Ergotamine enhances circadian amplitude and diurnally mitigates nitroglycerin-induced mechanical hypersensitivity.

Abstract

Cluster headache and migraine have a circadian timing of attacks and are linked to the trigeminovascular system. Recently the trigeminal ganglion was found to have a strong circadian rhythm, with the serotonin 2A receptor identified as a clock-controlled gene. Ergotamine is an acute treatment for cluster headache and migraine, acts on the trigeminal ganglion, and is a serotonin 2A receptor agonist. The circadian properties of ergotamine are unknown. We performed real-time bioluminescence monitoring and qPCR of Per2::LucSV reporter mouse fibroblast cultures after treatment with ergotamine. We examined receptor effects by treating Per2::LucSV fibroblast cultures with ergotamine and one of several serotoninergic, adrenergic, and/or dopaminergic receptor antagonists. Next, we treated Per2::LucSV reporter mouse trigeminal ganglion explants with ergotamine and monitored circadian reporter rhythms; finally we measured hindpaw sensitivity in a nitroglycerin chronic headache mouse model and administered ergotamine at two different times to examine a chronotherapeutic effect on pain behavior. Ergotamine caused a more than two-fold increase in the amplitude of Per2::LucSV fibroblasts without a change in period length; amplitude enhancement was also seen for expression of Clock, Bmal1, Period3, Cryptochrome2, Rev-erbα, and Rev-erbβ. Ergotamine's effect on circadian amplitude was dampened by the serotonin-1B/1D receptor antagonist GR127935, the serotonin-1D receptor antagonist BRL1557, the serotonin-1A/1B/2A/2B/2C, alpha1A-adrenergic, and dopamine D1-4 receptor antagonist asenapine, and the serotonin-2C receptor antagonist SB242084. In contrast to serotonin receptor antagonists, ergotamine's effects on clock amplitude were unchanged by other serotonin antagonists or by selective adrenergic or dopaminergic receptor antagonists, suggesting that ergotamine's amplitude effect is mediated by serotonin receptor activation. Furthermore, trigeminal ganglion explant cultures treated with ergotamine showed a significant increase in amplitude without a change in period. Finally, in the nitroglycerin chronic headache mouse model, ergotamine significantly raised hindpaw thresholds when administered during the daytime (ZT4) but not at night (ZT16). Ergotamine has substantial circadian rhythm modification effects in both cellular and animal models. Ergotamine's circadian effects appear to be mediated through serotonin 1D and 2C receptors, providing a rationale for why sub-psychedelic doses of psilocybin (which induces psychedelic responses through the serotonin 2A receptor) might be effective. Ergotamine's peak effect on hindpaw thresholds at ZT4 suggests that ergotamine may be more effective at certain times of day.