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

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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.