The first-line cluster headache medication verapamil alters the circadian period and elicits sex-specific sleep changes in mice

Verapamil is the first-line preventive medication for cluster headache, an excruciating disorder with strong circadian features. Whereas second- and third-line preventives include known modulators, such as melatonin, corticosteroids, lithium, effects of verapamil are poorly understood. Here, we characterize features using both in vitro vivo models. In Per2::LucSV reporter fibroblasts, treatment (0.03–10 µM) showed a dose-dependent period shortening rhythm which reached nadir at 1 µM, altered core clock gene expression 10 µM. Mouse wheel-running activity (1 mg/mL added to drinking water) also resulted significant reduction male female free-running wild-type C57BL6/J mice. The temporal patterns reduction, however, differ between two sexes. Importantly, piezo sleep recording revealed sexual dimorphism on timing bout duration, more pronounced adverse We found cerebellum, hypothalamus, trigeminal ganglion verapamil-treated did not affect rhythms ex suprachiasmatic nucleus (SCN) slices from Per2:Luc mice, perhaps due exceptionally tight coupling SCN. Thus, affects peripheral (trigeminal ganglion) central (hypothalamus cerebellum) nervous system structures involved headache pathophysiology, possibly network instead isolated SCN effects. These studies suggest that modulator laboratory models molecular behavioral levels, sex important biological variable medications. observations highlight potential convergent target medications different primary mechanisms action.