The onset of the headache phase in migraine with aura is believed to be influenced by cortical spreading depression (CSD) and the subsequent activation and sensitization of primary afferent neurons that innervate the intracranial meninges and their associated large vessels. However, the specific mechanisms behind this peripheral meningeal nociceptive response are not well understood. To explore this, we examined the impact of cortical astrocytes on CSD-induced meningeal nociception through extracellular single-unit recording of meningeal afferent activity and 2-photon imaging of cortical astrocyte calcium activity. We utilized pharmacological approaches, including fluoroacetate and L-a-aminoadipate, to inhibit astrocytic function through different mechanisms. The results showed that these inhibitors suppressed CSD-induced afferent mechanical sensitization but did not affect afferent activation. Furthermore, pharmacological inhibition of astrocytic function, which alleviated the sensitization of meningeal afferents, reduced basal astrocyte calcium activity but had minimal impact on the astrocytic calcium wave during CSD. In conclusion, our findings suggest that calcium-independent signaling in cortical astrocytes plays a crucial role in driving the sensitization of meningeal afferents and the subsequent intracranial mechanical hypersensitivity in migraine with aura.
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