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

Persistent Link:
http://hdl.handle.net/10150/610216
Title:
Sensitization of dural afferents underlies migraine-related behavior following meningeal application of interleukin-6 (IL-6)
Author:
Yan, Jin; Melemedjian, Ohannes; Price, Theodore; Dussor, Gregory
Affiliation:
Department of Pharmacology, University of Arizona College of Medicine, 1501 N Campbell Ave, PO Box 245050, Tucson, AZ 85724, USA; Graduate Interdisciplinary Program in Neuroscience, University of Arizona, 1548 E. Drachman St., PO Box 210476, Tucson, AZ 85719, USA; Bio5 Institute, University of Arizona, 1657 E Helen St., PO Box 210240, Tucson, AZ 85721, USA
Issue Date:
2012
Publisher:
BioMed Central
Citation:
Yan et al. Molecular Pain 2012, 8:6 http://www.molecularpain.com/content/8/1/6
Journal:
Molecular Pain
Rights:
© 2012 Yan et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0)
Collection Information:
This item is part of the UA Faculty Publications collection. For more information this item or other items in the UA Campus Repository, contact the University of Arizona Libraries at repository@u.library.arizona.edu.
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.
EISSN:
1744-8069
DOI:
10.1186/1744-8069-8-6
Keywords:
Migraine; Nav1.7; Interleukin-6; Dural afferents; Meninges; Pain; Headache
Version:
Final published version
Additional Links:
http://mpx.sagepub.com/content/8/1744-8069-8-6.full

Full metadata record

DC FieldValue Language
dc.contributor.authorYan, Jinen
dc.contributor.authorMelemedjian, Ohannesen
dc.contributor.authorPrice, Theodoreen
dc.contributor.authorDussor, Gregoryen
dc.date.accessioned2016-05-20T09:01:20Z-
dc.date.available2016-05-20T09:01:20Z-
dc.date.issued2012en
dc.identifier.citationYan et al. Molecular Pain 2012, 8:6 http://www.molecularpain.com/content/8/1/6en
dc.identifier.doi10.1186/1744-8069-8-6en
dc.identifier.urihttp://hdl.handle.net/10150/610216-
dc.description.abstractBACKGROUND: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.en
dc.language.isoenen
dc.publisherBioMed Centralen
dc.relation.urlhttp://mpx.sagepub.com/content/8/1744-8069-8-6.fullen
dc.rights© 2012 Yan et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0)en
dc.subjectMigraineen
dc.subjectNav1.7en
dc.subjectInterleukin-6en
dc.subjectDural afferentsen
dc.subjectMeningesen
dc.subjectPainen
dc.subjectHeadacheen
dc.titleSensitization of dural afferents underlies migraine-related behavior following meningeal application of interleukin-6 (IL-6)en
dc.typeArticleen
dc.identifier.eissn1744-8069en
dc.contributor.departmentDepartment of Pharmacology, University of Arizona College of Medicine, 1501 N Campbell Ave, PO Box 245050, Tucson, AZ 85724, USAen
dc.contributor.departmentGraduate Interdisciplinary Program in Neuroscience, University of Arizona, 1548 E. Drachman St., PO Box 210476, Tucson, AZ 85719, USAen
dc.contributor.departmentBio5 Institute, University of Arizona, 1657 E Helen St., PO Box 210240, Tucson, AZ 85721, USAen
dc.identifier.journalMolecular Painen
dc.description.collectioninformationThis item is part of the UA Faculty Publications collection. For more information this item or other items in the UA Campus Repository, contact the University of Arizona Libraries at repository@u.library.arizona.edu.en
dc.eprint.versionFinal published versionen
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