Sensitization of dural afferents underlies migraine-related behavior following meningeal application of interleukin-6 (IL-6)

Mol Pain. 2012 Jan 24;8:6. doi: 10.1186/1744-8069-8-6.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects
  • Animals
  • Behavior, Animal / drug effects*
  • Butadienes / pharmacology
  • Dura Mater / drug effects*
  • Dura Mater / pathology*
  • Dura Mater / physiopathology
  • Electric Stimulation
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Hyperalgesia / complications
  • Hyperalgesia / pathology
  • Hyperalgesia / physiopathology
  • Interleukin-6 / administration & dosage
  • Interleukin-6 / pharmacology*
  • MAP Kinase Signaling System / drug effects
  • Male
  • Meninges / drug effects
  • Meninges / pathology
  • Meninges / physiopathology*
  • Migraine Disorders / complications
  • Migraine Disorders / pathology
  • Migraine Disorders / physiopathology*
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • NAV1.7 Voltage-Gated Sodium Channel
  • Neurons, Afferent / drug effects
  • Neurons, Afferent / enzymology
  • Neurons, Afferent / pathology*
  • Nitriles / pharmacology
  • Protein Binding / drug effects
  • Rats
  • Rats, Sprague-Dawley
  • Sodium Channels / metabolism

Substances

  • Butadienes
  • Interleukin-6
  • NAV1.7 Voltage-Gated Sodium Channel
  • Nitriles
  • Scn9a protein, rat
  • Sodium Channels
  • U 0126
  • Extracellular Signal-Regulated MAP Kinases
  • Mitogen-Activated Protein Kinase Kinases