Cortical astrocyte activation triggers meningeal nociception and migraine-like pain

Abstract Cortical astrocytes were implicated in migraine attacks involving cortical spreading depolarizations and related aura symptoms. However, whether the activation of cortical astrocytes is sufficient to generate migraine headaches is unknown. We investigated the role of cortical astrocytes in migraine pain triggering using a DREADD-based chemogenetic approach to activate visual cortex astrocytes, assessing its effect on the responses of meningeal nociceptors, the development of migraine-like behaviors, and their dependence on peripheral CGRP signaling. In a rat model, activating cortical astrocytes was sufficient to induce prolonged ongoing discharge and mechanical sensitization of meningeal nociceptors. Cortical astrocytic activation also generated cephalic mechanical pain hypersensitivity, reduced exploratory behavior, and anxiety-like behaviors linked to migraine headaches. Blocking CGRP signaling with a monoclonal antibody suppressed astrocyte-driven meningeal nociceptor discharge and alleviated migraine-related behaviors. We propose that augmented activation of visual cortex astrocytes during cortical hyperexcitability events in migraine attacks with and without aura is sufficient to trigger meningeal nociception and the ensuing migraine pain. Our findings could aid the development of novel effective migraine treatments.