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

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    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
    
    Metadata
    Show full item record
    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
    ae974a485f413a2113503eed53cd6c53
    10.1186/1744-8069-10-45
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    UA Faculty Publications

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