Abstract
Chronic pain is a major clinical problem that is poorly treated with available therapeutics. Adenosine monophosphate-activated protein kinase (AMPK) has recently emerged as a novel target for the treatment of pain with the exciting potential for disease modification. AMPK activators inhibit signaling pathways that are known to promote changes in the function and phenotype of peripheral nociceptive neurons and promote chronic pain. AMPK activators also reduce the excitability of these cells suggesting that AMPK activators may be efficacious for the treatment of chronic pain disorders, like neuropathic pain, where changes in the excitability of nociceptors is thought to be an underlying cause. In agreement with this, AMPK activators have now been shown to alleviate pain in a broad variety of preclinical pain models indicating that this mechanism might be engaged for the treatment of many types of pain in the clinic. A key feature of the effect of AMPK activators in these models is that they can lead to a long-lasting reversal of pain hypersensitivity even long after treatment cessation, indicative of disease modification. Here, we review the evidence supporting AMPK as a novel pain target pointing out opportunities for further discovery that are likely to have an impact on drug discovery efforts centered around potent and specific allosteric activators of AMPK for chronic pain treatment.
Keywords
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Abe N, Borson SH, Gambello MJ, Wang F, Cavalli V (2010) Mammalian target of rapamycin (mTOR) activation increases axonal growth capacity of injured peripheral nerves. J Biol Chem 285:28034–28043
Adams JP, Anderson AE, Varga AW, Dineley KT, Cook RG, Pfaffinger PJ, Sweatt JD (2000) The A-type potassium channel Kv4.2 is a substrate for the mitogen-activated protein kinase ERK. J Neurochem 75:2277–2287
Agthong S, Kaewsema A, Tanomsridejchai N, Chentanez V (2006) Activation of MAPK ERK in peripheral nerve after injury. BMC Neurosci 7:45
Anand P, Shenoy R, Palmer JE, Baines AJ, Lai RY, Robertson J, Bird N, Ostenfeld T, Chizh BA (2011) Clinical trial of the p38 MAP kinase inhibitor dilmapimod in neuropathic pain following nerve injury. Eur J Pain 15:1040–1048
Andersen MN, Rasmussen HB (2012) AMPK: a regulator of ion channels. Commun Integr Biol 5:480–484
Argoff CE, Backonja MM, Belgrade MJ, Bennett GJ, Clark MR, Cole BE, Fishbain DA, Irving GA, McCarberg BH, McLean MJ (2006) Consensus guidelines: treatment planning and options. Diabetic peripheral neuropathic pain. Mayo Clinic Proc 81:S12–S25
Arrowsmith CH et al (2015) The promise and peril of chemical probes. Nat Chem Biol 11:536–541
Asante CO, Wallace VC, Dickenson AH (2009) Formalin-induced behavioural hypersensitivity and neuronal hyperexcitability are mediated by rapid protein synthesis at the spinal level. Mol Pain 5:27
Asante CO, Wallace VC, Dickenson AH (2010) Mammalian target of rapamycin signaling in the spinal cord is required for neuronal plasticity and behavioral hypersensitivity associated with neuropathy in the rat. J Pain 11(12):1356–1367
Asiedu MN, Tillu DV, Melemedjian OK, Shy A, Sanoja R, Bodell B, Ghosh S, Porreca F, Price TJ (2011) Spinal protein kinase M zeta underlies the maintenance mechanism of persistent nociceptive sensitization. J Neurosci 31:6646–6653
