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

Reference	BB/G001200/1
Principal Investigator / Supervisor	Professor Graeme Milligan
Co-Investigators / Co-Supervisors	Dr Juan Lopez-Gimenez
Institution	University of Glasgow
Department	School of Life Sciences
Funding type	Research
Value (£)	441,022
Status	Completed
Type	Research Grant
Start date	01/08/2008
End date	30/11/2011
Duration	40 months

Abstract

Morphine is a highly effective, clinically employed analgesic. However, the development of tolerance to morphine with sustained treatment severely restricts its longer term use. Because morphine produces little internalisation of its molecular target, the mu opioid receptor, it has been suggested that a lack of mu opioid receptor desensitisation, internalisation and recycling to the cell surface is integral to development of tolerance. Many G protein-coupled receptors are co-expressed in specific neurones and co-activation can modulate their actions. We have generated substantial preliminary data that morphine can cause highly efficient internalisation and desensitisation of the mu opioid receptor when a co-expressed 5-HT2A receptor is activated in parallel and that this effect requires activation of Gq/11-dependent signalling pathways. We plan to explore the molecular basis of these observations because our preliminary data indicate that it is clealry more complex than 5-HT2A receptor-mediated activation of protein kinase C resulting in direct phosphorylation of the mu opioid receptor. We also wish to ascertain whether such an effects are restricted to the 5-HT2A receptor or canm be mimicked by other Gq/11/linked G protein-coupled receptors that are known to be co-expressed with the mu opioid receptor. We will then expand these studies to determine if the observations can be reproduced in a neuronal cell model system that expresses the mu opioid receptor endogenously and in which we have performed a genome-wide G protein-coupled receptor screen to identify the expression pattern of Gq/11-coupled G protein-coupled receptors.

Summary

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.

Committee	Closed Committee - Biochemistry & Cell Biology (BCB)
Research Topics	Neuroscience and Behaviour, Pharmaceuticals
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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