Biology of Neuropeptides: Orexinergic Involvement in Primary Headache Disorders

Migraine is a very common, severe disabling condition that can last for days and strike multiple times per month. Attacks, often characterized by severe unilateral throbbing pain that is exacerbated by activity, are commonly preceded by several diverse symptoms including fatigue, irritability, and yawning. This premonitory (prodromal) phase represents the earliest identifiable feature of an attack that is a reliable predictor of ensuing headache. The diversity of these symptoms underlines the complex nature of migraine and focuses considerable attention on the hypothalamus due to its prominent role in homeostatic regulation allowing state dependent behavioral modifications. While multiple neurotransmitter and neuropeptide systems have been proposed to play a role in migraine, the current review will focus on the emerging role of the hypothalamic orexinergic system in primary headache disorders. Specifically the potential role of altered orexinergic signalling in premonitory symptomatology and the future potential of targeted orexinergic therapies that could with other approaches act during the premonitory phase to prevent the occurrence of the headache or reduce an individual's susceptibility to attacks by altering the brain's response to external and internal triggers.