Specific functions of cyclic nucleotide phosphodiesterases in pain processing

越来越多的证据表明，cGMP信号在不同的神经元细胞群体的伤害性系统基本上有助于疼痛的处理。然而，这些细胞中cGMP信号的持续时间和幅度如何调节仍然是难以捉摸的。一般来说，cGMP被磷酸二酯酶（PDE）水解，PDE分为几个家族，具有多种亚型和剪接变体。在初步工作中，我们发现磷酸二酯酶PDE10A和PDE11A在伤害感受神经元的不同亚群中表达并调节cGMP组织水平。基于它们的细胞定位，这些PDE可能在不同的疼痛模式的处理中发挥特定的功能。因此，我们现在计划进一步研究PDE10A和PDE11A在疼痛处理中的功能。在这里，我们将集中在以下问题：（1）哪些伤害性神经元亚群表达cGMP水解PDE？(2)PDE10A和PDE11A在体内疼痛处理过程中的功能作用是什么？(3)PDE10A和PDE11A通过何种机制调节伤害性信号传导？本项目将提高我们对不同cGMP信号通路的功能以及cGMP和cAMP在疼痛过程中的相互作用的理解。长期目标是找出靶向PDE是否可以作为未来疼痛治疗的新药理学方法。

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.