Balayssac D, Ferrier J, Descoeur J, Ling B, Pezet D, Eschalier A, Authier N (2011) Chemotherapy-induced peripheral neuropathies: from clinical relevance to preclinical evidence. Expert Opin Drug Saf 10:407–417
Banik RK, Brennan TJ (2008) Sensitization of primary afferents to mechanical and heat stimuli after incision in a novel in vitro mouse glabrous skin-nerve preparation. Pain 138:380–391
Banik RK, Subieta AR, Wu C, Brennan TJ (2005) Increased nerve growth factor after rat plantar incision contributes to guarding behavior and heat hyperalgesia. Pain 117:68–76
Baron R, Binder A, Wasner G (2010) Neuropathic pain: diagnosis, pathophysiological mechanisms, and treatment. Lancet Neurol 9:807–819
Basbaum AI, Bautista DM, Scherrer G, Julius D (2009) Cellular and molecular mechanisms of pain. Cell 139:267–284
Beggs S, Salter MW (2010) Microglia-neuronal signalling in neuropathic pain hypersensitivity 2.0. Curr Opin Neurobiol 20:474–480
Berta T, Liu T, Liu YC, Xu ZZ, Ji RR (2012) Acute morphine activates satellite glial cells and up-regulates IL-1beta in dorsal root ganglia in mice via matrix metalloprotease-9. Mol Pain 8:18
Bhalla V, Oyster NM, Fitch AC, Wijngaarden MA, Neumann D, Schlattner U, Pearce D, Hallows KR (2006) AMP-activated kinase inhibits the epithelial Na+ channel through functional regulation of the ubiquitin ligase Nedd4-2. J Biol Chem 281:26159–26169
Bierhaus A et al (2012) Methylglyoxal modification of Nav1.8 facilitates nociceptive neuron firing and causes hyperalgesia in diabetic neuropathy. Nat Med 18:926–933
Bongiorno D, Schuetz F, Poronnik P, Adams DJ (2011) Regulation of voltage-gated ion channels in excitable cells by the ubiquitin ligases Nedd4 and Nedd4-2. Channels (Austin) 5:79–88
Budde K, Becker T, Arns W, Sommerer C, Reinke P, Eisenberger U, Kramer S, Fischer W, Gschaidmeier H, Pietruck F (2011) Everolimus-based, calcineurin-inhibitor-free regimen in recipients of de-novo kidney transplants: an open-label, randomised, controlled trial. Lancet 377:837–847
Bullon P, Alcocer-Gomez E, Carrion AM, Garrido-Maraver J, Marin-Aguilar F, Roman-Malo L, Ruiz-Cabello J, Culic O, Ryffel B, Apetoh L, Ghiringhelli F, Battino M, Sanchez-Alcazar JA, Cordero MD (2015) AMPK phosphorylation modulates pain by activation of NLRP3-inflammasome. Antioxidants & redox signaling. Antioxid Redox Signal 24(3):157–170
Byrne F, Cheetham SC, Vickers SP, Chapman VR (2015) Characterisation of pain responses in the high fat diet/streptozotocin model of diabetes, and the analgesic effects of antidiabetic treatments. J Diabetes Res 2015:752481
Carattino MD, Edinger RS, Grieser HJ, Wise R, Neumann D, Schlattner U, Johnson JP, Kleyman TR, Hallows KR (2005) Epithelial sodium channel inhibition by AMP-activated protein kinase in oocytes and polarized renal epithelial cells. J Biol Chem 280:17608–17616
Carling D, Thornton C, Woods A, Sanders MJ (2012) AMP-activated protein kinase: new regulation, new roles? Biochem J 445:11–27
Cata JP, Weng HR, Lee BN, Reuben JM, Dougherty PM (2006) Clinical and experimental findings in humans and animals with chemotherapy-induced peripheral neuropathy. Minerva Anestesiol 72:151–169
Chapman PB (2013) Mechanisms of resistance to RAF inhibition in melanomas harboring a BRAF mutation. Am Soc Clin Oncol Educ Book. http://meetinglibrary.asco.org/content/158-132
Chen Y, Sommer C (2009) The role of mitogen-activated protein kinase (MAPK) in morphine tolerance and dependence. Mol Neurobiol 40:101–107
