Specific functions of cyclic nucleotide phosphodiesterases in pain processing

越来越多的证据表明，伤害性感觉系统中不同神经细胞群中的cGMP信号本质上参与了疼痛的处理。然而，这些细胞中cGMP信号的持续时间和幅度是如何调节的，仍然难以捉摸。通常情况下，cGMP被磷酸二酯酶(PDE)水解，PDE被分为几个家族，具有多种异构体和剪接变体。在前期工作中，我们发现磷酸二酯酶PDE10A和PDE11A在不同的伤害性神经元亚群中表达，并调节cGMP组织水平。基于它们的细胞定位，这些PDE可能在不同疼痛方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在疼痛处理中的作用。在这里，我们将集中讨论以下问题：(1)哪些伤害性神经元亚群表达cGMP水解型PDE？(2)PDE10A和PDE11A在体内痛觉处理过程中起什么作用？(3)PDE10A和PDE11A通过哪些机制调节伤害性信号？这个项目将加深我们对不同cGMP信号通路的功能以及cGMP和cAMP在疼痛处理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一种新的药理学方法。

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.