Delta-kappa opioid receptor interactions: Ligand-dependent effects

Delta-kappa 阿片受体相互作用：配体依赖性效应

• 批准号: 7640471
• 负责人: KELLY ANN BERG
• 金额: $ 21.08万
• 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: 2009-06-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7640471
• 关键词: Absence of pain sensation; Acute; Adverse effects; Afferent Neurons; Affinity; Agonist; American; Analgesics; Behavioral Assay; Behavioral Model; Binding; Chronic; Clinical; Clinical Research; Data; Dependence; Development; Drug effect disorder; Enkephalin, D-Penicillamine (2,5)-; Foundations; Grant; In Vitro; Lead; Left; Legal; Leucine-2-Alanine Enkephalin; Ligands; Mediating; Modeling; Morphine; Narcotic Antagonists; Neurons; Nociceptors; Opioid; Opioid Receptor; Pain; Pain Disorder; Pain management; Peripheral; Pharmaceutical Preparations; Rattus; Regulation; Reporting; Series; Small Interfering RNA; Structure of trigeminal ganglion; System; Testing; Treatment Efficacy; Work; allodynia; analog; improved; in vivo; interest; kappa opioid receptors; knock-down; mechanical allodynia; norbinaltorphimine; novel strategies; painful neuropathy; public health relevance; research study; response; 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. 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. Our preliminary data suggest that the affinity and/or efficacy of DOR agonists can be regulated by the k opioid receptor (KOR) antagonist, nor-BNI. In this R21 exploratory application, we propose to study the regulation of DOR systems by k opioid antagonists in primary cultures of rat trigeminal ganglion neurons and in behavioral models for analgesia. Our specific aims are: 1) To examine the effect of KOR antagonists on the efficacy and potency of selected DOR agonists. In this aim, we will determine the effect of the KOR antagonist, nor-BNI, on concentration-response curves to selected DOR agonists in primary cultures of rat sensory neurons of the trigeminal ganglion. We will also examine the effect of different KOR antagonists on the concentration-response curve to the DOR agonists DPDPE and DADLE. 2) To assess the mechanism by which KOR antagonists regulate DOR agonist responsiveness. Our preliminary data indicate that KOR occupancy with nor-BNI increases or decreases the potency of DOR agonists (DPDPE and DADLE, respectively). In this aim we will test the hypothesis that the effect of nor-BNI is due to a change in agonist affinity for DOR using competition binding experiments. We will also determine if the effect of nor-BNI is mediated by KOR using siRNA knock-down of KOR. 3) To investigate the effect of KOR antagonists on responsiveness to DOR agonists in a behavioral assay of thermal and mechanical allodynia. This aim provides a translational extension of the foundation work of Aims 1-2. We will determine the effect of occupancy of KOR with the antagonist nor-BNI on concentration-response curves to a series of DOR agonists in a behavioral assay of peripheral analgesia. We will also examine the effect of different KOR antagonists on the concentration-response curve to the DOR agonist DPDPE. If our preliminary results are substantiated, a new pharmacological approach for pain management with improved therapeutic efficacy and increased selectivity may be developed. PUBLIC HEALTH RELEVANCE: The 4 opioid receptor (DOR) in the periphery is an attractive target for analgesic drugs, however, in general, the efficacy of 4 opioid receptor agonists to promote analgesia by acting in the periphery is weak to moderate and variable. In this R21 exploratory application, we propose to study the regulation of DOR systems by k opioid antagonists in primary cultures of rat trigeminal ganglion neurons and in behavioral models for analgesia. The results obtained will provide a framework for a more comprehensive study (RO1) of the regulation of DOR agonist efficacy in nociceptors and may lead to the development of a new pharmacological approach for pain management with improved therapeutic efficacy and increased selectivity.

描述（由申请人提供）：作用于阿片受体（莫尔）的激动剂（例如吗啡及其类似物）是疼痛管理的主要药物;然而，存在严重的不良反应（例如依赖性）以及限制其使用的社会和法律的问题。因此，阿片类药物的外周镇痛作用引起了相当大的兴趣。除了莫尔之外，4阿片受体（DOR）是药物作用的有吸引力的靶标，因为与莫尔活化相比，其不良反应较少。但是，一般而言，4种激动剂促进镇痛的效力为弱至中度。我们的初步数据表明，DOR激动剂的亲和力和/或功效可以由k阿片受体（KOR）拮抗剂nor-BNI调节。在这个R21探索性应用中，我们建议研究K阿片受体拮抗剂在大鼠三叉神经节神经元的原代培养物和镇痛行为模型中对DOR系统的调节。我们的具体目标是：1）检查KOR拮抗剂对所选DOR激动剂的功效和效力的影响。在这个目标中，我们将确定的KOR拮抗剂，去甲-BNI，对选定的DOR激动剂在大鼠三叉神经节感觉神经元的原代培养的浓度-反应曲线的影响。我们还将研究不同KOR拮抗剂对DOR激动剂DPDPE和DADLE的浓度-反应曲线的影响。2)评估KOR拮抗剂调节DOR激动剂反应性的机制。我们的初步数据表明，与nor-BNI的KOR占用增加或减少DOR激动剂（DPDPE和DADLE，分别）的效力。在这个目标中，我们将测试的假设，即影响的nor-BNI是由于在激动剂的亲和力DOR使用竞争结合实验的变化。我们还将使用siRNA敲低KOR来确定nor-BNI的作用是否由KOR介导。3)研究KOR拮抗剂对DOR激动剂在热和机械异常性疼痛的行为测定中的反应性的影响。这一目标是目标1-2的基础工作的平移延伸。我们将在外周镇痛的行为测定中确定KOR与拮抗剂nor-BNI对一系列DOR激动剂的浓度-反应曲线的占用效应。我们还将研究不同KOR拮抗剂对DOR激动剂DPDPE的浓度-反应曲线的影响。如果我们的初步结果得到证实，一个新的药理学方法疼痛管理与改善治疗效果和增加选择性可能会被开发。 公共卫生关系：外周中的4阿片受体（DOR）是镇痛药物的有吸引力的靶点，然而，一般而言，4阿片受体激动剂通过作用于外周来促进镇痛的功效是弱至中等的且可变的。在这个R21探索性应用中，我们建议研究K阿片受体拮抗剂在大鼠三叉神经节神经元的原代培养物和镇痛行为模型中对DOR系统的调节。所获得的结果将提供一个框架，更全面的研究（RO 1）的调节DOR激动剂的疗效伤害感受器，并可能导致开发一种新的药理学方法，用于疼痛管理，提高疗效和选择性。