PACAP6-38 通过调节慢性偏头痛雄性大鼠模型中三叉神经尾核的突触可塑性来改善硝酸甘油诱导的中枢敏化,The Journal of Headache and Pain

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PACAP6-38 通过调节慢性偏头痛雄性大鼠模型中三叉神经尾核的突触可塑性来改善硝酸甘油诱导的中枢敏化
The Journal of Headache and Pain ( IF 7.3 ) Pub Date : 2023-06-05 , DOI: 10.1186/s10194-023-01603-3
Lily Zhang _{1,

2} , Yanjie Zhou _{1,

2} , Liu Yang _{1,

2} , Yue Wang _{1,

2} , Zheman Xiao _{1,

2}

Affiliation

慢性偏头痛（CM）是一种常见的神经系统疾病，发病机制复杂。有证据表明，垂体腺苷酸环化酶激活肽 (PACAP) 可诱发偏头痛样发作，可能成为偏头痛治疗的潜在新靶点，但靶向 PACAP 及其受体的治疗效果并不统一。因此，本研究的目的是研究 PACAP I 型受体 (PAC1R) 拮抗剂 PACAP6-38 对 CM 模型中硝酸甘油 (NTG) 诱导的中枢敏化的调节作用。Sprague-Dawley (SD) 大鼠反复注射 NTG 以构建 CM 模型。使用 Von Frey 灯丝和热板测试测量机械和热阈值。通过蛋白质印迹和免疫荧光染色测量 C-Fos 表达以评估中枢敏化。PACAP6-38被脑内注射到三叉神经尾核（TNC），然后改变c-Fos，突触相关蛋白，磷酸化ERK1 / 2（p-ERK1 / 2），环磷酸腺苷反应元件的磷酸化检测到结合蛋白（p-CREB）和脑源性神经营养因子（BDNF）。透射电子显微镜（TEM）和高尔基-考克斯染色用于观察TNC神经元突触和树突结构的超微结构。结果表明，在重复注射 NTG 后，PACAP 和 PAC1R 的表达在 TNC 中显着升高。此外，PACAP6-38 治疗减轻了伤害性敏感性，抑制了 NTG 诱导的 CM 大鼠 TNC 中 c-Fos 和突触相关蛋白的过度表达，恢复了异常的突触结构。此外，PACAP6-38抑制ERK/CREB/BDNF通路的表达。我们的研究结果表明，CM 的 TNC 中的异常突触结构可以通过下调 ERK/CREB/BDNF 信号通路抑制 PAC1R 来逆转。PACAP6-38 通过调节 CM 大鼠 TNC 中的突触可塑性来改善 NTG 诱导的中枢敏化，这可能为针对 PACAP/PAC1R 治疗偏头痛提供新的见解。

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PACAP6-38 improves nitroglycerin-induced central sensitization by modulating synaptic plasticity at the trigeminal nucleus caudalis in a male rat model of chronic migraine

Chronic migraine (CM) is a common neurological disorder with complex pathogenesis. Evidence suggests that pituitary adenylate cyclase-activating peptide (PACAP) induces migraine-like attacks and may be potential a new target for migraine treatment, but the therapeutic results of targeting PACAP and its receptors are not uniform. Therefore, the aim of this study was to investigate the regulatory effect of PACAP type I receptor (PAC1R) antagonist, PACAP6-38, on nitroglycerin (NTG)-induced central sensitization in a CM model. Sprague–Dawley (SD) rats received repeated injections of NTG to construct a CM model. Mechanical and thermal thresholds were measured using Von Frey filaments and hot plate tests. C-Fos expression was measured by western blotting and immunofluorescence staining to assess the central sensitization. PACAP6-38 was intracerebrally injected into the trigeminal nucleus caudalis (TNC), and then the changes in c-Fos, the synaptic-associated proteins, phospho-ERK1/2 (p-ERK1/2), phosphorylation of cyclic adenosine monophosphate response element-binding protein (p-CREB) and brain-derived neurotrophic factor (BDNF) were detected. Transmission electron microscopy (TEM) and Golgi-Cox staining were used to observe the ultrastructure of synapses and dendritic structures of TNC neurons. The results showed that PACAP and PAC1R expression were significantly raised in the TNC after repeated NTG injections. Additionally, PACAP6-38 treatment alleviated nociceptive sensitization, inhibited NTG-induced overexpression of c-Fos and synaptic-associated proteins in the TNC of CM rat, restored aberrant synaptic structures. Furthermore, the expression of ERK/CREB/BDNF pathway was depressed by PACAP6-38. Our results demonstrated that abnormal synaptic structure in the TNC of CM, which could be reversed by inhibition of PAC1R via down-regulating the ERK/CREB/BDNF signaling pathway. PACAP6-38 improves NTG-induced central sensitization by regulating synaptic plasticity in the TNC of CM rat, which may provide new insights into the treatments targeting PACAP/PAC1R in migraine.

更新日期：2023-06-05

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