Biology of Neuropeptides: Orexinergic Involvement in Primary Headache Disorders

Abstract

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.

Emerging Treatment Targets for Migraine and Other Headaches

“…Orexins, also known as hypocretins, have been widely implicated in homeostatic regulation; and dysfunction of the orexinergic system in migraine has recently been explored . The orexin family is comprised of 2 neuropeptides, orexin A (OXA) and orexin B (OXB), which are derived from the precursor peptide, prepro‐orexin .…”

“…Orexin A is 33 amino acids in length, while orexin B is 28 residues, and mature versions of these peptides are entirely (OXA) or highly (OXB) conserved in mammals . Although these peptides are synthesized exclusively in the dorsolateral hypothalamus, orexinergic neurons project throughout the CNS, including other hypothalamic nuclei, thalamus, cortex, trigeminal nucleus caudalis, and spinal cord . Both orexin peptides bind to orexin receptor 1 (ORX1) and orexin receptor 2 (ORX2), both of which are Gq GPCRs, and as such activation results in increased intracellular Ca 2+ .…”

“…OXA has equal affinity for both orexin receptors, while OXB has a ten‐fold increased affinity for OXR2 . The orexin receptors are broadly expressed in the brain, and usually correspond with orexin peptide expression …”

“…Orexins, also known as hypocretins, have been widely implicated in homeostatic regulation; and dysfunction of the orexinergic system in migraine has recently been explored. [90][91][92] The orexin family is comprised of 2 neuropeptides, orexin A (OXA) and orexin B (OXB), which are derived from the precursor peptide, prepro-orexin. 93 Orexin A is 33 amino acids in length, while orexin B is 28 residues, and mature versions of these peptides are entirely (OXA) or highly (OXB) conserved in mammals.…”

“…94 Although these peptides are synthesized exclusively in the dorsolateral hypothalamus, orexinergic neurons project throughout the CNS, including other hypothalamic nuclei, thalamus, cortex, trigeminal nucleus caudalis, and spinal cord. 90 Both orexin peptides bind to orexin receptor 1 (ORX1) and orexin receptor 2 (ORX2), both of which are Gq GPCRs, and as such activation results in increased intracellular Ca 2+ . 93 OXA has equal affinity for both orexin receptors, while OXB has a ten-fold increased affinity for OXR2.…”