Molecular basis of the functional regulation of mu opioid receptors by co-expressed Gq/G11-coupled GPCRs

共表达 Gq/G11 偶联 GPCR 对 mu 阿片受体功能调节的分子基础

• 批准号: BB/G001200/1
• 负责人: Graeme Milligan
• 金额: $ 56.2万
• 依托单位: University of Glasgow
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2008
• 资助国家: 英国
• 起止时间: 2008 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FG001200%2F1
• 关键词: Molecular; basis; functional; regulation; mu

Opioid alkaloids such as morphine and heroin are well known drugs of abuse. However, they are also highly effective analgesics. Morphine is the most effective analgesic for treatment of severe refractory pain. A major limitation in use of morphine in a clinical setting is that, over time, patients require higher and higher doses for effect. This is termed tolerance. If this could be prevented then morphine would be even more effective. Although the basis of tolerance is complex, one key element appears to be the lack of capacity of morphine to cause internalisation and desensitisation of its molecular target, the mu opioid receptor. A series of studies have suggested that if this could be achieved, tolerance would be limited or abolished. Using a model system we have shown that if the 5-HT2A receptor, a receptor that responds to the neurotransmitter serotonin and which is expressed in the same cells as the mu opioid receptor in a number of brain regions, is activated at the same time, morphine is now able to cause internalisation and desensitisation of the mu opioid receptor. We wish to explore the molecular basis of these observations and explore if they can be generalised to other co-expressed receptors.

阿片类生物碱如吗啡和海洛因是众所周知的滥用药物。然而，它们也是非常有效的止痛药。吗啡是治疗严重难治性疼痛最有效的镇痛药。在临床环境中使用吗啡的一个主要限制是，随着时间的推移，患者需要越来越高的剂量才能达到效果。这就是所谓的宽容。如果这可以预防，那么吗啡将更加有效。尽管耐受性的基础是复杂的，但一个关键因素似乎是吗啡缺乏引起其分子靶点mu阿片受体内化和脱敏的能力。一系列的研究表明，如果能够做到这一点，容忍将受到限制或取消。通过一个模型系统，我们已经证明，如果5-HT2A受体（一种对神经递质5-羟色胺有反应的受体，它与mu阿片受体在许多大脑区域的相同细胞中表达）同时被激活，吗啡现在能够引起mu阿片受体的内化和脱敏。我们希望探索这些观察的分子基础，并探索它们是否可以推广到其他共表达受体。

项目成果

The other side of opioid receptor signaling: regulation by protein-protein interaction.

• DOI: 10.1186/2193-1801-4-s1-l21
• 发表时间: 2015
• 期刊: SpringerPlus
• 作者: Georgoussi Z

M3 muscarinic acetylcholine receptor facilitates the endocytosis of mu opioid receptor mediated by morphine independently of the formation of heteromeric complexes.

M3 毒蕈碱乙酰胆碱受体促进吗啡介导的 mu 阿片受体的内吞作用，与异聚复合物的形成无关。

• DOI: 10.1016/j.cellsig.2017.04.006
• 发表时间: 2017
• 期刊: Cellular signalling
• 影响因子: 4.8
• 作者: Lopez-Gimenez JF

Opioid regulation of mu receptor internalisation: relevance to the development of tolerance and dependence.

• DOI: 10.2174/187152710793361522
• 发表时间: 2010-10
• 期刊: CNS & neurological disorders drug targets
• 作者: J. López-Giménez;G. Milligan