cGMP signalling in pain processing and regeneration after peripheral nerve injury

cGMP 信号在周围神经损伤后疼痛处理和再生中的作用

• 批准号: 290981373
• 负责人: Professor Dr. Achim Schmidtko
• 金额: --
• 依托单位: Institut für Pharmakologie und Klinische Pharmazie
• 依托单位国家: 德国
• 项目类别: Research Units
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/290981373?language=en
• 关键词: cGMP; signalling; pain; processing; regeneration

Painful stimuli are detected by sensory neurons whose cell somata are located in dorsal root ganglia and trigeminal ganglia. Previous studies in our and other labs revealed that pain processing in sensory neurons is associated with cGMP production, activation of cGMP-dependent protein kinase I (cGKI) and phosphorylation of cysteine-rich protein 4 (CRP4; formerly named CRP2). Recently, we observed that CRP4 phosphorylation in sensory neurons is evoked by C-type natriuretic peptide (CNP), but not by atrial natriuretic peptide (ANP) or NO, suggesting that a CNP/GC-B/cGMP/cGKI/CRP4 signalling pathway contributes to pain processing in this neuronal population. Using conditional knockout mice with a sensory neuron-specific deletion of GC-B, cGKI or CRP4, we will investigate the in vivo function of this signalling pathway during chronic pain induced by sciatic nerve crush injury, a model that involves degeneration and regeneration of primary afferent neurons. In particular, we will characterize the localization of CNP- and GC-B-positive cell populations in the nociceptive system, the kinetics of CNP release, the spatiotemporal dynamics of cGMP production in dorsal root ganglia after painful stimulation, and downstream mechanisms of this signalling pathway. After elucidation of the localization of CNP-expressing cells in the nociceptive system, we also plan to characterize tissue-specific CNP knockout mice in this context. In contrast to the signalling pathway mentioned above, NO-GC is not expressed in sensory neurons but in satellite glial cells that cover the surface of sensory neurons. Several studies demonstrated that after peripheral nerve injury, satellite glial cells proliferate and contribute to pain processing. Considering that NO synthase expression is markedly upregulated in sensory neurons after peripheral nerve injury, it is very likely that NO acts as a paracrine messenger to increase cGMP production in satellite glial cells. This neuron-glia crosstalk might contribute to the proliferation of satellite cells and their protective role to prevent loss of sensory neurons after peripheral nerve injury. However, the relative contribution of NO-GC isoforms in satellite glial cells and other cells of the nociceptive system to pain processing and regeneration after peripheral nerve injury is poorly understood. We will therefore investigate the in vivo functions of NO-GC signalling during chronic pain induced by sciatic nerve crush injury using conditional knockout mice lacking NO-GC isoforms. Altogether, this project will provide more information on how different cGMP signalling pathways contribute to pain processing and regeneration after nerve injury. The long-term goal is to find out whether targeting cGMP signalling could serve as a new approach for treatment of chronic pain.

痛刺激由感觉神经元检测，感觉神经元的细胞体位于背根神经节和三叉神经节。我们和其他实验室的先前研究表明，感觉神经元中的疼痛处理与cGMP产生、cGMP依赖性蛋白激酶I（cGKI）的激活和富含半胱氨酸的蛋白4（CRP 4;以前称为CRP 2）的磷酸化有关。最近，我们观察到感觉神经元中的CRP 4磷酸化是由C型利钠肽（CNP）引起的，而不是由心房利钠肽（ANP）或NO引起的，这表明CNP/GC-B/cGMP/cGKI/CRP 4信号通路有助于该神经元群体中的疼痛处理。使用感觉神经元特异性缺失GC-B、cGKI或CRP 4的条件性基因敲除小鼠，我们将研究坐骨神经挤压损伤诱导的慢性疼痛过程中该信号通路的体内功能，该模型涉及初级传入神经元的变性和再生。特别是，我们将表征CNP和GC-B阳性细胞群体在伤害性系统中的定位，CNP释放的动力学，疼痛刺激后背根神经节中cGMP产生的时空动力学，以及该信号通路的下游机制。在阐明CNP表达细胞在伤害性系统中的定位后，我们还计划在此背景下表征组织特异性CNP敲除小鼠。与上述信号通路相反，NO-GC不在感觉神经元中表达，而是在覆盖感觉神经元表面的卫星神经胶质细胞中表达。一些研究表明，周围神经损伤后，卫星神经胶质细胞增殖，并有助于疼痛处理。考虑到周围神经损伤后感觉神经元中NO合酶表达显著上调，NO很可能作为旁分泌信使增加卫星胶质细胞中cGMP的产生。这种神经元-胶质细胞的相互作用可能有助于卫星细胞的增殖，并发挥其保护作用，防止周围神经损伤后感觉神经元的丢失。然而，卫星神经胶质细胞和伤害性系统的其他细胞中的NO-GC亚型对周围神经损伤后疼痛处理和再生的相对贡献知之甚少。因此，我们将研究在坐骨神经挤压损伤诱导的慢性疼痛过程中，使用条件敲除小鼠缺乏NO-GC亚型的NO-GC信号转导的体内功能。总之，该项目将提供更多关于不同cGMP信号通路如何有助于神经损伤后疼痛处理和再生的信息。长期目标是找出靶向cGMP信号传导是否可以作为治疗慢性疼痛的新方法。