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Molecular Pain
Published in: Molecular Pain 1/2012

Open Access 01-12-2012 | Research

Resveratrol engages AMPK to attenuate ERK and mTOR signaling in sensory neurons and inhibits incision-induced acute and chronic pain

Authors: Dipti V Tillu, Ohannes K Melemedjian, Marina N Asiedu, Ning Qu, Milena De Felice, Gregory Dussor, Theodore J Price

Published in: Molecular Pain | Issue 1/2012

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Abstract

Background

Despite advances in our understanding of basic mechanisms driving post-surgical pain, treating incision-induced pain remains a major clinical challenge. Moreover, surgery has been implicated as a major cause of chronic pain conditions. Hence, more efficacious treatments are needed to inhibit incision-induced pain and prevent the transition to chronic pain following surgery. We reasoned that activators of AMP-activated protein kinase (AMPK) may represent a novel treatment avenue for the local treatment of incision-induced pain because AMPK activators inhibit ERK and mTOR signaling, two important pathways involved in the sensitization of peripheral nociceptors.

Results

To test this hypothesis we used a potent and efficacious activator of AMPK, resveratrol. Our results demonstrate that resveratrol profoundly inhibits ERK and mTOR signaling in sensory neurons in a time- and concentration-dependent fashion and that these effects are mediated by AMPK activation and independent of sirtuin activity. Interleukin-6 (IL-6) is thought to play an important role in incision-induced pain and resveratrol potently inhibited IL-6-mediated signaling to ERK in sensory neurons and blocked IL-6-mediated allodynia in vivo through a local mechanism of action. Using a model of incision-induced allodynia in mice, we further demonstrate that local injection of resveratrol around the surgical wound strongly attenuates incision-induced allodynia. Intraplantar IL-6 injection and plantar incision induces persistent nociceptive sensitization to PGE2 injection into the affected paw after the resolution of allodynia to the initial stimulus. We further show that resveratrol treatment at the time of IL-6 injection or plantar incision completely blocks the development of persistent nociceptive sensitization consistent with the blockade of a transition to a chronic pain state by resveratrol treatment.

