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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

基本信息

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
项目类别：
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

项目摘要

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.

抽象/总结