title: Evidence for orexinergic mechanisms in migraine.
abstract: OBJECTIVE
  To examine the effect of the orexinergic blockade with a dual orexin receptor antagonist (DORA) on experimental models of peripheral and central trigeminal as well as cortical activation relevant to migraine and migraine aura.
  
  
  METHODS
  In this study we used a precursor of suvorexant, a dual orexin receptor antagonist #12 (DORA-12) in established experimental in vivo models of dural trigeminovascular nociception in rat. Neurogenic dural vasodilation and electrophysiological recordings of second order trigeminocervical neurons were used to study trigeminal nociceptive mechanisms directly. KCl-evoked cortical spreading depression was also used as a surrogate for migraine aura.
  
  
  RESULTS
  Neurogenically-induced vasodilation of the middle meningeal artery, caused by nociceptive activation of peripheral afferent projections of the trigeminal nerve, was attenuated by intravenous DORA-12 (1 mgkg(-1)). Second-order trigeminocervical complex neuronal activity was significantly inhibited by intravenous DORA-12 (1 mgkg(-1)). DORA-12 significantly reduced susceptibility to KCl-evoked cortical spreading depression.
  
  
  CONCLUSIONS
  The study provides the first direct evidence, that simultaneous antagonism on both orexin receptors is able to attenuate trigeminal nociceptive activity as well as to induce an elevation of the threshold for the induction of a cortical spreading depression (CSD). In the clinical context, these data imply that targeting the hypothalamic orexinergic system may offer an entirely novel mechanism for the preventive treatment of migraine with and without aura.
authors.affiliation: Headache Group-Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
authors.forename: Jan
authors.initials: J
authors.lastname: Hoffmann
authors.affiliation: Headache Group-Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
authors.forename: Weera
authors.initials: W
authors.lastname: Supronsinchai
authors.affiliation: Headache Group-Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
authors.forename: Simon
authors.initials: S
authors.lastname: Akerman
authors.affiliation: Headache Group-Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
authors.forename: Anna P
authors.initials: AP
authors.lastname: Andreou
authors.affiliation: Neuroscience Department, Merck Research Laboratories, Sumneytown Pike, West Point, PA 19486, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Winrow
authors.affiliation: Neuroscience Department, Merck Research Laboratories, Sumneytown Pike, West Point, PA 19486, USA.
authors.forename: John
authors.initials: J
authors.lastname: Renger
authors.affiliation: Neuroscience Department, Merck Research Laboratories, Sumneytown Pike, West Point, PA 19486, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Hargreaves
authors.affiliation: Headache Group-Department of Neurology, University of California, San Francisco, San Francisco, CA, USA; NIHR-Wellcome Trust Clinical Research Facility, King's College London, UK. Electronic address: peter.goadsby@kcl.ac.uk.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Goadsby
mesh_terms: D000818:Animals; D001381:Azepines / Q000737:chemistry / Q000494:pharmacology*; D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology*; D002491:Central Nervous System Agents / Q000494:pharmacology; D013181:Cortical Spreading Depression / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004558:Electric Stimulation; D008297:Male; D008839:Microelectrodes; D008881:Migraine Disorders / Q000188:drug therapy* / Q000503:physiopathology*; D059225:Nociception / Q000187:drug effects / Q000502:physiology; D000068796:Orexin Receptor Antagonists / Q000737:chemistry / Q000494:pharmacology*; D064446:Orexin Receptors / Q000378:metabolism*; D011189:Potassium Chloride / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D014276:Trigeminal Nerve / Q000187:drug effects / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
chemical_list: D001381:Azepines; D001562:Benzimidazoles; D002491:Central Nervous System Agents; D000068796:Orexin Receptor Antagonists; D064446:Orexin Receptors; C000595055:dual orexin receptor antagonist 12; D011189:Potassium Chloride
keywords: Dual Orexin Receptor Antagonists; Headache; Migraine; Orexin; Sleep