Local translation and retrograde axonal transport of CREB regulates IL-6-induced nociceptive plasticity

Persistent Link:
http://hdl.handle.net/10150/610222
Title:
Local translation and retrograde axonal transport of CREB regulates IL-6-induced nociceptive plasticity
Author:
Melemedjian, Ohannes; Tillu, Dipti; Moy, Jamie; Asiedu, Marina; Mandell, Edward; Ghosh, Sourav; Dussor, Gregory; Price, Theodore
Affiliation:
Department of Pharmacology, The University of Arizona School of Medicine, Tucson, USA; Department of Cellular and Molecular Medicine, The University of Arizona School of Medicine, Tucson, USA; Bio5 Institute, Tucson, USA; Graduate Interdisciplinary Program in Neuroscience, Tucson, USA; The University of Texas at Dallas, School of Behavioral and Brain Sciences, Dallas, USA; Department of Neurology, Yale School of Medicine, New Haven, USA; School of Behavioral and Brain Sciences, University of Texas at Dallas, JO 4.212, 800 W Campbell Rd, Richardson, TX 75080, USA
Issue Date:
2014
Publisher:
BioMed Central
Citation:
Melemedjian et al. Molecular Pain 2014, 10:45 http://www.molecularpain.com/content/10/1/45
Journal:
Molecular Pain
Rights:
© 2014 Melemedjian 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/4.0)
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:
Transcriptional regulation of genes by cyclic AMP response element binding protein (CREB) is essential for the maintenance of long-term memory. Moreover, retrograde axonal trafficking of CREB in response to nerve growth factor (NGF) is critical for the survival of developing primary sensory neurons. We have previously demonstrated that hindpaw injection of interleukin-6 (IL-6) induces mechanical hypersensitivity and hyperalgesic priming that is prevented by the local injection of protein synthesis inhibitors. However, proteins that are locally synthesized that might lead to this effect have not been identified. We hypothesized that retrograde axonal trafficking of nascently synthesized CREB might link local, activity-dependent translation to nociceptive plasticity. To test this hypothesis, we determined if IL-6 enhances the expression of CREB and if it subsequently undergoes retrograde axonal transport. IL-6 treatment of sensory neurons in vitro caused an increase in CREB protein and in vivo treatment evoked an increase in CREB in the sciatic nerve consistent with retrograde transport. Importantly, co-injection of IL-6 with the methionine analogue azido-homoalanine (AHA), to assess nascently synthesized proteins, revealed an increase in CREB containing AHA in the sciatic nerve 2hrs post injection, indicating retrograde transport of nascently synthesized CREB. Behaviorally, blockade of retrograde transport by disruption of microtubules or inhibition of dynein or intrathecal injection of cAMP response element (CRE) consensus sequence DNA oligonucleotides, which act as decoys for CREB DNA binding, prevented the development of IL-6-induced mechanical hypersensitivity and hyperalgesic priming. Consistent with previous studies in inflammatory models, intraplantar IL-6 enhanced the expression of BDNF in dorsal root ganglion (DRG). This effect was blocked by inhibition of retrograde axonal transport and by intrathecal CRE oligonucleotides. Collectively, these findings point to a novel mechanism of axonal translation and retrograde trafficking linking locally-generated signals to long-term nociceptive sensitization.
EISSN:
1744-8069
DOI:
10.1186/1744-8069-10-45
Version:
Final published version
Additional Links:
http://mpx.sagepub.com/content/10/1744-8069-10-45.full

Full metadata record

DC FieldValue Language
dc.contributor.authorMelemedjian, Ohannesen
dc.contributor.authorTillu, Diptien
dc.contributor.authorMoy, Jamieen
dc.contributor.authorAsiedu, Marinaen
dc.contributor.authorMandell, Edwarden
dc.contributor.authorGhosh, Souraven
dc.contributor.authorDussor, Gregoryen
dc.contributor.authorPrice, Theodoreen
dc.date.accessioned2016-05-20T09:01:27Z-
dc.date.available2016-05-20T09:01:27Z-
dc.date.issued2014en
dc.identifier.citationMelemedjian et al. Molecular Pain 2014, 10:45 http://www.molecularpain.com/content/10/1/45en
dc.identifier.doi10.1186/1744-8069-10-45en
dc.identifier.urihttp://hdl.handle.net/10150/610222-
dc.description.abstractTranscriptional regulation of genes by cyclic AMP response element binding protein (CREB) is essential for the maintenance of long-term memory. Moreover, retrograde axonal trafficking of CREB in response to nerve growth factor (NGF) is critical for the survival of developing primary sensory neurons. We have previously demonstrated that hindpaw injection of interleukin-6 (IL-6) induces mechanical hypersensitivity and hyperalgesic priming that is prevented by the local injection of protein synthesis inhibitors. However, proteins that are locally synthesized that might lead to this effect have not been identified. We hypothesized that retrograde axonal trafficking of nascently synthesized CREB might link local, activity-dependent translation to nociceptive plasticity. To test this hypothesis, we determined if IL-6 enhances the expression of CREB and if it subsequently undergoes retrograde axonal transport. IL-6 treatment of sensory neurons in vitro caused an increase in CREB protein and in vivo treatment evoked an increase in CREB in the sciatic nerve consistent with retrograde transport. Importantly, co-injection of IL-6 with the methionine analogue azido-homoalanine (AHA), to assess nascently synthesized proteins, revealed an increase in CREB containing AHA in the sciatic nerve 2hrs post injection, indicating retrograde transport of nascently synthesized CREB. Behaviorally, blockade of retrograde transport by disruption of microtubules or inhibition of dynein or intrathecal injection of cAMP response element (CRE) consensus sequence DNA oligonucleotides, which act as decoys for CREB DNA binding, prevented the development of IL-6-induced mechanical hypersensitivity and hyperalgesic priming. Consistent with previous studies in inflammatory models, intraplantar IL-6 enhanced the expression of BDNF in dorsal root ganglion (DRG). This effect was blocked by inhibition of retrograde axonal transport and by intrathecal CRE oligonucleotides. Collectively, these findings point to a novel mechanism of axonal translation and retrograde trafficking linking locally-generated signals to long-term nociceptive sensitization.en
dc.language.isoenen
dc.publisherBioMed Centralen
dc.relation.urlhttp://mpx.sagepub.com/content/10/1744-8069-10-45.fullen
dc.rights© 2014 Melemedjian 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/4.0)en
dc.titleLocal translation and retrograde axonal transport of CREB regulates IL-6-induced nociceptive plasticityen
dc.typeArticleen
dc.identifier.eissn1744-8069en
dc.contributor.departmentDepartment of Pharmacology, The University of Arizona School of Medicine, Tucson, USAen
dc.contributor.departmentDepartment of Cellular and Molecular Medicine, The University of Arizona School of Medicine, Tucson, USAen
dc.contributor.departmentBio5 Institute, Tucson, USAen
dc.contributor.departmentGraduate Interdisciplinary Program in Neuroscience, Tucson, USAen
dc.contributor.departmentThe University of Texas at Dallas, School of Behavioral and Brain Sciences, Dallas, USAen
dc.contributor.departmentDepartment of Neurology, Yale School of Medicine, New Haven, USAen
dc.contributor.departmentSchool of Behavioral and Brain Sciences, University of Texas at Dallas, JO 4.212, 800 W Campbell Rd, Richardson, TX 75080, 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
All Items in UA Campus Repository are protected by copyright, with all rights reserved, unless otherwise indicated.