Regulation of opioid receptor function in trigeminal ganglion

三叉神经节阿片受体功能的调节

• 批准号: 8094524
• 负责人: WILLIAM P CLARKE
• 金额: $ 32.09万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-15 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8094524
• 关键词: Absence of pain sensation; Acute; Adenylate Cyclase; Adjuvant; Adverse effects; Afferent Neurons; Agonist; American; Analgesics; Arachidonic Acids; Behavioral Assay; Behavioral Model; Biological Models; Bradykinin; Bradykinin Receptor; Caenorhabditis elegans; Chronic; Clinical; Clinical Research; Competence; Dependence; Development; Drosophila genus; Drug Combinations; Drug effect disorder; Foundations; GTP-Binding Proteins; Genes; Genomics; Health; Human; Inflammation; Inflammatory; Kinetics; Lead; Legal; Maintenance; Mediating; Methods; Modeling; Morphine; Mus; Mutation; Naloxone; Neurons; Neuropeptides; Neurosecretion; Nociceptors; Opioid; Opioid Analgesics; Opioid Receptor; Orofacial Pain; Pain; Pain Disorder; Pain management; Peripheral; Pharmaceutical Preparations; Play; Process; Rattus; Receptor Signaling; Regulation; Reporting; Role; Signal Transduction; Stimulus; Structure of trigeminal ganglion; Synapses; Synaptic plasticity; System; Time; Tissues; Vesicle; Work; analog; desensitization; improved; in vitro Model; in vivo; insight; interest; novel strategies; novel therapeutic intervention; painful neuropathy; protein activation; receptor; receptor function; research study; response; seryl-leucyl-isoleucyl-glycyl--arginyl-leucinamide; social

Description (provided by applicant): Agonists acting at the 5 opioid receptor (MOR) (e.g. morphine and its analogs) are the mainstay of pain management; however there are serious adverse effects (e.g. dependence) and social and legal issues which limit their use. Consequently there has been considerable interest in the peripheral analgesic effects of opioids. However, although opioid receptor systems are expressed in sensory neurons, they are functionally inactive under most basal conditions, but become functionally competent when some stimulus (inflammation) is present in the peripheral tissue. In addition to MOR, the 4 opioid receptor (DOR) is an attractive target for drug action since there are fewer adverse effects than with MOR activation. However, in general, the efficacy of 4 agonists to promote analgesia is weak to moderate. Here we propose to study mechanisms involved in the regulation of the functional competence of the MOR and DOR systems to inhibit adenylyl cyclase activity and neuropeptide release in primary cultures of rat trigeminal ganglion neurons and in behavioral models of peripheral analgesia. Our specific aims are: 1) To characterize the kinetics of induction and maintenance of functional competence of MOR and DOR systems. We will delineate the time course for induction of competence, and the persistence of competence after induction, by administration of bradykinin (BK), arachidonic acid (AA) and naloxone. 2) To determine the changes in the MOR and DOR systems which underlie the development of functional competence In this aim, we will determine the mechanism for the priming-induced increase in opioid receptor-mediated G protein activation. 3) To determine if functional competence of MOR and DOR receptor systems induced by naloxone and BK pre-treatment is due to reduced constitutive desensitization.. We hypothesize that the MOR/DOR receptor systems exist in a constitutively desensitized state thus are non-responsive to agonist. Treatment with inverse agonists should reduce this constitutive desensitization leading to enhanced agonist responsiveness. Also priming with other agents (e.g. BK) may induce competence by reducing constitutive desensitization. 4) To investigate the functional competence of MOR and DOR in behavioral assays of analgesia. This aim provides a translational extension of the foundation work of Aims 1-3. Using a newly developed model of orofacial pain, we will 1) determine if functional competence of the MOR and DOR systems can be induced by BK, AA, and naloxone, 2) investigate the time course of competence, 3) delineate the role of PKC5 in induction of functional competence induced by BK, AA and naloxone and 4) determine the role of BK receptors and PKC in mediating functional competence in an inflammatory model of pain. These experiments will increase our understanding of the regulation of 5 and 4 opioid receptor signaling in primary sensory neurons and may lead to novel therapeutic approaches for the treatment of pain. PUBLIC HEALTH RELEVANCE: In the last few years many mutations in different genes have been isolated in C. elegans, D. Melanogaster and mice which plays role in vesicle fusion and synaptic plasticity. Fundamental insights into the processes and regulation of human synaptic plasticity will occur when we understand how different conserved signaling mechanism controls this process. The neurosecretion study of Drosophila as a model system provides extraordinary opportunities to use different methods of gene manipulation and of genomics with direct relevance to mammalian synaptic release and plasticity.

描述（由申请人提供）：作用于 5 阿片受体（MOR）的激动剂（例如吗啡及其类似物）是疼痛管理的支柱；然而，存在严重的不利影响（例如依赖性）以及限制其使用的社会和法律问题。因此，人们对阿片类药物的外周镇痛作用产生了相当大的兴趣。然而，尽管阿片受体系统在感觉神经元中表达，但它们在大多数基础条件下功能不活跃，但当周围组织中存在某些刺激（炎症）时，它们在功能上变得活跃。除了 MOR 之外，4 阿片受体 (DOR) 也是药物作用的一个有吸引力的靶标，因为与 MOR 激活相比，其副作用较少。但总体而言，4种激动剂促进镇痛的功效为弱至中等。在这里，我们建议研究参与调节 MOR 和 DOR 系统功能的机制，以抑制大鼠三叉神经节神经元原代培养物和周围镇痛行为模型中的腺苷酸环化酶活性和神经肽释放。我们的具体目标是： 1) 表征 MOR 和 DOR 系统功能能力的诱导和维持的动力学。我们将通过施用缓激肽 (BK)、花生四烯酸 (AA) 和纳洛酮来描绘能力诱导的时间过程以及诱导后能力的持续性。 2) 确定MOR和DOR系统的变化，这些变化是功能能力发展的基础。在这个目标中，我们将确定启动诱导的阿片受体介导的G蛋白激活增加的机制。 3) 确定纳洛酮和 BK 预处理诱导的 MOR 和 DOR 受体系统的功能能力是否是由于组成性脱敏减少所致。我们假设 MOR/DOR 受体系统以组成性脱敏状态存在，因此对激动剂。用反向激动剂治疗应减少这种组成性脱敏，从而增强激动剂反应性。此外，用其他药物（例如 BK）启动可能会通过减少组成性脱敏来诱导能力。 4) 研究MOR和DOR在镇痛行为测定中的功能能力。这一目标提供了目标 1-3 基础工作的转化延伸。使用新开发的口面部疼痛模型，我们将 1) 确定 BK、AA 和纳洛酮是否可以诱导 MOR 和 DOR 系统的功能能力，2) 研究能力的时间过程，3) 描述 PKC5 的作用4) 确定 BK 受体和 PKC 在介导疼痛炎症模型中功能能力中的作用。这些实验将增加我们对初级感觉神经元中 5 和 4 阿片受体信号传导调节的理解，并可能带来治疗疼痛的新方法。公共健康相关性：过去几年，在秀丽隐杆线虫、黑腹果蝇和小鼠中分离出许多不同基因的突变，这些突变在囊泡融合和突触可塑性中发挥作用。当我们了解不同的保守信号机制如何控制这一过程时，就会对人类突触可塑性的过程和调节产生基本的了解。以果蝇为模型系统的神经分泌研究为使用与哺乳动物突触释放和可塑性直接相关的不同基因操作和基因组学方法提供了绝佳的机会。