cGMP signaling in pain processing and regeneration after peripheral nerve injury

慢性疼痛是一个非常普遍且管理不善的健康问题。了解痛觉产生的分子机制是合理开发新型止痛药的重要前提。我们和其他实验室之前的研究表明，疼痛处理与伤害感受系统中cGMP的产生有关。越来越多的证据表明，慢性疼痛过程中cGMP的产生不仅由一氧化氮(NO)启动，也由利钠肽(NP)启动。然而，在这种情况下，NO和NP依赖的cGMP产生的细胞分布和功能影响仍然难以捉摸。在之前的资助期间，我们发现了两种不敏感的可溶性鸟苷酸环化酶亚型(NO-GC1和NO-GC2)定位于脊髓中不同的中间神经元亚群。有趣的是，NO-GC1参与了周围神经损伤后神经病理性疼痛的处理，而NO-GC2则调控炎症性疼痛的处理。此外，我们还发现，在伤害性感受系统的NO-GC阴性神经元中，NP可能启动cGMP的产生。基于我们以前的工作和最近建立的组织特异性条件小鼠系，我们现在将扩大我们的研究，以了解更多关于慢性疼痛期间依赖NO和NP的cGMP信号的机制。主要目的是(1)研究周围神经损伤后神经病理性疼痛过程中脊髓中间神经元NO/cGMP信号的下游靶点；(2)确定感觉神经元中颗粒鸟苷酸环化酶对疼痛处理和神经再生的影响；(3)阐明伤害性感觉系统中导致NP释放的机制。总之，这个项目将提供更多关于不同的cGMP信号通路如何促进疼痛处理的信息。长期目标是找出靶向cGMP信号是否可以作为治疗疼痛的新的药理学方法。

Chronic pain is a highly prevalent and poorly managed health problem. Unraveling the molecular mechanisms underlying pain processing is a crucial prerequisite for the rational development of novel analgesic drugs. Previous studies in our and other labs revealed that pain processing is associated with cGMP production in the nociceptive system. There is accumulating evidence that cGMP production during chronic pain is not only initiated by nitric oxide (NO) but also by natriuretic peptides (NP). However, the cellular distribution and the functional impact of NO- and NP-dependent cGMP production in this context remains elusive. In the previous funding period, we found that the two isoforms of ‘soluble’, NO-sensitive guanylyl cyclase (NO-GC1 and NO-GC2) are localized to distinct subpopulations of interneurons in the spinal cord. Interestingly, NO-GC1 contributes to the processing of neuropathic pain after peripheral nerve injury, whereas NO-GC2 modulates the processing of inflammatory pain. Moreover, we found that NP may initiate cGMP production in NO-GC-negative neurons of the nociceptive system. Based on our previous work and recently established tissue-specific conditional mouse lines, we will now extend our studies to learn more about the mechanisms underlying NO- and NP-dependent cGMP signaling during chronic pain. The major aims that will be approached are (1) to characterize downstream targets of NO/cGMP signaling in spinal interneurons during neuropathic pain after peripheral nerve injury, (2) to determine the impact of particulate guanylyl cyclases in sensory neurons on pain processing and nerve regeneration, and (3) to elucidate the mechanisms leading to NP release in the nociceptive system. Altogether, this project will provide more information on how different cGMP signaling pathways contribute to pain processing. The long-term goal is to find out whether targeting cGMP signaling could serve as a new pharmacological approach for treatment of pain.