描述ERK在调节周围感觉神经元KOR功能中的作用；2)研究JNK对周围感觉神经元KOR功能的调控作用；3)描述急性脱敏在调节KOR激动剂在外周感觉神经元中的作用。我们的总体目标是提高外周限制性卡帕阿片类镇痛药物的可靠性和治疗效果。通过了解参与调节kappa阿片受体系统对周围感觉神经元的反应性的细胞机制，可以开发改进的治疗疼痛的方法，提高治疗效果，并且没有衰弱的中枢神经系统介导的不良反应。利用培养的初级感觉神经元进行严格的机制研究与行为研究的转化价值相结合，为理解kappa阿片受体激动剂在生理相关系统中的功效调节提供了强有力的途径，并可能为改进疼痛药物治疗提供新方法。

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.