Chronic migraine, with a global prevalence of 12%, represents a serious social issue whose pathophysiology remains an unresolved biomedical challenge. Migraine is an inflammatory process involving trigeminal nociceptors that release CGRP, causing vasodilation of extracranial vessels in the dura mater. Therapies targeting the CGRP pathway are clinically effective for severe chronic migraine sufferers. Migraine exhibits a strong sexual dimorphism, being three times more prevalent in women than in men.

This dimorphism begins at puberty and coincides with the fertile period in women, indicating the involvement of hormonal cycles during the menstrual cycle. The mechanisms underlying hormonal modulation of migraine remain elusive. A key finding of our previous project revealed the role of the TRPM8 channel as a testosterone receptor, which provides antinociceptive resistance exclusively in males. Inhibition of this protective mechanism in males induced persistent migraine-like symptoms, while the administration of testosterone to females facilitated recovery. These findings suggest that the testosterone-TRPM8 pathway is fundamental to the sexual dimorphism of migraine and indicate that modulators of this pathway could be effective anti-migraine drugs. Consequently, this hypothesis requires urgent exploration to uncover the underlying mechanisms by which sex hormones regulate nociceptor function, as well as the differences between male and female nociceptors, to develop novel therapies that account for the sexual dimorphism of the disease, thereby improving patients’ quality of life. This is precisely the long-term objective of the GIOCONDA project.

Project funded by the Ministry of Science, Innovation, and Universities (PID2021-126423OB-C21).

PROJECT EXECUTION PERIOD
Start date: 01/09/2022
End date: 30/08/2025