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: 3.19). 07/2007; 47(6):951-62. DOI: 10.1111/j.1526-4610.2007.00842.x
Source: PubMed

ABSTRACT 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.
    Frontiers in Neuroscience 10/2015; 9:1-10. DOI:10.3389/fnins.2015.00065 · 3.70 Impact Factor
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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.
    Médecine du Sommeil 01/2013; 10(1):12–18. DOI:10.1016/j.msom.2012.12.003
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    • "Indeed, recent preclinical (dog and rat) and phase I (healthy male subjects; single dose) investigations have shown that the dual OX 1/OX2 receptors antagonist almorexant (ACT-078573) promoted sleep (NREM and REM) in animals and humans without disrupting sleep architecture, an action that validated the notion that OX receptor antagonists could be effective hypnotics for the treatment of insomnia (Brisbare-Roch et al., 2007). Moreover, the orexin neuronal system has also been implicated in pain modulation within the CNS (Holland and Goadsby, 2007). The genetic linkage and haplotype analyses have shown an association between the OX2 receptor gene and cluster headaches (Rainero et al., 2007; 2008). "
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    ABSTRACT: Background and purpose:  The OX2 receptor is a G-protein-coupled receptor that is abundantly found in the tuberomammillary nucleus, an important site for the regulation of the sleep-wake state. Herein, we describe the in vitro and in vivo properties of a selective OX2 receptor antagonist, N-ethyl-2-[(6-methoxy-pyridin-3-yl)-(toluene-2-sulphonyl)-amino]-N-pyridin-3-ylmethyl-acetamide (EMPA).Experimental approach:  The affinity of [3H]EMPA was assessed in membranes from HEK293-hOX2-cells using saturation and binding kinetics. The antagonist properties of EMPA were determined by Schild analysis using the orexin-A- or orexin-B-induced accumulation of [3H]inositol phosphates (IP). Quantitative autoradiography was used to determine the distribution and abundance of OX2 receptors in rat brain. The in vivo activity of EMPA was assessed by reversal of [Ala11,D-Leu15]orexin-B-induced hyperlocomotion during the resting phase in mice and the reduction of spontaneous locomotor activity (LMA) during the active phase in rats.Key results:  [3H]EMPA bound to human and rat OX2-HEK293 membranes with KD values of 1.1 and 1.4 nmol·L−1 respectively. EMPA competitively antagonized orexin-A- and orexin-B-evoked accumulation of [3H]IP at hOX2 receptors with pA2 values of 8.6 and 8.8 respectively. Autoradiography of rat brain confirmed the selectivity of [3H]EMPA for OX2 receptors. EMPA significantly reversed [Ala11,D-Leu15]orexin-B-induced hyperlocomotion dose-dependently during the resting phase in mice. EMPA, injected i.p. in rats during the active phase, reduced LMA dose-dependently. EMPA did not impair performance of rats in the rotarod procedure.Conclusions and implications:  EMPA is a high-affinity, reversible and selective OX2 receptor antagonist, active in vivo, which should prove useful for analysis of OX2 receptor function.
    British Journal of Pharmacology 04/2009; 156(8):1326 - 1341. DOI:10.1111/j.1476-5381.2009.00127.x · 4.99 Impact Factor
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