Cheng HT, Dauch JR, Porzio MT, Yanik BM, Hsieh W, Smith AG, Singleton JR, Feldman EL (2013) Increased axonal regeneration and swellings in intraepidermal nerve fibers characterize painful phenotypes of diabetic neuropathy. J Pain 14:941–947
Cheung A, Podgorny P, Martinez JA, Chan C, Toth C (2015) Epidermal axonal swellings in painful and painless diabetic peripheral neuropathy. Muscle Nerve 51(4):505–513
Christopher JEW (2001) Sirolimus (rapamycin) in clinical transplantation. Transplant Rev 15:165–177
Clark JD, Shi X, Li X, Qiao Y, Liang D, Angst MS, Yeomans DC (2007) Morphine reduces local cytokine expression and neutrophil infiltration after incision. Mol Pain 3:28
Cool B, Zinker B, Chiou W, Kifle L, Cao N, Perham M, Dickinson R, Adler A, Gagne G, Iyengar R, Zhao G, Marsh K, Kym P, Jung P, Camp HS, Frevert E (2006) Identification and characterization of a small molecule AMPK activator that treats key components of type 2 diabetes and the metabolic syndrome. Cell Metab 3:403–416
Cui Y, Liao XX, Liu W, Guo RX, Wu ZZ, Zhao CM, Chen PX, Feng JQ (2008) A novel role of minocycline: attenuating morphine antinociceptive tolerance by inhibition of p38 MAPK in the activated spinal microglia. Brain Behav Immun 22:114–123
Decensi A, Puntoni M, Goodwin P, Cazzaniga M, Gennari A, Bonanni B, Gandini S (2010) Metformin and cancer risk in diabetic patients: a systematic review and meta-analysis. Cancer Prev Res (Phila) 3:1451–1461
Dib-Hajj SD, Cummins TR, Black JA, Waxman SG (2010) Sodium channels in normal and pathological pain. Annu Rev Neurosci 33:325–347
Dokla EM, Fang CS, Lai PT, Kulp SK, Serya RA, Ismail NS, Abouzid KA, Chen CS (2015) Development of potent adenosine monophosphate activated protein kinase (AMPK) activators. ChemMedChem 10:1915–1923
Dworkin RH et al (2010) Recommendations for the pharmacological management of neuropathic pain: an overview and literature update. Mayo Clin Proc 85:S3–S14
Ebenezer G, Polydefkis M (2014) Epidermal innervation in diabetes. Handb Clin Neurol 126:261–274
Education IoMCoAPRCa (2011) Relieving pain in America: a blueprint for transforming prevention, care, education, and research. Washington, DC
Ferrier J, Pereira V, Busserolles J, Authier N, Balayssac D (2013) Emerging trends in understanding chemotherapy-induced peripheral neuropathy. Curr Pain Headache Rep 17:364
Foller M, Jaumann M, Dettling J, Saxena A, Pakladok T, Munoz C, Ruth P, Sopjani M, Seebohm G, Ruttiger L, Knipper M, Lang F (2012) AMP-activated protein kinase in BK-channel regulation and protection against hearing loss following acoustic overstimulation. FASEB J 26:4243–4253
Forslund K et al (2015) Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota. Nature 528:262–266
Fukagawa H, Koyama T, Kakuyama M, Fukuda K (2013) Microglial activation involved in morphine tolerance is not mediated by toll-like receptor 4. J Anesth 27:93–97
Furic L, Rong L, Larsson O, Koumakpayi IH, Yoshida K, Brueschke A, Petroulakis E, Robichaud N, Pollak M, Gaboury LA, Pandolfi PP, Saad F, Sonenberg N (2010) eIF4E phosphorylation promotes tumorigenesis and is associated with prostate cancer progression. Proc Natl Acad Sci U S A 107:14134–14139
Gao B, Roux PP (2015) Translational control by oncogenic signaling pathways. Biochim Biophys Acta 1849:753–765
