Orexins and primary headaches: an overview of the neurobiology and clinical impact

ABSTRACT

Introduction

Primary headaches, including migraines and cluster headaches, are highly prevalent disorders that significantly impact quality of life. Several factors suggest a key role for the hypothalamus, including neuroimaging studies, attack periodicity, and the presence of altered homeostatic regulation. The orexins are two neuropeptides synthesized almost exclusively in the lateral hypothalamus with widespread projections across the central nervous system. They are involved in an array of functions including homeostatic regulation and nociception, suggesting a potential role in primary headaches.

Areas covered

This review summarizes current knowledge of the neurobiology of orexins, their involvement in sleep-wake regulation, nociception, and functions relevant to the associated symptomology of headache disorders. Preclinical reports of the antinociceptive effects of orexin-A in preclinical models are discussed, as well as clinical evidence for the potential involvement of the orexinergic system in headache.

Expert opinion

Several lines of evidence support the targeted modulation of orexinergic signaling in primary headaches. Critically, orexins A and B, acting differentially via the orexin 1 and 2 receptors, respectively, demonstrate differential effects on trigeminal pain processing, indicating why dual-receptor antagonists failed to show clinical efficacy. The authors propose that orexin 1 receptor agonists or positive allosteric modulators should be the focus of future research.

KEYWORDS:

• Headache
• orexin
• hypocretin
• migraine
• sleep

Article highlights

• The orexinergic system is postulated to play a role in nociceptive transmission as well as in a range of homeostatic functions including arousal, endocrine regulation, and appetite.

• Modulation of the orexinergic system in preclinical animal models may directly facilitate or attenuate trigeminal nociceptive processing, highlighting the relevance of the orexins in headache pathophysiology.

• Patients with migraine and cluster headache show potential alterations in orexin levels and genetic factors related to the orexinergic pathway.

• There is limited clinical evidence for the efficacy of orexin-based therapeutic targets in primary headaches.

• Future research should focus on selective activation of the orexin 1 receptor via selected routes.

Declaration of interest

PR Holland reports, unrelated to this work, grants from Amgen, Eli Lilly and Company, Kallyope and Bristol-Myers Squibb as well as honoraria and travel expenses in relation to educational duties from Allergan, Novartis, Teva, Pfizer and Almirall. J Hoffmann reports honoraria for consulting activities and/or serving on advisory boards and/or for giving lectures/presentations from AbbVie, Allergan, Autonomic Technologies Inc., Cannovex BV, Chordate Medical AB, MD-Horizonte, Eli Lilly and Company, Hormosan Pharma, Lundbeck, Novartis, Sanofi and Teva. He also holds stock options from Chordate Medical AB and has received personal fees for Medico-Legal work from NEJM Journal Watch, Oxford University Press, Quintessence Publishing, Sage Publishing and Springer Healthcare. He also reports a research grant from Bristol Myers Squibb. All these activities are unrelated to the submitted work. EC Stanyer received PhD funding from the King’s College London MRC-DTP Programme grant no: MR/N013700/1. EC Stanyer also reports honoraria from Lindus Health Ltd and FCLabs Ltd unrelated to this work. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers in this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

The authors are funded by the Medical Research Council via grants MR/P006264/1 and MR/N013700/1.