Specific functions of cyclic nucleotide phosphodiesterases in pain processing

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Accumulating evidence suggests that cGMP signaling in distinct neuronal cell populations of the nociceptive system essentially contributes to the processing of pain. However, how the duration and amplitude of cGMP signals in these cells are regulated remains elusive. In general, cGMP is hydrolyzed by phosphodiesterases (PDEs), which are classified in several families with multiple isoforms and splice variants. In preliminary work, we found that the phosphodiesterases PDE10A and PDE11A are expressed in distinct subpopulations of nociceptive neurons and regulate cGMP tissue levels. Based on their cellular localization, these PDEs might exert specific functions in the processing of different pain modalities. Therefore, we now plan to further investigate the functions of PDE10A and PDE11A in pain processing. Here, we will focus on the following questions: (1) Which subpopulations of nociceptive neurons express cGMP-hydrolyzing PDEs? (2) What are the functional roles of PDE10A and PDE11A during pain processing in vivo? (3) By which mechanisms do PDE10A and PDE11A modulate nociceptive signaling? This project will improve our understanding of the functions of different cGMP signaling pathways and the cross-talk between cGMP and cAMP during pain processing. The long-term goal is to find out whether targeting PDEs could serve as a new pharmacological approach for pain therapy in the future.