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 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。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激动剂促进镇痛的功效为弱至中等。我们的初步数据表明，DOR 激动剂的亲和力和/或功效可以通过 k 阿片受体 (KOR) 拮抗剂、nor-BNI 来调节。在此 R21 探索性应用中，我们建议研究 k 阿片拮抗剂在大鼠三叉神经节神经元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。为此，我们将确定 KOR 拮抗剂、nor-BNI 对三叉神经节大鼠感觉神经元原代培养物中选定的 DOR 激动剂的浓度-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 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，KOR 与 Nor-BNI 的结合会增加或降低 DOR 激动剂（分别为 DPDPE 和 DADLE）的效力。为此，我们将使用竞争结合实验来检验这样的假设：nor-BNI 的作用是由于 DOR 激动剂亲和力的变化所致。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) 在热和机械异常性疼痛行为测定中研究 KOR 拮抗剂对 DOR 激动剂反应性的影响。这一目标提供了目标 1-2 基础工作的转化延伸。我们将在外周镇痛行为测定中确定 KOR 与拮抗剂 Nor-BNI 的占据对一系列 DOR 激动剂的浓度-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 浓度-反应曲线的影响。如果我们的初步结果得到证实，则可能会开发出一种新的疼痛管理药理学方法，以提高治疗效果和增加选择性。 公共健康相关性：外周的 4 种阿片受体 (DOR) 是镇痛药物的一个有吸引力的靶点，然而，一般来说，4 种阿片受体激动剂通过作用于外周来促进镇痛的功效为弱至中等且可变。在此 R21 探索性应用中，我们建议研究 k 阿片拮抗剂在大鼠三叉神经节神经元原代培养物和镇痛行为模型中对 DOR 系统的调节。获得的结果将为DOR激动剂对伤害感受器的功效调节进行更全面的研究（RO1）提供框架，并可能导致开发一种新的疼痛管理药理学方法，以提高治疗功效和增加选择性。