Cold Receptor TRPM8 as a target for Migraine-associated Pain and Affective Comorbidities

Cold Receptor TRPM8 as a target for Migraine-associated Pain and Affective Comorbidities | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Short Report Cold Receptor TRPM8 as a target for Migraine-associated Pain and Affective Comorbidities David Cabañero, Edward P Carter, Rafael González-Cano, Enrique J Cobos, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6305891/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 23 Jun, 2025 Read the published version in The Journal of Headache and Pain → Version 1 posted 9 You are reading this latest preprint version Abstract Background: Genetic variations in the Trpm8 gene that encodes the cold receptor TRPM8 have been linked to protection against polygenic migraine, a disabling condition primarily affecting women. Noteworthy, TRPM8 has been recently found in brain areas related to emotional processing, suggesting an unrecognized role in migraine comorbidities. Here, we use mouse behavioural models to investigate the role of Trpm8 in migraine-related phenotypes. Subsequently, we test the efficacy of rapamycin, a clinically relevant TRPM8 agonist, in these behavioural traits and in human induced pluripotent stem cell (iPSC)-derived sensory neurons. Findings: We report that Trpm8 null mice exhibited impulsive and depressive-like behaviours, while also showing frequent pain-like facial expressions detected by an artificial intelligence algorithm. In a nitroglycerin-induced migraine model, Trpm8 knockout mice of both sexes developed anxiety and mechanical hypersensitivity, whereas wild-type females also displayed depressive-like phenotype and hypernociception. Notably, rapamycin alleviated pain-related behaviour through both TRPM8-dependent and independent mechanisms but lacked antidepressant activity, consistent with a peripheral action. The macrolide ionotropically activated TRPM8 signalling in human sensory neurons, emerging as a new candidate for intervention. Significance: Together, our findings underscore the potential of TRPM8 for migraine relief and its involvement in affective comorbidities, emphasizing the importance of addressing emotional symptoms to improve clinical outcomes for migraine sufferers, especially in females. Migraine Mouse Behavioural Model TRPM8 Anxiety Depression Rapamycin Artificial Intelligence Spontaneous Pain Human Peripheral Sensory Neuron Full Text Additional Declarations No competing interests reported. Supplementary Files SupplementaryDataTrpm8.zip Cite Share Download PDF Status: Published Journal Publication published 23 Jun, 2025 Read the published version in The Journal of Headache and Pain → Version 1 posted Editorial decision: Revision requested 09 Apr, 2025 Reviews received at journal 09 Apr, 2025 Reviews received at journal 28 Mar, 2025 Reviewers agreed at journal 28 Mar, 2025 Reviewers agreed at journal 27 Mar, 2025 Reviewers invited by journal 27 Mar, 2025 Editor assigned by journal 26 Mar, 2025 Submission checks completed at journal 26 Mar, 2025 First submitted to journal 25 Mar, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6305891","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Short Report","associatedPublications":[],"authors":[{"id":440824230,"identity":"fb072740-4c84-426c-b553-d8e405b6a5ae","order_by":0,"name":"David 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