Despite robust evidence on the role of calcitonin gene-related peptide (CGRP) in migraine via both central and peripheral actions, relatively less is known about how CGRP in the limbic system is involved in migraine progression. This study investigated whether CGRP production machinery exists in the two key limbic regions including hippocampus and amygdala using cortical spreading depression (CSD) as a model of migraine and whether such alteration by CSD is sensitive to N-methyl-d-aspartate (NMDA) receptor regulation in rats. A single or repetitive CSD was induced by topical application of KCl and monitored using electrophysiological methods. The NR2A-containing NMDA receptor antagonist, NVP-AAM077, or its vehicle, was perfused into the contralateral cerebroventricular ventricle of rat. Quantitative PCR was used to measure CGRP mRNA levels in the ipsilateral and contralateral hippocampus and amygdala after CSD events and compared to respective sham treatments. The results showed that neither a single CSD nor repetitive CSD affected CGRP mRNA levels in both the contralateral and ipsilateral hippocampus at 24 h post CSD induction. Differently, significant elevation of CGRP gene expression was observed in the ipsilateral amygdala at 24 h post multiple CSD, but not contralateral side, and not post-single CSD. Further results showed that the CSD-induced CGRP gene expression in the amygdala was markedly reduced by NVP-AAM077 and this reduction corresponded to a reduced cortical susceptibility to CSD in rats. We conclude that repetitive CSD events induce CGRP gene expression in amygdala, which is sensitive to NR2A regulation.

中文翻译：

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抑制NR2A降低大鼠杏仁核皮质扩散抑制诱导的降钙素基因相关肽基因表达

尽管有强有力的证据表明降钙素基因相关肽 (CGRP) 通过中枢和外周作用在偏头痛中发挥作用，但对边缘系统中的 CGRP 如何参与偏头痛进展的了解相对较少。本研究使用皮质扩散抑制 (CSD) 作为偏头痛模型，调查了包括海马和杏仁核在内的两个关键边缘区域是否存在 CGRP 产生机制，以及 CSD 的这种改变是否对 N-甲基-d-天冬氨酸 (NMDA) 受体敏感大鼠的调节。通过局部应用 KCl 诱导单一或重复 CSD，并使用电生理方法进行监测。将含有 NR2A 的 NMDA 受体拮抗剂 NVP-AAM077 或其载体灌注到大鼠的对侧脑室。定量 PCR 用于测量 CSD 事件后同侧和对侧海马和杏仁核中的 CGRP mRNA 水平，并与各自的假治疗进行比较。结果表明，在 CSD 诱导后 24 小时，单一 CSD 和重复 CSD 均不影响对侧和同侧海马中的 CGRP mRNA 水平。不同的是，在多次 CSD 后 24 小时，同侧杏仁核中观察到 CGRP 基因表达显着升高，但对侧没有，单次 CSD 后也没有。进一步的结果表明，NVP-AAM077 显着降低了杏仁核中 CSD 诱导的 CGRP 基因表达，这种降低对应于大鼠皮质对 CSD 的敏感性降低。我们得出结论，重复的 CSD 事件诱导杏仁核中的 CGRP 基因表达，杏仁核对 NR2A 调节敏感。