Geranton SM, Jimenez-Diaz L, Torsney C, Tochiki KK, Stuart SA, Leith JL, Lumb BM, Hunt SP (2009) A rapamycin-sensitive signaling pathway is essential for the full expression of persistent pain states. J Neurosci 29:15017–15027
Ghosh S, Tergaonkar V, Rothlin CV, Correa RG, Bottero V, Bist P, Verma IM, Hunter T (2006) Essential role of tuberous sclerosis genes TSC1 and TSC2 in NF-kappaB activation and cell survival. Cancer Cell 10:215–226
Gingras AC, Raught B, Sonenberg N (1999) eIF4 initiation factors: effectors of mRNA recruitment to ribosomes and regulators of translation. Annu Rev Biochem 68:913–963
Gingras AC, Raught B, Sonenberg N (2004) mTOR signaling to translation. Curr Top Microbiol Immunol 279:169–197
Giordanetto F, Karis D (2012) Direct AMP-activated protein kinase activators: a review of evidence from the patent literature. Expert Opin Ther Pat 22:1467–1477
Giuditta A, Kaplan BB, van Minnen J, Alvarez J, Koenig E (2002) Axonal and presynaptic protein synthesis: new insights into the biology of the neuron. Trends Neurosci 25:400–404
Gkogkas CG, Khoutorsky A, Cao R, Jafarnejad SM, Prager-Khoutorsky M, Giannakas N, Kaminari A, Fragkouli A, Nader K, Price TJ, Konicek BW, Graff JR, Tzinia AK, Lacaille JC, Sonenberg N (2014) Pharmacogenetic inhibition of eIF4E-dependent Mmp9 mRNA translation reverses fragile X syndrome-like phenotypes. Cell Rep 9:1742–1755
Hallows KR, Raghuram V, Kemp BE, Witters LA, Foskett JK (2000) Inhibition of cystic fibrosis transmembrane conductance regulator by novel interaction with the metabolic sensor AMP-activated protein kinase. J Clin Invest 105:1711–1721
Hameed H, Hameed M, Christo PJ (2010) The effect of morphine on glial cells as a potential therapeutic target for pharmacological development of analgesic drugs. Curr Pain Headache Rep 14:96–104
Han Y, Smith MT (2013) Pathobiology of cancer chemotherapy-induced peripheral neuropathy (CIPN). Front Pharmacol 4:156
Han Y, Jiang C, Tang J, Wang C, Wu P, Zhang G, Liu W, Jamangulova N, Wu X, Song X (2014) Resveratrol reduces morphine tolerance by inhibiting microglial activation via AMPK signalling. Eur J Pain 18:1458–1470
Hardie DG (2013) AMPK: a target for drugs and natural products with effects on both diabetes and cancer. Diabetes 62:2164–2172
Hardie DG, Ross FA, Hawley SA (2012) AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat Rev Mol Cell Biol 13:251–262
Hawley SA, Fullerton MD, Ross FA, Schertzer JD, Chevtzoff C, Walker KJ, Peggie MW, Zibrova D, Green KA, Mustard KJ, Kemp BE, Sakamoto K, Steinberg GR, Hardie DG (2012) The ancient drug salicylate directly activates AMP-activated protein kinase. Science 336:918–922
Herdy B et al (2012) Translational control of the activation of transcription factor NF-kappaB and production of type I interferon by phosphorylation of the translation factor eIF4E. Nat Immunol 13:543–550
Horvath RJ, Romero-Sandoval EA, De Leo JA (2010) Inhibition of microglial P2X4 receptors attenuates morphine tolerance, Iba1, GFAP and mu opioid receptor protein expression while enhancing perivascular microglial ED2. Pain 150:401–413
Hosono K, Endo H, Takahashi H, Sugiyama M, Uchiyama T, Suzuki K, Nozaki Y, Yoneda K, Fujita K, Yoneda M, Inamori M, Tomatsu A, Chihara T, Shimpo K, Nakagama H, Nakajima A (2010) Metformin suppresses azoxymethane-induced colorectal aberrant crypt foci by activating AMP-activated protein kinase. Mol Carcinog 49:662–671