Conclusions

These results highlight the importance of signaling to translation control in peripheral sensitization of nociceptors and provide further evidence for activation of AMPK as a novel treatment avenue for acute and chronic pain states.
Appendix
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Literature
1.
Aasvang EK, Gmaehle E, Hansen JB, Gmaehle B, Forman JL, Schwarz J, Bittner R, Kehlet H: Predictive risk factors for persistent postherniotomy pain. Anesthesiology 2010,112(4):957–969. 10.1097/ALN.0b013e3181d31ff8CrossRefPubMed
2.
Kehlet H, Jensen TS, Woolf CJ: Persistent postsurgical pain: risk factors and prevention. Lancet 2006,367(9522):1618–1625. 10.1016/S0140-6736(06)68700-XCrossRefPubMed
3.
Perkins FM, Kehlet H: Chronic pain as an outcome of surgery. A review of predictive factors. Anesthesiology 2000,93(4):1123–1133. 10.1097/00000542-200010000-00038CrossRefPubMed
4.
Apfelbaum JL, Chen C, Mehta SS, Gan TJ: Postoperative pain experience: results from a national survey suggest postoperative pain continues to be undermanaged. Anesth Analg 2003,97(2):534–540. table of contents 10.1213/01.ANE.0000068822.10113.9ECrossRefPubMed
5.
Pavlin DJ, Chen C, Penaloza DA, Polissar NL, Buckley FP: Pain as a factor complicating recovery and discharge after ambulatory surgery. Anesth Analg 2002,95(3):627–634.PubMed
6.
Holzheimer RG, Steinmetz W: Local and systemic concentrations of pro- and anti-inflammatory cytokines in human wounds. Eur J Med Res 2000,5(8):347–355.PubMed
7.
Notarnicola A, Moretti L, Tafuri S, Vacca A, Marella G, Moretti B: Postoperative pain monitor after total knee replacement. Musculoskelet Surg 2011,95(1):19–24. 10.1007/s12306-011-0102-2CrossRefPubMed
8.
Pandazi A, Kapota E, Matsota P, Paraskevopoulou P, Dervenis C, Kostopanagiotou G: Preincisional versus postincisional administration of parecoxib in colorectal surgery: effect on postoperative pain control and cytokine response. A randomized clinical trial World J Surg 2010,34(10):2463–2469.PubMed
9.
Lin E, Calvano SE, Lowry SF: Inflammatory cytokines and cell response in surgery. Surgery 2000,127(2):117–126. 10.1067/msy.2000.101584CrossRefPubMed
10.
Bryan D, Walker KB, Ferguson M, Thorpe R: Cytokine gene expression in a murine wound healing model. Cytokine 2005,31(6):429–438. 10.1016/j.cyto.2005.06.015CrossRefPubMed
11.
Sato Y, Ohshima T: The expression of mRNA of proinflammatory cytokines during skin wound healing in mice: a preliminary study for forensic wound age estimation (II). Int J Legal Med 2000,113(3):140–145. 10.1007/s004140050285CrossRefPubMed
12.
Sahbaie P, Shi X, Guo TZ, Qiao Y, Yeomans DC, Kingery WS, Clark JD: Role of substance P signaling in enhanced nociceptive sensitization and local cytokine production after incision. Pain 2009,145(3):341–349. 10.1016/j.pain.2009.06.037PubMedCentralCrossRefPubMed
13.
Liang D, Shi X, Qiao Y, Angst MS, Yeomans DC, Clark JD: Chronic morphine administration enhances nociceptive sensitivity and local cytokine production after incision. Mol Pain 2008, 4: 7. 10.1186/1744-8069-4-7PubMedCentralCrossRefPubMed
14.
Clark JD, Shi X, Li X, Qiao Y, Liang D, Angst MS, Yeomans DC: Morphine reduces local cytokine expression and neutrophil infiltration after incision. Mol Pain 2007, 3: 28. 10.1186/1744-8069-3-28PubMedCentralCrossRefPubMed
15.
Quarta S, Vogl C, Constantin CE, Uceyler N, Sommer C, Kress M: Genetic evidence for an essential role of neuronally expressed IL-6 signal transducer gp130 in the induction and maintenance of experimentally induced mechanical hypersensitivity in vivo and in vitro. Mol Pain 2011, 7: 73. 10.1186/1744-8069-7-73PubMedCentralCrossRefPubMed
16.
Andratsch M, Mair N, Constantin CE, Scherbakov N, Benetti C, Quarta S, Vogl C, Sailer CA, Uceyler N, Brockhaus J, et al.: A key role for gp130 expressed on peripheral sensory nerves in pathological pain. The Journal of neuroscience: the official journal of the Society for Neuroscience 2009,29(43):13473–13483. 10.1523/JNEUROSCI.1822-09.2009CrossRef
