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Molecular Pain
Published in: Molecular Pain 1/2014

Open Access 01-12-2014 | Research

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

Authors: Ohannes K Melemedjian, Dipti V Tillu, Jamie K Moy, Marina N Asiedu, Edward K Mandell, Sourav Ghosh, Gregory Dussor, Theodore J Price

Published in: Molecular Pain | Issue 1/2014

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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 2 hrs 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.
Appendix
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Literature
1.
Woolf CJ, Walters ET: Common patterns of plasticity contributing to nociceptive sensitization in mammals and Aplysia. Trends Neurosci 1991,14(2):74–78.PubMedCrossRef
2.
3.
Reichling DB, Green PG, Levine JD: The fundamental unit of pain is the cell. Pain 2013.,154(Suppl 1): 10.1016/j.pain.2013.05.037
4.
Weragoda RM, Ferrer E, Walters ET: Memory-like alterations in Aplysia axons after nerve injury or localized depolarization. J Neurosci 2004,24(46):10393–10401.PubMedCrossRef
5.
Price TJ, Geranton SM: Translating nociceptor sensitivity: the role of axonal protein synthesis in nociceptor physiology. Eur J Neurosci 2009,29(12):2253–2263.PubMedCentralPubMedCrossRef
6.
Melemedjian OK, Asiedu MN, Tillu DV, Peebles KA, Yan J, Ertz N, Dussor GO, Price TJ: IL-6- and NGF-induced rapid control of protein synthesis and nociceptive plasticity via convergent signaling to the eIF4F complex. J Neurosci 2010,30(45):15113–15123.PubMedCentralPubMedCrossRef
7.
Obara I, Geranton SM, Hunt SP: Axonal protein synthesis: a potential target for pain relief? Curr Opin Pharmacol 2012,12(1):42–48.PubMedCrossRef
8.
Gunstream JD, Castro GA, Walters ET: Retrograde transport of plasticity signals in Aplysia sensory neurons following axonal injury. J Neurosci 1995,15(1 Pt 1):439–448.PubMed
9.
Melemedjian OK, Asiedu MN, Tillu DV, Sanoja R, Yan J, Lark A, Khoutorsky A, Johnson J, Peebles KA, Lepow T, Sonenberg N, Dussor G, Price TJ: Targeting adenosine monophosphate-activated protein kinase (AMPK) in preclinical models reveals a potential mechanism for the treatment of neuropathic pain. Mol Pain 2011, 7: 70.PubMedCentralPubMedCrossRef
10.
Melemedjian OK, Mejia GL, Lepow TS, Zoph OK, Price TJ: Bidirectional regulation of P body formation mediated by eIF4F complex formation in sensory neurons. Neurosci Lett 2013,155(7):1238–1244.
11.
Aasvang E, Kehlet H: Chronic postoperative pain: the case of inguinal herniorrhaphy. Br J Anaesth 2005,95(1):69–76.PubMedCrossRef
12.
13.
Asiedu MN, Tillu DV, Melemedjian OK, Shy A, Sanoja R, Bodell B, Ghosh S, Porreca F, Price TJ: Spinal protein kinase M zeta underlies the maintenance mechanism of persistent nociceptive sensitization. J Neurosci 2011,31(18):6646–6653.PubMedCentralPubMedCrossRef
14.
Melemedjian OK, Tillu DV, Asiedu MN, Mandell EK, Moy JK, Blute VM, Taylor CJ, Ghosh S, Price TJ: BDNF regulates atypical PKC at spinal synapses to initiate and maintain a centralized chronic pain state. Mol Pain 2013, 9: 12.PubMedCentralPubMedCrossRef
15.
Cox LJ, Hengst U, Gurskaya NG, Lukyanov KA, Jaffrey SR: Intra-axonal translation and retrograde trafficking of CREB promotes neuronal survival. Nat Cell Biol 2008,10(2):149–159.PubMedCentralPubMedCrossRef
16.
Firestone AJ, Weinger JS, Maldonado M, Barlan K, Langston LD, O'Donnell M, Gelfand VI, Kapoor TM, Chen JK: Small-molecule inhibitors of the AAA + ATPase motor cytoplasmic dynein. Nature 2012,484(7392):125–129.PubMedCentralPubMedCrossRef
17.
Tao X, Finkbeiner S, Arnold DB, Shaywitz AJ, Greenberg ME: Ca2+ influx regulates BDNF transcription by a CREB family transcription factor-dependent mechanism. Neuron 1998,20(4):709–726.PubMedCrossRef
18.
