Local translation and retrograde axonal transport of CREB regulates IL-6-induced nociceptive plasticity
Author
Melemedjian, OhannesTillu, 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, USADepartment 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
Metadata
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BioMed CentralCitation
Melemedjian et al. Molecular Pain 2014, 10:45 http://www.molecularpain.com/content/10/1/45Journal
Molecular PainRights
© 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
1744-8069Version
Final published versionAdditional Links
http://mpx.sagepub.com/content/10/1744-8069-10-45.fullae974a485f413a2113503eed53cd6c53
10.1186/1744-8069-10-45