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CREB-KIF1A-CGRP-positive feedback loop drives central sensitization in chronic migraine
Wei Jiang1, Peng Yu2, Yan-Min Shi3
1Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, 1 Xinmin Street, Changchun, 130021, China.
The Journal of Headache and Pain
|October 1, 2025
Summary
Researchers uncovered a CREB-KIF1A-CGRP positive feedback loop driving chronic migraine. Targeting this pathway, involving CREB regulation of KIF1A and CGRP, offers potential new treatments for migraine.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- Chronic migraine (CM) is a complex neurological disorder with unclear upstream regulation of calcitonin gene-related peptide (CGRP).
- Kinesin family member 1A (KIF1A), crucial for axonal transport, is regulated by cAMP response element-binding protein (CREB).
Purpose of the Study:
- To investigate the role of the CREB-KIF1A-CGRP signaling axis in migraine pathogenesis.
- To elucidate the upstream regulation of CGRP in chronic migraine.
Main Methods:
- Generated chronic migraine models in mice using nitroglycerin (NTG) injections.
- Analyzed molecular changes in the spinal trigeminal nucleus caudalis (SP5C) and Neuro-2a cells via immunoblotting, qPCR, and immunofluorescence.
- Performed chromatin immunoprecipitation, dual-luciferase assays, coimmunoprecipitation, and synaptosomal CGRP analysis.
Main Results:
- NTG activated the CREB-KIF1A-CGRP pathway, inducing migraine-like hypersensitivity.
- CREB activation upregulated KIF1A and CGRP; inhibition reversed these effects.
- KIF1A physically associated with CGRP, and Kif1a knockdown alleviated hypersensitivity.
Conclusions:
- A CREB-KIF1A-CGRP positive feedback loop drives migraine-like hypersensitivity.
- CREB directly regulates KIF1A, promoting CGRP expression and signaling.
- Disrupting this axis attenuated migraine behaviors, indicating potential therapeutic targets.
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