Nociceptor-localized cGMP-dependent protein kinase I is a critical generator for central sensitization and neuropathic pain.
Nociceptor-localized cGMP-dependent protein kinase I is a critical generator for central sensitization and neuropathic pain.
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伤害性感受器定位的cGMP依赖的蛋白激酶I是中枢敏感化和神经病理性疼痛的关键生成器。
DOI：
10.1097/j.pain.0000000000002013
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发表时间：
2020-08
期刊：
影响因子：
7.4
通讯作者：
Fei Wang;Sui-bin Ma;Zhijun Tian;Yanmang Cui;X. Cong;Wen-Bin Wu;Fu-Dong Wang;Zhen-Zhen Li-Zhen;Wen-juan Han;Tao-Zhi Wang;Zhi-Chuan Sun;Fan-Liang Zhang;Rou-gang Xie;Sheng-Xi Wu;C. Luo
中科院分区：
文献类型：
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作者：
Fei Wang;Sui-bin Ma;Zhijun Tian;Yanmang Cui;X. Cong;Wen-Bin Wu;Fu-Dong Wang;Zhen-Zhen Li-Zhen;Wen-juan Han;Tao-Zhi Wang;Zhi-Chuan Sun;Fan-Liang Zhang;Rou-gang Xie;Sheng-Xi Wu;C. Luo
神经性疼痛的患者通常会经历夸张的疼痛和焦虑。中枢致敏与神经性疼痛的维持有关，并可能成为一个自主的疼痛发生器。相反，越来越多的证据表明，中枢敏化是由持续的伤害性初级传入输入启动和维持的。然而，这种现象背后的机制仍然难以捉摸，以及哪种外周候选物质有助于导致疼痛超敏反应和疼痛相关焦虑的中枢敏化。先前的研究表明，外周定位的cgmp依赖性蛋白激酶I （PKG-I）参与伤害感受器的可塑性和脊髓突触传递以及炎症性痛觉过敏。然而，外周PKG-I是否有助于皮质可塑性，从而维持神经损伤引起的疼痛过敏和焦虑尚不清楚。本研究显示PKG-I在同侧L3 DRG中显著上调，L4 DRG无变化，L5 DRG在备用神经损伤（SNI）时下调。基因消融痛觉感受器中的PKG-I或治疗后椎间孔注射PKG-I拮抗剂KT5823可减轻sni诱导的双侧疼痛超敏反应和焦虑的发展和维持。机制分析显示，痛觉感受器中PKG-I的激活通过涉及BDNF信号的突触前机制，负责周围神经病变ACC的突触增强。我们的研究结果表明，痛觉感受器中PKG-I的表达是神经损伤后扣带突触可塑性的关键决定因素，这有助于维持疼痛超敏反应和焦虑。因此，本研究为开辟新的治疗靶点提供了坚实的基础，痛觉感受器中的PKG-I可用于治疗神经性疼痛和焦虑的合并症，且副作用最小。
Patients with neuropathic pain often experience exaggerated pain and anxiety. Central sensitization has been linked with the maintenance of neuropathic pain and may become an autonomous pain generator. Conversely, emerging evidence accumulated that central sensitization is initiated and maintained by ongoing nociceptive primary afferent inputs. However, it remains elusive what mechanisms underlie this phenomenon and which peripheral candidate contributes to central sensitization that accounts for pain hypersensitivity and pain-related anxiety. Previous studies have implicated peripherally-localized cGMP-dependent protein kinase I (PKG-I) in plasticity of nociceptors and spinal synaptic transmission as well as inflammatory hyperalgesia. However, whether peripheral PKG-I contributes to cortical plasticity and hence maintains nerve injury-induced pain hypersensitivity and anxiety is unknown. Here we demonstrated significant upregulation of PKG-I in ipsilateral L3 DRG, no change in L4 DRG and downregulation in L5 DRG upon spared nerve injury (SNI). Genetic ablation of PKG-I specifically in nociceptors or posttreatment with intervertebral foramen injection of PKG-I antagonist, KT5823 attenuated the development and maintenance of SNI-induced bilateral pain hypersensitivity and anxiety. Mechanistic analysis revealed that activation of PKG-I in nociceptors is responsible for synaptic potentiation in ACC upon peripheral neuropathy via presynaptic mechanisms involving BDNF signaling. Our results revealed that PKG-I expressed in nociceptors is a key determinant for cingulate synaptic plasticity after nerve injury, which contributes to the maintenance of pain hypersensitivity and anxiety. Thereby, this study presents a strong basis for opening up a novel therapeutic target, PKG-I in nociceptors for treatment of comorbidity of neuropathic pain and anxiety with least side effects.