Impact Factor 3.552

The 2nd most cited open-access journal in Clinical Neurology

Hypothesis and Theory ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Neurol. | doi: 10.3389/fneur.2018.00095


 Ilaria Bitetti1, Antonietta Messina1, Francesco Precenzano1,  Giovanni Messina2*, Michele Roccella3, Lucia Parisi3, Margherita Parisi3,  Anna Valenzano2, Agata Maltese3, Monica Salerno2,  Francesco Sessa2, Davide Albano2, Rosa Marotta4,  Ines Villano1, Marsala Gabriella5, Christian Zammit6, Francesco Lavano4, Marcellino Monda1, Giuseppe Cibelli2, Serena M. Lavano4, Beatrice Gallai7, Roberto Toraldo1,  Vincenzo Monda1 and  Marco Carotenuto1
  • 1Università degli Studi della Campania L. Vanvitelli Naples, Italy
  • 2University of Foggia, Italy
  • 3Università degli Studi di Palermo, Italy
  • 4Magna Græcia University, Italy
  • 5Azienda Ospedaliero-Universitaria Ospedali Riuniti di Foggia, Italy
  • 6University of Malta, Malta
  • 7University of Perugia, Italy

Introduction: Sleep and migraine share a common pathophysiological substrate, although the underlying mechanisms are unknown. The serotonergic and orexinergic systems are both involved in the regulation of sleep/wake cycle and numerous studies show that both are involved in the migraine etiopathogenesis. These two systems are anatomically and functionally interconnected. Our hypothesis is that in migraine a dysfunction of orexinergic projections on the median raphe nuclei, interfering with serotonergic regulation, may cause NREM parasomnias, such as somnambulism.
Hypothesis/Theory: Acting on the serotonergic neurons of the raphe nuclei, the dysfunction of orexinergic neurons would conduct to a higher release of serotonin. The activation of serotonergic receptors located on the walls of large cerebral vessels would lead to abnormal vasodilatation and consequently increasing of transmural pressure. This process could activate the trigeminal nerve terminals that innervate vascular walls. By consequence, there is activation of sensory nerve endings at the level of hard vessels in the meninges, with release of pro-inflammatory peptides (e.g. substance P and CGRP). Within this hypothetical frame, the released serotonin could also interact with trigemino-vascular afferents to activate and/or facilitate the release of the neuropeptide at the level of the trigeminal ganglion. The dysregulation of the physiological negative feedback of serotonin on the orexinergic neurons, in turn, would contribute to an alteration of the whole system, altering the sleep-wake cycle.
Conclusion: Serotonergic neurons of the median raphe nuclei receive an excitatory input from hypothalamic orexin/hypocretin neurons and reciprocally inhibit orexin/hypocretin neurons through the serotonin 1A receptor (or 5-HT1A receptor). Considering this complex system, if there is an alteration it may facilitate the pathophysiologic mechanisms involved in the migraine, while it may produce at the same time an alteration of the sleep-wake rhythm, causing sleep disorders such as sleepwalking. Understanding the complex mechanisms underlying migraine and sleep disorders and how these mechanisms can interact with each other it would be crucial to pave the way for new therapeutic strategies.

Keywords: serononergic system, Orexinergic System, sleep-wake rhythm, Migraine, pro-inflammatory peptides

Received: 29 Jul 2017; Accepted: 09 Feb 2018.

Edited by:

Hruda N. Mallick, All India Institute of Medical Sciences, India

Reviewed by:

Thomas C. Thannickal, University of California, Los Angeles, United States
Rhiannan H. Williams, Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt, Germany  

Copyright: © 2018 Bitetti, Messina, Precenzano, Messina, Roccella, Parisi, Parisi, Valenzano, Maltese, Salerno, Sessa, Albano, Marotta, Villano, Gabriella, Zammit, Lavano, Monda, Cibelli, Lavano, Gallai, Toraldo, Monda and Carotenuto. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Giovanni Messina, University of Foggia, Foggia, Italy,