17.
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. 10.1523/JNEUROSCI.3947-10.2010PubMedCentralCrossRefPubMed
18.
Melemedjian OK, Asiedu MN, Tillu DV, Sanoja R, Yan J, Lark A, Khoutorsky A, Johnson J, Peebles KA, Lepow T, et al.: 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. 10.1186/1744-8069-7-70PubMedCentralCrossRefPubMed
19.
Hardie DG: AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy. Nat Rev Mol Cell Biol 2007,8(10):774–785. 10.1038/nrm2249CrossRefPubMed
20.
Kim J, Yoon MY, Choi SL, Kang I, Kim SS, Kim YS, Choi YK, Ha J: Effects of stimulation of AMP-activated protein kinase on insulin-like growth factor 1- and epidermal growth factor-dependent extracellular signal-regulated kinase pathway. J Biol Chem 2001,276(22):19102–19110. 10.1074/jbc.M011579200CrossRefPubMed
21.
Dasgupta B, Milbrandt J: Resveratrol stimulates AMP kinase activity in neurons. Proc Natl Acad Sci USA 2007,104(17):7217–7222. 10.1073/pnas.0610068104PubMedCentralCrossRefPubMed
22.
Howitz KT, Bitterman KJ, Cohen HY, Lamming DW, Lavu S, Wood JG, Zipkin RE, Chung P, Kisielewski A, Zhang LL, et al.: Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 2003,425(6954):191–196. 10.1038/nature01960CrossRefPubMed
23.
Wood JG, Rogina B, Lavu S, Howitz K, Helfand SL, Tatar M, Sinclair D: Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature 2004,430(7000):686–689. 10.1038/nature02789CrossRefPubMed
24.
Viswanathan M, Kim SK, Berdichevsky A, Guarente L: A role for SIR-2.1 regulation of ER stress response genes in determining C. elegans life span. Dev Cell 2005,9(5):605–615. 10.1016/j.devcel.2005.09.017CrossRefPubMed
25.
Jarolim S, Millen J, Heeren G, Laun P, Goldfarb DS, Breitenbach M: A novel assay for replicative lifespan in Saccharomyces cerevisiae. FEMS Yeast Res 2004,5(2):169–177. 10.1016/j.femsyr.2004.06.015CrossRefPubMed
26.
Beher D, Wu J, Cumine S, Kim KW, Lu SC, Atangan L, Wang M: Resveratrol is not a direct activator of SIRT1 enzyme activity. Chem Biol Drug Des 2009,74(6):619–624. 10.1111/j.1747-0285.2009.00901.xCrossRefPubMed
27.
Pacholec M, Bleasdale JE, Chrunyk B, Cunningham D, Flynn D, Garofalo RS, Griffith D, Griffor M, Loulakis P, Pabst B, et al.: SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1. J Biol Chem 2010,285(11):8340–8351. 10.1074/jbc.M109.088682PubMedCentralCrossRefPubMed
28.
Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C, Kalra A, Prabhu VV, Allard JS, Lopez-Lluch G, Lewis K, et al.: Resveratrol improves health and survival of mice on a high-calorie diet. Nature 2006,444(7117):337–342. 10.1038/nature05354CrossRefPubMed
29.
Zang M, Xu S, Maitland-Toolan KA, Zuccollo A, Hou X, Jiang B, Wierzbicki M, Verbeuren TJ, Cohen RA: Polyphenols stimulate AMP-activated protein kinase, lower lipids, and inhibit accelerated atherosclerosis in diabetic LDL receptor-deficient mice. Diabetes 2006,55(8):2180–2191. 10.2337/db05-1188CrossRefPubMed
30.
Dasgupta B, Milbrandt J: Resveratrol stimulates AMP kinase activity in neurons. Proc Natl Acad Sci USA 2007,104(17):7217–7222. 10.1073/pnas.0610068104PubMedCentralCrossRefPubMed
31.
Um JH, Park SJ, Kang H, Yang S, Foretz M, McBurney MW, Kim MK, Viollet B, Chung JH: AMP-activated protein kinase-deficient mice are resistant to the metabolic effects of resveratrol. Diabetes 2010,59(3):554–563. 10.2337/db09-0482PubMedCentralCrossRefPubMed
32.
Raught B, Gingras AC, Gygi SP, Imataka H, Morino S, Gradi A, Aebersold R, Sonenberg N: Serum-stimulated, rapamycin-sensitive phosphorylation sites in the eukaryotic translation initiation factor 4GI. EMBO J 2000,19(3):434–444. 10.1093/emboj/19.3.434PubMedCentralCrossRefPubMed
33.
Harris TE, Chi A, Shabanowitz J, Hunt DF, Rhoads RE, Lawrence JC Jr: mTOR-dependent stimulation of the association of eIF4G and eIF3 by insulin. EMBO J 2006,25(8):1659–1668. 10.1038/sj.emboj.7601047PubMedCentralCrossRefPubMed
