PDF(Pubmed)
Abstract：
BACKGROUND: Recent animal and clinical findings consistently highlight the critical role of calcitonin gene-related peptide (CGRP) in chronic migraine (CM) and related emotional responses. CGRP antibodies and receptor antagonists have been approved for CM treatment. However, the underlying CGRP-related signaling pathways in the pain-related cortex remain poorly understood.
METHODS: The SD rats were used to establish the CM model by dural infusions of inflammatory soup. Periorbital mechanical thresholds were assessed using von-Frey filaments, and anxiety-like behaviors were observed via open field and elevated plus maze tests. Expression of c-Fos, CGRP and NMDA GluN2B receptors was detected using immunofluorescence and western blotting analyses. The excitatory synaptic transmission was detected by whole-cell patch-clamp recording. A human-used adenylate cyclase 1 (AC1) inhibitor, hNB001, was applied via insula stereotaxic and intraperitoneal injections in CM rats.
RESULTS: The insular cortex (IC) was activated in the migraine model rats. Glutamate-mediated excitatory transmission and NMDA GluN2B receptors in the IC were potentiated. CGRP levels in the IC significantly increased during nociceptive and anxiety-like activities. Locally applied hNB001 in the IC or intraperitoneally alleviated periorbital mechanical thresholds and anxiety behaviors in migraine rats. Furthermore, CGRP expression in the IC decreased after the hNB001 application.
CONCLUSIONS: Our study indicated that AC1-dependent IC plasticity contributes to migraine and AC1 may be a promising target for treating migraine in the future.
METHODS: The SD rats were used to establish the CM model by dural infusions of inflammatory soup. Periorbital mechanical thresholds were assessed using von-Frey filaments, and anxiety-like behaviors were observed via open field and elevated plus maze tests. Expression of c-Fos, CGRP and NMDA GluN2B receptors was detected using immunofluorescence and western blotting analyses. The excitatory synaptic transmission was detected by whole-cell patch-clamp recording. A human-used adenylate cyclase 1 (AC1) inhibitor, hNB001, was applied via insula stereotaxic and intraperitoneal injections in CM rats.
RESULTS: The insular cortex (IC) was activated in the migraine model rats. Glutamate-mediated excitatory transmission and NMDA GluN2B receptors in the IC were potentiated. CGRP levels in the IC significantly increased during nociceptive and anxiety-like activities. Locally applied hNB001 in the IC or intraperitoneally alleviated periorbital mechanical thresholds and anxiety behaviors in migraine rats. Furthermore, CGRP expression in the IC decreased after the hNB001 application.
CONCLUSIONS: Our study indicated that AC1-dependent IC plasticity contributes to migraine and AC1 may be a promising target for treating migraine in the future.
摘要：
背景：最近的动物和临床研究结果一致强调了降钙素基因相关肽（CGRP）在慢性偏头痛（CM）和相关情绪反应中的关键作用。CGRP抗体和受体拮抗剂已被批准用于CM治疗。然而,疼痛相关皮质中潜在的CGRP相关信号通路仍知之甚少.
方法：SD大鼠采用硬膜灌注炎性汤建立CM模型。使用von-Frey细丝评估眶周机械阈值，通过开阔视野和高架迷宫测试观察到焦虑样行为。c-Fos的表达,使用免疫荧光和蛋白质印迹分析检测CGRP和NMDAGluN2B受体。通过全细胞膜片钳记录检测兴奋性突触传递。人类使用的腺苷酸环化酶1（AC1）抑制剂，通过脑岛立体定位和腹膜内注射在CM大鼠中应用hNB001。
结果：偏头痛模型大鼠的岛叶皮层（IC）被激活。谷氨酸介导的兴奋性传递和IC中的NMDAGluN2B受体增强。在伤害性和焦虑样活动期间，IC中的CGRP水平显着增加。在IC中局部应用hNB001或腹膜内减轻偏头痛大鼠的眶周机械阈值和焦虑行为。此外，CGRP在IC中表达下降后应用hNB001。
结论：我们的研究表明AC1依赖性IC可塑性有助于偏头痛，AC1可能是未来治疗偏头痛的一个有希望的靶点。
方法：SD大鼠采用硬膜灌注炎性汤建立CM模型。使用von-Frey细丝评估眶周机械阈值，通过开阔视野和高架迷宫测试观察到焦虑样行为。c-Fos的表达,使用免疫荧光和蛋白质印迹分析检测CGRP和NMDAGluN2B受体。通过全细胞膜片钳记录检测兴奋性突触传递。人类使用的腺苷酸环化酶1（AC1）抑制剂，通过脑岛立体定位和腹膜内注射在CM大鼠中应用hNB001。
结果：偏头痛模型大鼠的岛叶皮层（IC）被激活。谷氨酸介导的兴奋性传递和IC中的NMDAGluN2B受体增强。在伤害性和焦虑样活动期间，IC中的CGRP水平显着增加。在IC中局部应用hNB001或腹膜内减轻偏头痛大鼠的眶周机械阈值和焦虑行为。此外，CGRP在IC中表达下降后应用hNB001。
结论：我们的研究表明AC1依赖性IC可塑性有助于偏头痛，AC1可能是未来治疗偏头痛的一个有希望的靶点。
