Cortical astrocyte activation triggers meningeal nociception and migraine-like pain

Summary Migraine attacks are believed to originate in the brain, but the exact mechanisms by which the brain generates peripheral nociceptive signals that drive migraine pain remain unclear. Sensory cortex hyperexcitability has been observed consistently across different migraine subtypes. Astrocytes detect aberrant increases in cortical activity via their Gq-coupled receptors and respond by releasing gliotransmitters and other factors with proinflammatory and nociceptive properties. In the present study, we used a rat model to investigate whether heightened cortical astrocyte Gq-coupled signaling is sufficient to drive peripheral trigeminal meningeal nociceptive responses linked to the generation of migraine headaches. We used an AAV-based chemogenetic approach that allows selective activation of cortical astrocyte Gq-GPCR signaling. We targeted astrocytes in the visual cortex as hyperexcitability in this region has been implicated in migraine. Furthermore, the meninges overlying the visual cortex are densely innervated by nociceptive fibers. We combined this chemogenetic approach with in vivo single-unit recording of meningeal nociceptors to assess changes in their ongoing activity and mechanosensitivity, along with testing of migraine-like behaviors. We further targeted calcitonin gene-related peptide (CGRP), using a monoclonal antibody (anti-CGRP mAb), to 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 meningeal nociceptors. Cortical astrocytic activation also generated cephalic mechanical pain hypersensitivity, reduced exploratory behavior, and anxiety-like behaviors linked to migraine headaches. Blocking calcitonin gene-related peptide signaling suppressed astrocyte-mediated increases in meningeal nociceptor discharge and alleviated associated 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. Competing Interest Statement JS was an employee of Teva Pharmaceutical, which manufactured the anti-CGRP mAb used in the study. All other authors report no competing interests. Footnotes ↵3 Lead Contact This version of the manuscript has been revised to update the following: Typos, grammar and style: abstract, introduction, results, discussion, Figure legends.