Park YG, Nesterova M, Agrawal S, Cho-Chung YS: Dual blockade of cyclic AMP response element- (CRE) and AP-1-directed transcription by CRE-transcription factor decoy oligonucleotide. gene-specific inhibition of tumor growth. J Biol Chem 1999,274(3):1573–1580.PubMedCrossRef
19.
Alper O, Bergmann-Leitner ES, Abrams S, Cho-Chung YS: Apoptosis, growth arrest and suppression of invasiveness by CRE-decoy oligonucleotide in ovarian cancer cells: protein kinase A downregulation and cytoplasmic export of CRE-binding proteins. Mol Cell Biochem 2001,218(1–2):55–63.PubMedCrossRef
20.
Lee YN, Park YG, Choi YH, Cho YS, Cho-Chung YS: CRE-transcription factor decoy oligonucleotide inhibition of MCF-7 breast cancer cells: cross-talk with p53 signaling pathway. Biochemistry 2000,39(16):4863–4868.PubMedCrossRef
21.
22.
Finkbeiner S, Tavazoie SF, Maloratsky A, Jacobs KM, Harris KM, Greenberg ME: CREB: a major mediator of neuronal neurotrophin responses. Neuron 1997,19(5):1031–1047.PubMedCrossRef
23.
24.
McClung CA, Nestler EJ: Regulation of gene expression and cocaine reward by CREB and DeltaFosB. Nat Neurosci 2003,6(11):1208–1215.PubMedCrossRef
25.
Pham TA, Rubenstein JL, Silva AJ, Storm DR, Stryker MP: The CRE/CREB pathway is transiently expressed in thalamic circuit development and contributes to refinement of retinogeniculate axons. Neuron 2001,31(3):409–420.PubMedCrossRef
26.
Barco A, Alarcon JM, Kandel ER: Expression of constitutively active CREB protein facilitates the late phase of long-term potentiation by enhancing synaptic capture. Cell 2002,108(5):689–703.PubMedCrossRef
27.
Miletic G, Pankratz MT, Miletic V: Increases in the phosphorylation of cyclic AMP response element binding protein (CREB) and decreases in the content of calcineurin accompany thermal hyperalgesia following chronic constriction injury in rats. Pain 2002,99(3):493–500.PubMedCrossRef
28.
Kawasaki Y, Kohno T, Zhuang ZY, Brenner GJ, Wang H, Van Der Meer C, Befort K, Woolf CJ, Ji RR: Ionotropic and metabotropic receptors, protein kinase A, protein kinase C, and Src contribute to C-fiber-induced ERK activation and cAMP response element-binding protein phosphorylation in dorsal horn neurons, leading to central sensitization. J Neurosci 2004,24(38):8310–8321.PubMedCrossRef
29.
Miletic G, Hanson EN, Miletic V: Brain-derived neurotrophic factor-elicited or sciatic ligation-associated phosphorylation of cyclic AMP response element binding protein in the rat spinal dorsal horn is reduced by block of tyrosine kinase receptors. Neurosci Lett 2004,361(1–3):269–271.PubMedCrossRef
30.
Niederberger E, Ehnert C, Gao W, Coste O, Schmidtko A, Popp L, Gall C, Korf HW, Tegeder I, Geisslinger G: The impact of CREB and its phosphorylation at Ser142 on inflammatory nociception. Biochem Biophys Res Commun 2007,362(1):75–80.PubMedCrossRef
31.
Yu SJ, Xia CM, Kay JC, Qiao LY: Activation of extracellular signal-regulated protein kinase 5 is essential for cystitis- and nerve growth factor-induced calcitonin gene-related peptide expression in sensory neurons. Mol Pain 2012, 8: 48.PubMedCentralPubMedCrossRef
32.
Ma W, Quirion R: Increased phosphorylation of cyclic AMP response element-binding protein (CREB) in the superficial dorsal horn neurons following partial sciatic nerve ligation. Pain 2001,93(3):295–301.PubMedCrossRef
33.
Hoeger-Bement MK, Sluka KA: Phosphorylation of CREB and mechanical hyperalgesia is reversed by blockade of the cAMP pathway in a time-dependent manner after repeated intramuscular acid injections. J Neurosci 2003,23(13):5437–5445.PubMed
34.
Molliver DC, Cook SP, Carlsten JA, Wright DE, McCleskey EW: ATP and UTP excite sensory neurons and induce CREB phosphorylation through the metabotropic receptor, P2Y2. Eur J Neurosci 2002,16(10):1850–1860.PubMedCrossRef
35.
Ji RR, Rupp F: Phosphorylation of transcription factor CREB in rat spinal cord after formalin-induced hyperalgesia: relationship to c-fos induction. J Neurosci 1997,17(5):1776–1785.PubMed
36.