34.
Berset C, Trachsel H, Altmann M: The TOR (target of rapamycin) signal transduction pathway regulates the stability of translation initiation factor eIF4G in the yeast Saccharomyces cerevisiae. Proc Natl Acad Sci USA 1998,95(8):4264–4269. 10.1073/pnas.95.8.4264PubMedCentralCrossRefPubMed
35.
Sonenberg N, Hinnebusch AG: Regulation of translation initiation in eukaryotes: mechanisms and biological targets. Cell 2009,136(4):731–745. 10.1016/j.cell.2009.01.042PubMedCentralCrossRefPubMed
36.
Beretta L, Gingras AC, Svitkin YV, Hall MN, Sonenberg N: Rapamycin blocks the phosphorylation of 4E-BP1 and inhibits cap-dependent initiation of translation. EMBO J 1996,15(3):658–664.PubMedCentralPubMed
37.
Nayagam VM, Wang X, Tan YC, Poulsen A, Goh KC, Ng T, Wang H, Song HY, Ni B, Entzeroth M, et al.: SIRT1 modulating compounds from high-throughput screening as anti-inflammatory and insulin-sensitizing agents. J Biomol Screen 2006,11(8):959–967. 10.1177/1087057106294710CrossRefPubMed
38.
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. 10.1523/JNEUROSCI.6286-10.2011PubMedCentralCrossRefPubMed
39.
Price TJ, Rashid MH, Millecamps M, Sanoja R, Entrena JM, Cervero F: Decreased nociceptive sensitization in mice lacking the fragile X mental retardation protein: role of mGluR1/5 and mTOR. J Neurosci 2007,27(51):13958–13967. 10.1523/JNEUROSCI.4383-07.2007PubMedCentralCrossRefPubMed
40.
Jimenez-Diaz L, Geranton SM, Passmore GM, Leith JL, Fisher AS, Berliocchi L, Sivasubramaniam AK, Sheasby A, Lumb BM, Hunt SP: Local translation in primary afferent fibers regulates nociception. PLoS One 2008,3(4):e1961. 10.1371/journal.pone.0001961PubMedCentralCrossRefPubMed
41.
Geranton SM, Jimenez-Diaz L, Torsney C, Tochiki KK, Stuart SA, Leith JL, Lumb BM, Hunt SP: A rapamycin-sensitive signaling pathway is essential for the full expression of persistent pain states. J Neurosci 2009,29(47):15017–15027. 10.1523/JNEUROSCI.3451-09.2009PubMedCentralCrossRefPubMed
42.
Obara I, Tochiki KK, Geranton SM, Carr FB, Lumb BM, Liu Q, Hunt SP: Systemic inhibition of the mammalian target of rapamycin (mTOR) pathway reduces neuropathic pain in mice. Pain 2011,152(11):2582–2595. 10.1016/j.pain.2011.07.025CrossRefPubMed
43.
44.
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. The Journal of neuroscience: the official journal of the Society for Neuroscience 2011,31(18):6646–6653. 10.1523/JNEUROSCI.6286-10.2011CrossRef
45.
Zoncu R, Efeyan A, Sabatini DM: mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol 2011,12(1):21–35. 10.1038/nrm3025PubMedCentralCrossRefPubMed
46.
Cool B, Zinker B, Chiou W, Kifle L, Cao N, Perham M, Dickinson R, Adler A, Gagne G, Iyengar R, et al.: Identification and characterization of a small molecule AMPK activator that treats key components of type 2 diabetes and the metabolic syndrome. Cell Metab 2006,3(6):403–416. 10.1016/j.cmet.2006.05.005CrossRefPubMed
47.
Shaw RJ, Lamia KA, Vasquez D, Koo SH, Bardeesy N, Depinho RA, Montminy M, Cantley LC: The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science 2005,310(5754):1642–1646. 10.1126/science.1120781PubMedCentralCrossRefPubMed
48.
Ouyang J, Parakhia RA, Ochs RS: Metformin activates AMP kinase through inhibition of AMP deaminase. J Biol Chem 2011,286(1):1–11. 10.1074/jbc.M110.121806PubMedCentralCrossRefPubMed
49.
Corradetti MN, Inoki K, Bardeesy N, DePinho RA, Guan KL: Regulation of the TSC pathway by LKB1: evidence of a molecular link between tuberous sclerosis complex and Peutz-Jeghers syndrome. Genes Dev 2004,18(13):1533–1538. 10.1101/gad.1199104PubMedCentralCrossRefPubMed
50.
Tzatsos A, Tsichlis PN: Energy depletion inhibits phosphatidylinositol 3-kinase/Akt signaling and induces apoptosis via AMP-activated protein kinase-dependent phosphorylation of IRS-1 at Ser-794. J Biol Chem 2007,282(25):18069–18082. 10.1074/jbc.M610101200CrossRefPubMed
