Targeted Orexin and Hypothalamic Neuropeptides for Migraine

Abstract

The hypothalamus is involved in the regulation of homeostatic mechanisms and migraine-related trigeminal nociception and as such has been hypothesized to play a central role in the migraine syndrome from the earliest stages of the attack. The hypothalamus hosts many key neuropeptide systems that have been postulated to play a role in this pathophysiology. Such neuropeptides include but are not exclusive too orexins, oxytocin, neuropeptide Y, and pituitary adenylate cyclase activating protein, which will be the focus of this review. Each of these peptides has its own unique physiological role and as such many preclinical studies have been conducted targeting these peptide systems with evidence supporting their role in migraine pathophysiology. Preclinical studies have also begun to explore potential therapeutic compounds targeting these systems with some success in all cases. Clinical efficacy of dual orexin receptor antagonists and intranasal oxytocin have been tested; however, both have yet to demonstrate clinical effect. Despite this, there were limitations in these cases and strong arguments can be made for the further development of intranasal oxytocin for migraine prophylaxis. Regarding neuropeptide Y, work has yet to begun in a clinical setting, and clinical trials for pituitary adenylate cyclase activating protein are just beginning to be established with much optimism. Regardless, it is becoming increasingly clear the prominent role that the hypothalamus and its peptide systems have in migraine pathophysiology. Much work is required to better understand this system and the early stages of the attack to develop more targeted and effective therapies aimed at reducing attack susceptibility with the potential to prevent the attack all together.Electronic supplementary materialThe online version of this article (10.1007/s13311-017-0602-3) contains supplementary material, which is available to authorized users.

Emerging Treatment Targets for Migraine and Other Headaches

“…Knockout of the orexin peptides or mutation of the ORX2 receptor results in murine and canine narcolepsy, and human narcoleptics show decreased circulating levels of orexin . Consistent with the role of orexin in migraine, narcoleptic patients have a significantly higher prevalence for migraine, and 64% of female and 45% of males suffer from migraine compared to 30% and 8%, respectively, in the general population . More generally, sleep disturbances are known to increase susceptibility to migraine; and orexin may act at the interface between changes in circadian rhythm and headache disorders.…”

“…In this randomized, double‐blind, placebo‐controlled trial patients were treated with 10 mg nightly for 3 months. There was no statistically significant difference between filorexant treated and placebo controls, which may be explained by the dosing regimen or half‐life of the drug . Although disappointing, there is still hope for targeting the orexinergic system in migraine.…”

“…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 .…”

“…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 …”

Migraine Therapy: Current Approaches and New Horizons

“…While several hypothalamic neuropeptides have been proposed to show clinical promise, the orexins, as reviewed by Drs. Strother, Srikiatkhachorn and Supronsinchai [31], have demonstrated clear preclinical impact [32,33]. Unfortunately, a single clinical trial exploring a dual orexin receptor antagonist failed to show any effect in migraine prophylaxis [34]; however, several limitations likely explain this negative result.…”