Ma W, Hatzis C, Eisenach JC: Intrathecal injection of cAMP response element binding protein (CREB) antisense oligonucleotide attenuates tactile allodynia caused by partial sciatic nerve ligation. Brain Res 2003,988(1–2):97–104.PubMedCrossRef
37.
Pezet S, Malcangio M, McMahon SB: BDNF: a neuromodulator in nociceptive pathways? Brain Res Brain Res Rev 2002,40(1–3):240–249.PubMedCrossRef
38.
Zhao J, Seereeram A, Nassar MA, Levato A, Pezet S, Hathaway G, Morenilla-Palao C, Stirling C, Fitzgerald M, McMahon SB, Wood JN: Nociceptor-derived brain-derived neurotrophic factor regulates acute and inflammatory but not neuropathic pain. Mol Cell Neurosci 2006,31(3):539–548.PubMedCrossRef
39.
Trang T, Beggs S, Salter MW: Brain-derived neurotrophic factor from microglia: a molecular substrate for neuropathic pain. Neuron Glia Biol 2011,7(1):99–108.PubMedCentralPubMedCrossRef
40.
Mannion RJ, Costigan M, Decosterd I, Amaya F, Ma QP, Holstege JC, Ji RR, Acheson A, Lindsay RM, Wilkinson GA, Woolf CJ: Neurotrophins: peripherally and centrally acting modulators of tactile stimulus-induced inflammatory pain hypersensitivity. Proc Natl Acad Sci U S A 1999,96(16):9385–9390.PubMedCentralPubMedCrossRef
41.
Morioka N, Yoshida Y, Nakamura Y, Hidaka N, Hisaoka-Nakashima K, Nakata Y: The regulation of exon-specific brain-derived neurotrophic factor mRNA expression by protein kinase C in rat cultured dorsal root ganglion neurons. Brain Res 2013, 1509: 20–31.PubMedCrossRef
42.
43.
Bogen O, Alessandri-Haber N, Chu C, Gear RW, Levine JD: Generation of a pain memory in the primary afferent nociceptor triggered by PKCepsilon activation of CPEB. J Neurosci 2012,32(6):2018–2026.PubMedCentralPubMedCrossRef
44.
Ferrari LF, Bogen O, Chu C, Levine JD: Peripheral administration of translation inhibitors reverses increased hyperalgesia in a model of chronic pain in the rat. J Pain 2013,14(7):731–738.PubMedCentralPubMedCrossRef
45.
Ferrari LF, Bogen O, Levine JD: Role of nociceptor alphaCaMKII in transition from acute to chronic pain (hyperalgesic priming) in male and female rats. J Neurosci 2013,33(27):11002–11011.PubMedCentralPubMedCrossRef
46.
47.
Coull JA, Beggs S, Boudreau D, Boivin D, Tsuda M, Inoue K, Gravel C, Salter MW, De Koninck Y: BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature 2005,438(7070):1017–1021.PubMedCrossRef
48.
Ferrini F, De Koninck Y: Microglia control neuronal network excitability via BDNF signalling. Neural Plast 2013, 2013: 429815.PubMedCentralPubMed
49.
Andreassi C, Zimmermann C, Mitter R, Fusco S, De Vita S, Saiardi A, Riccio A: An NGF-responsive element targets myo-inositol monophosphatase-1 mRNA to sympathetic neuron axons. Nat Neurosci 2010,13(3):291–301.PubMedCrossRef
50.
51.
Hendricks AG, Twelvetrees AE, Holzbaur EL: Intracellular transport: new tools provide insights into multi-motor transport. Curr Biol 2012,22(24):R1053-R1055.PubMedCrossRef
52.
53.
Mar FM, Simoes AR, Leite S, Morgado MM, Santos TE, Rodrigo IS, Teixeira CA, Misgeld T, Sousa MM: CNS axons globally increase axonal transport after peripheral conditioning. J Neurosci 2014,34(17):5965–5970.PubMedCrossRef
54.
Price TJ, Dussor G: AMPK: An emerging target for modification of injury-induced pain plasticity. Neurosci Lett 2013,557(Pt A):9–18.PubMedCrossRef
55.
Barco A, Pittenger C, Kandel ER: CREB, memory enhancement and the treatment of memory disorders: promises, pitfalls and prospects. Expert Opin Ther Targets 2003,7(1):101–114.PubMedCrossRef
Metadata
Title
Local translation and retrograde axonal transport of CREB regulates IL-6-induced nociceptive plasticity
Authors
Ohannes K Melemedjian
Dipti V Tillu
Jamie K Moy
Marina N Asiedu
Edward K Mandell
Sourav Ghosh
Gregory Dussor
Theodore J Price
Publication date
01-12-2014
Publisher
BioMed Central
Published in
Molecular Pain / Issue 1/2014
Electronic ISSN: 1744-8069
DOI
https://doi.org/10.1186/1744-8069-10-45

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