The Hypothalamic Orexinergic System: Pain and Primary Headaches

Headache Group, Institute of Neurology, The National Hospital for Neurology and Neurosurgery, London, UK.
Headache The Journal of Head and Face Pain (Impact Factor: 2.71). 07/2007; 47(6):951-62. DOI: 10.1111/j.1526-4610.2007.00842.x
Source: PubMed


The primary headaches are a group of distinct individually characterized attack forms, which although varying in presentation, share some common anatomical basis responsible for the pain component of the attack. The hypothalamus is known to modulate a multitude of functions and has been shown to be involved in the pathophysiology of a variety of primary headaches including cluster headache and chronic migraine. It seems likely that it may be involved in other primary headache disorders due to their episodic nature and may underlie many of their diverse symptoms. We discuss the hypothalamic involvement in the modulation of trigeminovascular processing and examine the involvement of the hypothalamic orexinergic system as a key regulator of this function.

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    • "Importantly, the hypothalamus controls neuroendocrine stress responses and nociceptive processing (Hsieh et al., 1996; Matthews, 2002). Direct afferent and efferent relays connect hypothalamic nuclei to brain areas involved in the active modulation of pain and nociception such as the dorsal horn of the spinal cord and the periaqueductal gray (PAG; Holland and Goadsby, 2007; Todd, 2010). Additionally, subregions such as the perifornical and lateral hypothalamic areas are key brain structures coordinating behavioral and autonomic stress responses and receive significant corticolimbic input (Millan, 2002). "
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    ABSTRACT: Exposure to early life physiological stressors, such as infection, is thought to contribute to the onset of psychopathology in adulthood. In animal models, injections of the bacterial immune challenge, lipopolysaccharide (LPS), during the neonatal period has been shown to alter both neuroendocrine function and behavioral pain responses in adulthood. Interestingly, recent evidence suggests a role for the lateral hypothalamic peptide orexin in stress and nociceptive processing. However, whether neonatal LPS exposure affects the reactivity of the orexin system to formalin-induced inflammatory pain in later life remains to be determined. Male Wistar rats (n = 13) were exposed to either LPS or saline (0.05 mg/kg, i.p) on postnatal days (PND) 3 and 5. On PND 80–97, all rats were exposed to a subcutaneous hindpaw injection of 2.25% formalin. Following behavioral testing, animals were perfused and brains processed for Fos-protein and orexin immunohistochemistry. Rats treated with LPS during the neonatal period exhibited decreased licking behaviors during the interphase of the formalin test, the period typically associated with the active inhibition of pain, and increased grooming responses to formalin in adulthood. Interestingly, these behavioral changes were accompanied by an increase in the percentage of Fos-positive orexin cells in the dorsomedial and perifornical hypothalamus in LPS-exposed animals. Similar increases in Fos-protein were also observed in stress and pain sensitive brain regions that receive orexinergic inputs. These findings highlight a potential role for orexin in the behavioral responses to pain and provide further evidence that early life stress can prime the circuitry responsible for these responses in adulthood.
    Full-text · Article · Oct 2015 · Frontiers in Neuroscience
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    • "The central role of the hypothalamus in regulating autonomic functions and homeostasis suggests that it may underlie some autonomic symptoms associated with migraine [2], [4]–[7] or its prodromal phase [4], [5], [7], [8]. Evidence linking the hypothalamus to migraine include (a) imaging data showing that the hypothalamus is activated during spontaneous migraine without aura [9], (b) prevalence of obesity among chronic migraineures [5], [6], [10], (c) the cyclic nature of the condition [11], and (d) its greater prevalence in women after puberty and in homosexual men [12]–[14]. Partially responsible for changes in hypothalamic functions may be attributed to the large input it receives from ascending trigeminovascular neurons in the spinal trigeminal nucleus [7]. "
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    ABSTRACT: The hypothalamus has been implicated in migraine based on the manifestation of autonomic symptoms with the disease, as well as neuroimaging evidence of hypothalamic activation during attacks. Our objective was to determine functional connectivity (FC) changes between the hypothalamus and the rest of the brain in migraine patients vs. control subjects. This study uses fMRI (functional magnetic resonance imaging) to acquire resting state scans in 12 interictal migraine patients and 12 healthy matched controls. Hypothalamic connectivity seeds were anatomically defined based on high-resolution structural scans, and FC was assessed in the resting state scans. Migraine patients had increased hypothalamic FC with a number of brain regions involved in regulation of autonomic functions, including the locus coeruleus, caudate, parahippocampal gyrus, cerebellum, and the temporal pole. Stronger functional connections between the hypothalamus and brain areas that regulate sympathetic and parasympathetic functions may explain some of the hypothalamic-mediated autonomic symptoms that accompany or precede migraine attacks.
    Full-text · Article · Apr 2014 · PLoS ONE
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    • "Les neurones sécrétant les orexines ont des projections dans tout le système nerveux central, en particulier sur les structures du tronc cérébral sérotoninergiques et monoaminergiques , et sont impliqués dans de nombreuses foncions : l'alimentation, l'éveil, l'addiction médicamenteuse, la modulation de la douleur. . . L'implication du système orexinergique apparaît comme un élément important dans la physiopathologie des céphalées primaires [50] et permet de proposer une explication pour le lien privilégié entre céphalées primaires et sommeil. Enfin, l'utilisation de la mélatonine dans la migraine n'a pas prouvé son efficacité [51], et s'est avérée peu convaincante dans l'algie vasculaire de la face [52]. "
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    ABSTRACT: This article synthesizes the current knowledge on the links between primary headaches and sleep on the one hand, and primary headaches and sleep disorders on the other hand. Among primary headaches, migraine, cluster headache and hypnic headache will be discussed. These three types of headaches have close relationships with sleep, arising only during sleep for the hypnic headache, and being favored in their release, or at the opposite, improved by the occurrence of the sleep for migraine. REM sleep has been considered as having a particular link with headache, but recent data raise the question of this exclusive association. The relation of migraine and, to a lesser degree, of cluster headache with sleep disorders, such as obstructive sleep apnea syndrome, restless legs syndrome, parasomnia or hypersomnia have been investigated. Migraine is more frequently observed in patients suffering from these sleep disorders. These comorbidities could be explained by common physiopathological mechanisms. The hypothalamus seems to play a central role in pain, autonomic symptoms and sleep.
    Full-text · Article · Mar 2013 · Médecine du Sommeil
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