Functional Interactions of Mu and Delta Opioid Receptors

Mu 和 Delta 阿片受体的功能相互作用

• 批准号: 7613402
• 负责人: Erica Sawyer Levitt
• 金额: $ 2.48万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7613402
• 关键词: Address; Agonist; Analgesics; Animals; Attenuated; Biochemical; Biological Assay; Brain; Caveolins; Cell Line; Cells; Cellular Assay; Cholesterol; Clinical; Complex; Dependence; Development; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Epitopes; G Protein-Coupled Receptor Signaling; GTP-Binding Proteins; Goals; Heterodimerization; Lead; Measures; Mediating; Membrane Microdomains; Morphine; Mus; Neurons; Opioid; Opioid Receptor; Pain; Pharmacology; Property; Receptor Cross-Talk; Receptor Signaling; Rodent; Role; Signal Transduction; Signaling Protein; Simvastatin; Swiss Mice; Testing; United States National Institutes of Health; delta opioid receptor; design; in vivo; insight; naltrindole; receptor; research study

DESCRIPTION (provided by applicant): Opioids such as morphine are highly prescribed for moderate to severe pain, however, their euphoric properties contribute to their widespread abuse. The ¿-opioid receptor is primarily responsible for both the analgesic and euphoric effects, while agonists at the d -opioid receptor retain some analgesic properties, but have a lower abuse liability and have been suggested to attenuate some of the negative effects of ¿ agonists. For instance, eliminating the action of the d -receptor blocks the development of morphine tolerance and dependence in rodents. This interaction could be explained by heterodimerization of ¿ and d receptors, or by compartmentalization into membrane microdomains, such as lipid rafts, to form functional signaling complexes. In support of this, ¿ and d receptors colocalize in certain brain neurons and can heterodimerize in biochemical assays, while n and K receptors localize to lipid rafts with functional signaling consequences. The hypothesis of this proposal is that lipid rafts are required for ¿ and d -opioid receptor pharmacology including cross-talk. Two specific aims have been designed to test this hypothesis. The goal of specific aim #1 is to investigate the role of lipid rafts on ¿ and d receptor signaling by addressing the following questions: a) Are ¿ and d receptors and their associated signaling proteins localized to lipid rafts? and b) Are lipid rafts required for efficient signaling of ¿ and d receptors and for cross-talk between these receptors? All experiments in aim 1 will be performed in HEK293 cells expressing epitope-tagged ¿ and/or d receptors. The goal of specific aim #2 is to determine the impact of cholesterol-lowering on ¿/ d receptor interactions in vivo, by measuring ¿ and d agoinst-mediated antinociception, tolerance and dependence in mice treated with the clinically-used cholesterol-lowering agent simvastatin. The effect of cholesterol-lowering on opioid signaling will provide insight into the mechanism behind the cross-talk between ¿ and d receptors. This understanding could lead to the development of highly efficacious analgesics with a decreased abuse liability. Generally, the effect of cholesterol-lowering on opioid and GPCR signaling is important to study because of the increasing use of cholesterol-lowering agents and the continuously lowering clinical cholesterol goals.

描述（由申请人提供）：吗啡等阿片类药物常被用于治疗中度至重度疼痛，然而，它们的欣快特性导致其广泛滥用。 κ-阿片受体主要负责镇痛和欣快作用，而d-阿片受体激动剂保留了一些镇痛特性，但具有较低的滥用倾向，并且已被建议可以减弱¿激动剂的一些负面影响。例如，消除 d 受体的作用可以阻止啮齿类动物吗啡耐受和依赖性的发展。这种相互作用可以通过 和 d 受体的异二聚化来解释，或者通过划分为膜微结构域（例如脂筏）以形成功能性信号复合物来解释。为了支持这一点，¿ 和 d 受体共定位于某些大脑神经元，并且可以在生化测定中异二聚化，而 n 和 K 受体定位于脂筏，具有功能性信号传导结果。该提议的假设是 ¿ 和 d-阿片受体药理学（包括串扰）需要脂筏。设计了两个具体目标来检验这一假设。具体目标 #1 的目标是通过解决以下问题来研究脂筏对 ¿ 和 d 受体信号传导的作用：a) ¿ 和 d 受体及其相关信号传导蛋白是否定位于脂筏？ b) ¿ 和 d 受体的有效信号传导以及这些受体之间的串扰是否需要脂筏？目标 1 中的所有实验都将在表达表位标记的 ¿ 和/或 d 受体的 HEK293 细胞中进行。具体目标#2的目标是通过测量临床使用的降胆固醇药物辛伐他汀治疗的小鼠中的 和 d 激动剂介导的镇痛作用、耐受性和依赖性，确定降胆固醇对体内 ¿/d 受体相互作用的影响。降低胆固醇对阿片类药物信号传导的影响将有助于深入了解 ¿ 和 d 受体之间串扰背后的机制。这种理解可能会导致高效镇痛药的开发，同时降低滥用可能性。一般来说，由于降胆固醇药物的使用不断增加以及临床胆固醇目标的不断降低，降胆固醇对阿片类药物和 GPCR 信号传导的影响非常重要。