Chronic pain is a debilitating condition that exerts a high social cost in terms of productivity, economic impact and quality of life. Currently available therapies yield limited success in treating such pain, suggesting the need for new insight into underlying mechanism(s). Opioid peptides modulate pain sensation by binding and activating the opioid receptors, but their usefulness for pain treatment is limited due to their peptidic properties i.e. lack of blood brain barrier crossing and fast inactivation by metabolic enzymes. The small molecule alkaloid morphine, on the other hand, is a powerful analgesic that can be easily administered and activates the same receptors. The G protein coupled receptor, GPR7, is a receptor that shares sequence similarities with opioid receptors. GPR7 is activated by the neuropeptides NPW and NPB which have been recently discovered. GPR7 is thought to regulate pain perception in the periphery. Most notably, while under normal conditions GPR7 is expressed at low levels in the spinal cord; its expression is dramatically increased in patients suffering from inflammatory/immune-mediated neuropathies. Presently there are no small molecules available which could be used to modulate the GPR7 system. We therefore propose to use our recently developed robust and simple assay system for GPR7 in a high-throughput screen of molecular libraries conducted by one of the centers of the MLSCN. Compounds identified through our screening assay will represent valuable basic research tools that will greatly facilitate the long term goal of this project to understand the involvement of GPR7 in chronic pain, its role in the mechanism of pain transmission and its interaction with other pain- related pathways. Small compounds will be in particular useful to study the system with regard to its role in inflammatory neuropathies where established animal models are available.
? There is a significant medical need for novel compounds for treating chronic pain that are effective, long lasting and safe. The overall objective of the proposed research is to identify small molecule, selective agonist and antagonists for the opioid receptor related G protein-coupled receptor GPR7 using a high-throughput assay format. Compounds identified through our screening assay will represent valuable basic research tools that will greatly facilitate the long term goal of this project to understand the involvement of GPR7 in chronic pain. ? ? ?
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