Department of Neurology, The First Medical Center, Chinese PLA General Hospital, Beijing, China.
Medical School of Chinese PLA, Beijing, China.
J Headache Pain. 2024 May 17;25(1):81. doi: 10.1186/s10194-024-01778-3.
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.
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.
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.
Our study indicated that AC1-dependent IC plasticity contributes to migraine and AC1 may be a promising target for treating migraine in the future.
最近的动物和临床研究结果一致强调降钙素基因相关肽（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，疼痛相关皮层中与 CGRP 相关的信号通路仍知之甚少。
使用硬膜内输注炎性汤的方法建立 SD 大鼠 CM 模型。使用 von-Frey 纤维评估眶周机械阈值，通过旷场和高架十字迷宫测试观察焦虑样行为。使用免疫荧光和 Western blot 分析检测 c-Fos、CGRP 和 NMDA GluN2B 受体的表达。通过全细胞膜片钳记录检测兴奋性突触传递。在 CM 大鼠中通过岛叶立体定向和腹腔内注射应用一种人用腺苷酸环化酶 1（AC1）抑制剂 hNB001。
偏头痛模型大鼠的岛叶皮层（IC）被激活。IC 中的谷氨酸能介导的兴奋传递和 NMDA GluN2B 受体被增强。在痛觉和焦虑样活动期间，IC 中的 CGRP 水平显著增加。局部应用 hNB001 于 IC 或腹腔内可减轻偏头痛大鼠的眶周机械阈值和焦虑行为。此外，hNB001 应用后 IC 中的 CGRP 表达减少。
我们的研究表明，AC1 依赖性 IC 可塑性导致偏头痛，AC1 可能是未来治疗偏头痛的有希望的靶点。
