| Chronic pain associated with inflammation forms a major clinical problem and is difficult to treat. I have found that low GRK2 in sensory neurons prolongs PGE2-induced pain via a cAMP-Epac dependent pathway. Dr. Wood has shown the importance of voltage-gated sodium channels (Nav) in sensory neurons for inflammatory pain. Changes in distribution and function of Nav-channels regulate sensory neurons excitability and thereby pain responses. GRK2 interacts with several proteins known to regulate Nav distribution and functioning. The aim of this project is to investigate the contribution of GRK2 and the cAMP-Epac pathway to inflammation-induced changes in Nav1.8 trafficking and function that regulate neuronal excitability and peripheral pain thresholds. I will acquire patch clamp, immunohistochemistry, co-immunoprecipitation, RNAi, and overexpression techniques to determine how GRK2 and cAMP-Epac regulate inflammation-induced changes in the association of key Nav1.8-binding proteins with the channel. Additionally, the functional consequences of Nav1.8 distribution into specific membrane domains in conditions of low GRK2 will be assessed. This study will reveal how Nav1.8 that is one of the keys to pain-signalling, is regulated at the level of membrane distribution and how this process is affected by GRK2. These studies will generate novel insights into the neurobiology of inflammation-associated chronic pain. |
