Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Boston MA 02115.
Harvard Medical School, Boston, Massachusetts 02215, and.
J Neurosci. 2019 Jul 24;39(30):6001-6011. doi: 10.1523/JNEUROSCI.0232-19.2019. Epub 2019 May 24.
Cortical spreading depression (CSD) is a wave of neuronal depolarization thought to underlie migraine aura. Calcitonin gene-related peptide (CGRP) is a potent vasodilator involved in migraine pathophysiology. Evidence for functional connectivity between CSD and CGRP has triggered scientific interest in the possibility that CGRP antagonism may disrupt vascular responses to CSD and the ensuing plasma protein extravasation (PPE). Using imaging tools that allow us to generate continuous, live, high-resolution views of spatial and temporal changes that affect arteries and veins in the dura and pia, we determined the extent to which CGRP contributes to the induction of arterial dilatation or PPE by CSD in female rats, and how these events are affected by the anti-CGRP monoclonal antibody (anti-CGRP-mAb) fremanezumab. We found that the CSD-induced brief dilatation and prolonged constriction of pial arteries, prolonged dilatation of dural arteries and PPE are all unaffected by fremanezumab, whereas the brief constriction and prolonged dilatation of pial veins are affected. In comparison, although CGRP infusion gave rise to the expected dilatation of dural arteries, which was effectively blocked by fremanezumab, it did not induce dilatation in pial arteries, pial veins, or dural veins. It also failed to induce PPE. Regardless of whether the nociceptors become active before or after the induction of arterial dilatation or PPE by CSD, the inability of fremanezumab to prevent them suggests that these events are not mediated by CGRP, a conclusion with important implications for our understanding of the mechanism of action of anti-CGRP-mAbs in migraine prevention. The current study identifies fundamental differences between two commonly used models of migraine, CSD induction and systemic CGRP infusion. It raises the possibility that conclusions drawn from one model may not be true or relevant to the other. It sharpens the need to accept the view that there is more than one truth to migraine pathophysiology and that it is unlikely that one theory will explain all types of migraine headache or the mechanisms of action of drugs that prevent it. Regarding the latter, it is concluded that not all vascular responses in the meninges are born alike and, consequently, that drugs that prevent vascular dilatation through different molecular pathways may have different therapeutic outcomes in different types of migraine.
皮质扩散性抑制（CSD）是一种神经元去极化波，被认为是偏头痛先兆的基础。降钙素基因相关肽（CGRP）是一种强效的血管扩张剂，参与偏头痛的病理生理学。CSD 与 CGRP 之间功能连接的证据引发了科学界的兴趣，即 CGRP 拮抗剂可能会破坏 CSD 对血管的反应以及随之而来的血浆蛋白外渗（PPE）。我们使用成像工具，可以连续、实时地生成影响硬脑膜和软脑膜中的动脉和静脉的空间和时间变化的高分辨率视图，以确定 CGRP 在多大程度上促进雌性大鼠 CSD 诱导的动脉扩张或 PPE，以及这些事件如何受到抗 CGRP 单克隆抗体（抗 CGRP-mAb）fremanezumab 的影响。我们发现，CSD 诱导的软脑膜动脉短暂扩张和长期收缩、硬脑膜动脉长期扩张和 PPE 均不受 fremanezumab 影响，而软脑膜静脉短暂收缩和长期扩张则受影响。相比之下，尽管 CGRP 输注引起了预期的硬脑膜动脉扩张，这种扩张被 fremanezumab 有效阻断，但它没有引起软脑膜动脉、软脑膜静脉或硬脑膜静脉扩张，也没有引起 PPE。无论伤害感受器是在 CSD 诱导动脉扩张或 PPE 之前还是之后变得活跃，fremanezumab 都无法阻止它们，这表明这些事件不是由 CGRP 介导的，这一结论对我们理解抗 CGRP-mAb 在偏头痛预防中的作用机制具有重要意义。本研究确定了两种常用偏头痛模型（CSD 诱导和系统性 CGRP 输注）之间的根本差异。它提出了一种可能性，即从一种模型中得出的结论可能不是真实的，或者与另一种模型不相关。它尖锐地提醒人们需要接受这样一种观点，即偏头痛的病理生理学有不止一个真相，而且一种理论不太可能解释所有类型的偏头痛头痛或预防它的药物的作用机制。关于后者，可以得出结论，脑膜中的并非所有血管反应都是天生的，因此，通过不同分子途径预防血管扩张的药物在不同类型的偏头痛中可能有不同的治疗效果。
