title: Sensitization of dural afferents underlies migraine-related behavior following meningeal application of interleukin-6 (IL-6).
abstract: BACKGROUND
  Migraine headache is one of the most common neurological disorders, but the pathophysiology contributing to migraine is poorly understood. Intracranial interleukin-6 (IL-6) levels have been shown to be elevated during migraine attacks, suggesting that this cytokine may facilitate pain signaling from the meninges and contribute to the development of headache.
  
  
  METHODS
  Cutaneous allodynia was measured in rats following stimulation of the dura with IL-6 alone or in combination with the MEK inhibitor, U0126. The number of action potentials and latency to the first action potential peak in response to a ramp current stimulus as well as current threshold were measured in retrogradely-labeled dural afferents using patch-clamp electrophysiology. These recordings were performed in the presence of IL-6 alone or in combination with U0126. Association between ERK1 and Nav1.7 following IL-6 treatment was also measured by co-immunoprecipitation.
  
  
  RESULTS
  Here we report that in awake animals, direct application of IL-6 to the dura produced dose-dependent facial and hindpaw allodynia. The MEK inhibitor U0126 blocked IL-6-induced allodynia indicating that IL-6 produced this behavioral effect through the MAP kinase pathway. In trigeminal neurons retrogradely labeled from the dura, IL-6 application decreased the current threshold for action potential firing. In response to a ramp current stimulus, cells treated with IL-6 showed an increase in the numbers of action potentials and a decrease in latency to the first spike, an effect consistent with phosphorylation of the sodium channel Nav1.7. Pretreatment with U0126 reversed hyperexcitability following IL-6 treatment. Moreover, co-immunoprecipitation experiments demonstrated an increased association between ERK1 and Nav1.7 following IL-6 treatment.
  
  
  CONCLUSIONS
  Our results indicate that IL-6 enhances the excitability of dural afferents likely via ERK-mediated modulation of Nav1.7 and these responses contribute to migraine-related pain behavior in vivo. These data provide a cellular mechanism by which IL-6 in the meninges causes sensitization of dural afferents therefore contributing to the pathogenesis of migraine headache.
authors.affiliation: Department of Pharmacology, University of Arizona College of Medicine, 1501 N Campbell Ave, PO Box 245050, Tucson, AZ 85724, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Yan
authors.forename: Ohannes K
authors.initials: OK
authors.lastname: Melemedjian
authors.forename: Theodore J
authors.initials: TJ
authors.lastname: Price
authors.forename: Gregory
authors.initials: G
authors.lastname: Dussor
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D002070:Butadienes / Q000494:pharmacology; D004388:Dura Mater / Q000187:drug effects* / Q000473:pathology* / Q000503:physiopathology; D004558:Electric Stimulation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006930:Hyperalgesia / Q000150:complications / Q000473:pathology / Q000503:physiopathology; D015850:Interleukin-6 / Q000008:administration & dosage / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D008578:Meninges / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D008881:Migraine Disorders / Q000150:complications / Q000473:pathology / Q000503:physiopathology*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D062556:NAV1.7 Voltage-Gated Sodium Channel; D009475:Neurons, Afferent / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D009570:Nitriles / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D015222:Sodium Channels / Q000378:metabolism
chemical_list: D002070:Butadienes; D015850:Interleukin-6; D062556:NAV1.7 Voltage-Gated Sodium Channel; D009570:Nitriles; C503480:Scn9a protein, rat; D015222:Sodium Channels; C113580:U 0126; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases