Migraine is linked to circadian rhythms with attack onset disproportionately in the morning, jet lag is a known trigger, and a mutation in the clock regulatory kinase, casein kinase 1δ (CK1δ), is comorbid for migraine with aura and Familial Advance Sleep Phase (FASP). Here, we sought to explore the effect of circadian rhythms on periorbital (PO) mechanosensitivity in mice and characterize migraine-like phenotypes in transgenic mice harboring the CK1δ mutation or a second mutation for FASP affecting the clock specific protein Per2.

To investigate the role of environmental and genetic perturbations of circadian rhythms on migraine pathophysiology.

In C57bl/6J (n=24), PO mechosensitivity was measured using the von Frey assay at zeitgeber time (ZT) 0, 6, 12, 18; chronic jet lag was modelled by changing light cycles and mechanosensitivity assessed at ZT0 and 12. Migraine-like phenotypes including cortical spreading depression (CSD) and nitroglycerin-induced PO mechanosensitivity were assessed in CK1δ-T44A (n=24), Per2-S662G (n=25) and WT littermates (n=47). CSD was chemically induced (1M KCl) in anaesthetized mice and recorded for 1hr. Mechanosensitivity was measured at baseline and 2hrs post nitroglycerin (5mg/kg i.p.).

PO mechanosensitivity exhibits circadian variation (F_2,26=25.40; p<0.0001). Additionally, thresholds were significantly lower at both time points after changing light cycles (ZT0: t₄₄ = 2.74, p<0.05; ZT12: t₄₄ = 5.87, p<0.0001). Both transgenic lines showed increased CSD susceptibility (WT=7, CK1δ-T44A=10; U=12, p<0.0001) (WT=6, Per2-S662G=7; U=30, p<0.05). Transgenics also showed increased PO mechanosensitivity following nitroglycerin (WT vs CK1δ-T44A: F_1,22=41.61; p<0.0001; WT vs Per2-S662G: F_1,22=32.13; p<0.0001)

C57bl/6J exhibit circadian variation in PO mechanosensitivity suggestive of a rhythmicity in sensory processing that could underlie the circadian nature of migraine. Additionally, changing light cycles seems to impact migraine-relevant pain processing. Furthermore, disruption to Per2 is, at least in part, sufficient to induce migraine-like phenotypes, implicating a purely circadian gene in migraine pathophysiology for the first time.