Non-Rapid Eye Movement Sleep Parasomnias and Migraine: A Role of Orexinergic Projections

Abstract

IntroductionSleep 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 (MR) nuclei, interfering with serotonergic regulation, may cause Non-Rapid Eye Movement parasomnias, such as somnambulism.Hypothesis/theoryActing on the serotonergic neurons of the raphe nuclei, the dysfunction of orexinergic neurons would lead 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 increase transmural pressure. This process could activate the trigeminal nerve terminals that innervate vascular walls. As a 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 trigeminovascular 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.ConclusionSerotonergic neurons of the MR 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 pathophysiological 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.

The Metabolic Rearrangements of Bariatric Surgery: Focus on Orexin-A and the Adiponectin System

“…Orexin-A exerts its functions by binding its receptors, Orexin-1 receptor (Ox1) and Orexin-2 receptor (Ox2), two G-protein coupled receptors [ 18 , 19 , 20 ]. The Orexin system is involved in physiological and pathophysiological processes [ 21 , 22 , 23 ] ( Figure 1 B). Many metabolic molecules influence Orexin-A activity; in particular, glucose, leptin, and amino acids and also some environmental factors increase Orexin-A levels during the waking phase of the circadian cycles and fasting or periods of caloric restriction.…”

Evaluation of Orexin-A serum levels in karate athletes cohort

“…Indeed, are required technical skills and high levels of precision and velocity. In addition, the performance may be influenced by cognitive abilities and efficient attentional processes (Bianco et al, 2018;Francavilla et al, 2017;Messina A. et al, 2018;. Also, it is well know that the physical exercise protects against cardiovascular, bone and joint, and metabolic disorders such as diabetes and that it is an effective means in the prevention and treatment of certain types of cancer (Francavilla C et al,2013, Francavilla et al, 2015Messina G. et al 2015;Penna et al, 2019;Patti et al, 2017).…”

“…Orexin-A is involved also in stimulation of food intake, hunger and hypoglycaemia, it plays an important role in the regulation of metabolic status (Messina. et al, 2014;Messina et al, 2018). Orexin-A modulates energy metabolism, excitement, and physical activity, playing a pivotal role fighting obesity, increasing physical activity, and thermogenesis during non-exercise activities, as well as energy expenditure (Sakurai, 2014).…”

Orexin supplementation in narcolepsy treatment: A review

“…By interacting with the circadian cycle, controlling orexin neurons may act as a stabilizer between wakefulness‐maintaining and sleep‐promoting systems, thus preventing sudden and inappropriate transitions between the two systems . Widespread neuronal orexigenic projections suggest the involvement of orexins in various regulatory systems other than sleep/wake cycle control, such as temperature control, transmural pressure via interconnection with serotonergic receptors, energy homeostasis, reward systems, cognition and mood, and feed and water balance regulation …”