51.
Argetsinger LS, Hsu GW, Myers MG Jr, Billestrup N, White MF, Carter-Su C: Growth hormone, interferon-gamma, and leukemia inhibitory factor promoted tyrosyl phosphorylation of insulin receptor substrate-1. J Biol Chem 1995,270(24):14685–14692. 10.1074/jbc.270.24.14685CrossRefPubMed
52.
53.
Campillo A, Cabanero D, Romero A, Garcia-Nogales P, Puig MM: Delayed postoperative latent pain sensitization revealed by the systemic administration of opioid antagonists in mice. Eur J Pharmacol 2011,657(1–3):89–96. 10.1016/j.ejphar.2011.01.059CrossRefPubMed
54.
Shin SM, Cho IJ, Kim SG: Resveratrol protects mitochondria against oxidative stress through AMP-activated protein kinase-mediated glycogen synthase kinase-3beta inhibition downstream of poly(ADP-ribose)polymerase-LKB1 pathway. Mol Pharmacol 2009,76(4):884–895. 10.1124/mol.109.058479CrossRefPubMed
55.
Subbaramaiah K, Chung WJ, Michaluart P, Telang N, Tanabe T, Inoue H, Jang M, Pezzuto JM, Dannenberg AJ: Resveratrol inhibits cyclooxygenase-2 transcription and activity in phorbol ester-treated human mammary epithelial cells. J Biol Chem 1998,273(34):21875–21882. 10.1074/jbc.273.34.21875CrossRefPubMed
56.
Utreras E, Terse A, Keller J, Iadarola MJ, Kulkarni AB: Resveratrol inhibits Cdk5 activity through regulation of p35 expression. Mol Pain 2011, 7: 49. 10.1186/1744-8069-7-49PubMedCentralCrossRefPubMed
57.
Kim HI, Kim TH, Song JH: Resveratrol inhibits Na + currents in rat dorsal root ganglion neurons. Brain Res 2005,1045(1–2):134–141. 10.1016/j.brainres.2005.03.019CrossRefPubMed
58.
Torres-Lopez JE, Ortiz MI, Castaneda-Hernandez G, Alonso-Lopez R, Asomoza-Espinosa R, Granados-Soto V: Comparison of the antinociceptive effect of celecoxib, diclofenac and resveratrol in the formalin test. Life Sci 2002,70(14):1669–1676. 10.1016/S0024-3205(02)01491-1CrossRefPubMed
59.
Gentilli M, Mazoit JX, Bouaziz H, Fletcher D, Casper RF, Benhamou D, Savouret JF: Resveratrol decreases hyperalgesia induced by carrageenan in the rat hind paw. Life Sci 2001,68(11):1317–1321. 10.1016/S0024-3205(00)01018-3CrossRefPubMed
60.
Wuertz K, Quero L, Sekiguchi M, Klawitter M, Nerlich A, Konno S, Kikuchi S, Boos N: The red wine polyphenol resveratrol shows promising potential for the treatment of nucleus pulposus-mediated pain in vitro and in vivo. Spine 2011,36(21):E1373-E1384. 10.1097/BRS.0b013e318221e655CrossRefPubMed
61.
Larrosa M, Azorin-Ortuno M, Yanez-Gascon MJ, Garcia-Conesa MT, Tomas-Barberan F, Espin JC: Lack of effect of oral administration of resveratrol in LPS-induced systemic inflammation. Eur J Nutr 2011,50(8):673–678. 10.1007/s00394-011-0178-3CrossRefPubMed
62.
Aasvang EK, Hansen JB, Malmstrom J, Asmussen T, Gennevois D, Struys MM, Kehlet H: The effect of wound instillation of a novel purified capsaicin formulation on postherniotomy pain: a double-blind, randomized, placebo-controlled study. Anesth Analg 2008,107(1):282–291. 10.1213/ane.0b013e31816b94c9CrossRefPubMed
63.
Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL: Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods 1994,53(1):55–63. 10.1016/0165-0270(94)90144-9CrossRefPubMed
64.
Banik RK, Woo YC, Park SS, Brennan TJ: Strain and sex influence on pain sensitivity after plantar incision in the mouse. Anesthesiology 2006,105(6):1246–1253. 10.1097/00000542-200612000-00025CrossRefPubMed
Metadata
Title
Resveratrol engages AMPK to attenuate ERK and mTOR signaling in sensory neurons and inhibits incision-induced acute and chronic pain
Authors
Dipti V Tillu
Ohannes K Melemedjian
Marina N Asiedu
Ning Qu
Milena De Felice
Gregory Dussor
Theodore J Price
Publication date
01-12-2012
Publisher
BioMed Central
Published in
Molecular Pain / Issue 1/2012
Electronic ISSN: 1744-8069
DOI
https://doi.org/10.1186/1744-8069-8-5

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