Cortical astrocyte activation triggers meningeal nociception and migraine-like pain
Although migraine attacks are considered to arise in the brain, the exact mechanisms by which the brain can generate migraine pain remain unclear. Visual cortex hyperexcitability has been observed consistently across different migraine subtypes. During cortical hyperexcitability events, aberrant neurotransmitter release drives heightened G-coupled receptor signaling in cortical astrocytes, which in turn release gliotransmitters and other factors with algesic properties. This study investigated whether heightened activation of cortical astrocytes Gq-coupled signaling is sufficient to drive peripheral meningeal nociceptive responses linked to the generation of migraine headaches. Using a rat model, we employed an AAV-based chemogenetic approach that allows selective activation of visual cortex astrocyte Gq-GPCR signaling. We combined this chemogenetic approach with in vivo single-unit recording of trigeminal meningeal nociceptors to assess changes in their ongoing activity and mechanosensitivity. We further used behavioral testing of migraine-like behaviors and pharmacological targeting of calcitonin gene-related peptide (CGRP), using a monoclonal antibody (anti-CGRP mAb) to further assess the relevance of cortical astrocyte activation to migraine. We discovered that heightened activation of Gq-coupled signaling in visual cortex astrocytes drives persistent discharge and increased mechanosensitivity of trigeminal nociceptors innervating the meninges overlying the visual cortex. Cortical astrocytic activation also generated cephalic mechanical pain hypersensitivity, reduced exploratory behavior, and anxiety-like behaviors linked to migraine headaches. Targeting calcitonin gene-related peptide signaling, implicated in migraine pathophysiology, using a monoclonal antibody effectively suppressed astrocyte-mediated meningeal nociceptor discharge and alleviated migraine-related behaviors. Our findings reveal a previously unappreciated role for augmented visual cortex astrocyte signaling as a triggering factor sufficient to generate meningeal nociception and migraine pain and greatly expand our understanding of migraine pathophysiology.