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

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，它们也是高效的止痛药。吗啡是治疗严重顽固性疼痛最有效的止痛剂。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，患者需要越来越大的剂量才能产生效果。这就是所谓的宽容。如果这种情况能够预防，那么吗啡将会更有效。尽管耐受的基础是复杂的，但一个关键因素似乎是吗啡缺乏导致其分子靶标--u阿片受体--内化和脱敏的能力。一系列研究表明，如果能够实现这一点，宽容将受到限制或废除。使用一个模型系统，我们已经证明，如果5-HT2a受体，一种对神经递质5-羟色胺作出反应的受体，在许多大脑区域与u阿片受体在同一细胞中表达，同时被激活，吗啡现在能够引起u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的受体。

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.