Regulation of Kappa opioid receptor-mediated signaling and peripheral analgesia

Kappa 阿片受体介导的信号传导和外周镇痛的调节

• 批准号: 8794814
• 负责人: WILLIAM P CLARKE
• 金额: $ 9.96万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-15 至 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8794814
• 关键词: Absence of pain sensation; Acute; Adenylate Cyclase; Adult; Adverse effects; Affect; Afferent Neurons; Agonist; American; Analgesics; Attention; Behavioral; Behavioral Model; Clinical Research; Coronary heart disease; Data; Development; Diabetes Mellitus; Dose; Dose-Limiting; Foundations; Goals; Heart Diseases; Human; Inflammation; Inflammation Mediators; Investigation; Lead; Legal; Ligands; Malignant Neoplasms; Measures; Mediating; Medical; Mitogen-Activated Protein Kinases; Morphine; N-terminal; Neurons; Nociception; Nociceptors; Opioid; Opioid Analgesics; Opioid Receptor; Pain; Pain management; Patients; Peripheral; Pharmaceutical Preparations; Pharmacotherapy; Phase; Phosphotransferases; Primary Cell Cultures; Quality of life; Rattus; Receptor Signaling; Regulation; Research; Role; Shapes; Stimulus; System; Translating; Treatment Efficacy; United States; Ventilatory Depression; Work; addiction; cost; desensitization; improved; in vivo; inflammatory pain; inhibitor/antagonist; novel; novel strategies; public health relevance; receptor function; receptor-mediated signaling; research study; response; salvinorin A; social; stress-activated protein kinase 1

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.

摘要/总结 疼痛影响的美国人比糖尿病、心脏病和癌症的总和还要多。阿片类药物是关键 然而，用于疼痛治疗的药物类别存在显着的缺点（例如中枢神经系统不良反应、社会和 法律问题）限制了它们用于有效治疗疼痛的用途。因此，小说的开发 改善疼痛控制的方法是一个至关重要的研究目标。消除不利的中枢神经系统- 为了产生衍生效应，人们的注意力已转向靶向表达于疼痛的外周阿片受体。 感知神经元本身。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，并且从其他系统（CNS、异源表达 系统等）并不总是转化为外周感觉神经元。因此，了解阿片受体 外周感觉神经元的功能，必须用外周感觉神经元进行实验。 该项目的目标是研究 kappa 阿片受体 (KOR) 信号系统的调节 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行为模型 伤害感受。我们的具体目标是 1) 描述 ERK 在调节外周 KOR 功能中的作用 感觉神经元； 2) 阐明JNK在调节外周感觉神经元KOR功能中的作用； 3) 描述急性脱敏在调节 KOR 激动剂外周感觉功效中的作用 神经元。 我们的总体目标是提高外周限制 kappa 的可靠性和治疗效果 阿片类镇痛药。通过了解参与调节的细胞机制 kappa阿片受体系统对周围感觉神经元的反应，改进的治疗方法 可以开发出改善治疗效果且不会导致中枢神经系统介导的衰弱性疼痛的方法 不良影响。使用培养中的初级感觉神经元进行严格的机制研究相结合 行为研究的转化价值提供了一种强有力的方法来理解 调节 kappa 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 改进疼痛药物治疗的方法。