The genesis of the headache phase in migraine with aura is thought to be mediated by cortical spreading depression (CSD) and the subsequent activation and sensitization of primary afferent neurons that innervate the intracranial meninges and their related large vessels. Yet, the exact mechanisms underlying this peripheral meningeal nociceptive response remain poorly understood. We investigated the relative contribution of cortical astrocytes to CSD-evoked meningeal nociception using extracellular single-unit recording of meningeal afferent activity and 2-photon imaging of cortical astrocyte calcium activity, in combination with 2 pharmacological approaches to inhibit astrocytic function. We found that fluoroacetate and l-α-aminoadipate, which inhibit astrocytes through distinct mechanisms, suppressed CSD-evoked afferent mechanical sensitization, but did not affect afferent activation. Pharmacological inhibition of astrocytic function, which ameliorated meningeal afferents' sensitization, reduced basal astrocyte calcium activity but had a minimal effect on the astrocytic calcium wave during CSD. We propose that calcium-independent signaling in cortical astrocytes plays an important role in driving the sensitization of meningeal afferents and the ensuing intracranial mechanical hypersensitivity in migraine with aura.

中文翻译：

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星形胶质细胞介导与偏头痛相关的颅内脑膜机械过敏。

有先兆偏头痛的头痛阶段的发生被认为是由皮质扩散抑制（CSD）以及随后支配颅内脑膜及其相关大血管的初级传入神经元的激活和敏化介导的。然而，这种外周脑膜伤害性反应背后的确切机制仍然知之甚少。我们使用脑膜传入活动的细胞外单单元记录和皮质星形胶质细胞钙活性的 2 光子成像，结合 2 种抑制星形胶质细胞功能的药理学方法，研究了皮质星形胶质细胞对 CSD 诱发的脑膜伤害性感受的相对贡献。我们发现氟乙酸盐和 l-α-氨基己二酸通过不同的机制抑制星形胶质细胞，抑制 CSD 诱发的传入机械敏化，但不影响传入激活。星形胶质细胞功能的药物抑制可改善脑膜传入神经的敏化，降低基础星形胶质细胞钙活性，但对 CSD 期间星形胶质细胞钙波的影响最小。我们提出，皮质星形胶质细胞中的钙独立信号传导在驱动脑膜传入神经的敏化以及随之而来的先兆偏头痛的颅内机械超敏反应中发挥着重要作用。