Huang Q, Chen Y, Gong N, Wang Y (2016) Methylglyoxal mediates streptozotocin-induced diabetic neuropathic pain via activation of the peripheral TRPA1 and Nav1.8 channels. Metabolism 65(4):463–474
Ikematsu N, Dallas ML, Ross FA, Lewis RW, Rafferty JN, David JA, Suman R, Peers C, Hardie DG, Evans AM (2011) Phosphorylation of the voltage-gated potassium channel Kv2.1 by AMP-activated protein kinase regulates membrane excitability. Proc Natl Acad Sci U S A 108:18132–18137
Jakobsen SN, Hardie DG, Morrice N, Tornqvist HE (2001) 5′-AMP-activated protein kinase phosphorylates IRS-1 on Ser-789 in mouse C2C12 myotubes in response to 5-aminoimidazole-4-carboxamide riboside. J Biol Chem 276:46912–46916
Ji RR, Woolf CJ (2001) Neuronal plasticity and signal transduction in nociceptive neurons: implications for the initiation and maintenance of pathological pain. Neurobiol Dis 8:1–10
Ji RR, Kohno T, Moore KA, Woolf CJ (2003) Central sensitization and LTP: do pain and memory share similar mechanisms? Trends Neurosci 26:696–705
Ji RR, Kawasaki Y, Zhuang ZY, Wen YR, Zhang YQ (2007) Protein kinases as potential targets for the treatment of pathological pain. Handb Exp Pharmacol:359–389
Ji RR, Xu ZZ, Wang X, Lo EH (2009a) Matrix metalloprotease regulation of neuropathic pain. Trends Pharmacol Sci 30:336–340
Ji RR, Gereau RW, Malcangio M, Strichartz GR (2009b) MAP kinase and pain. Brain Res Rev 60:135–148
Jimenez-Diaz L, Geranton SM, Passmore GM, Leith JL, Fisher AS, Berliocchi L, Sivasubramaniam AK, Sheasby A, Lumb BM, Hunt SP (2008) Local translation in primary afferent fibers regulates nociception. PLoS One 3, e1961
Jung H, Holt CE (2011) Local translation of mRNAs in neural development. Wiley Interdiscip Rev RNA 2:153–165
Jung H, Yoon BC, Holt CE (2012) Axonal mRNA localization and local protein synthesis in nervous system assembly, maintenance and repair. Nat Rev Neurosci 13:308–324
Kawasaki Y, Xu ZZ, Wang X, Park JY, Zhuang ZY, Tan PH, Gao YJ, Roy K, Corfas G, Lo EH, Ji RR (2008) Distinct roles of matrix metalloproteases in the early- and late-phase development of neuropathic pain. Nat Med 14:331–336
Kehlet H, Jensen TS, Woolf CJ (2006) Persistent postsurgical pain: risk factors and prevention. Lancet 367:1618–1625
Khan GM, Chen SR, Pan HL (2002) Role of primary afferent nerves in allodynia caused by diabetic neuropathy in rats. Neuroscience 114:291–299
Kim T, Davis J, Zhang AJ, He X, Mathews ST (2009) Curcumin activates AMPK and suppresses gluconeogenic gene expression in hepatoma cells. Biochem Biophys Res Commun 388:377–382
Kim MH, Nahm FS, Kim TK, Chang MJ, Do SH (2014) Comparison of postoperative pain in the first and second knee in staged bilateral total knee arthroplasty: clinical evidence of enhanced pain sensitivity after surgical injury. Pain 155:22–27
King JD Jr, Fitch AC, Lee JK, McCane JE, Mak DO, Foskett JK, Hallows KR (2009) AMP-activated protein kinase phosphorylation of the R domain inhibits PKA stimulation of CFTR. Am J Physiol Cell Physiol 297:C94–C101
King TS, Russe OQ, Moser CV, Ferreiros N, Kynast KL, Knothe C, Olbrich K, Geisslinger G, Niederberger E (2015) AMP-activated protein kinase is activated by non-steroidal anti-inflammatory drugs. Eur J Pharmacol 762:299–305
Klann E, Antion MD, Banko JL, Hou L (2004) Synaptic plasticity and translation initiation. Learn Mem 11:365–372
Koenig E, Giuditta A (1999) Protein-synthesizing machinery in the axon compartment. Neuroscience 89:5–15
Koltzenburg M (1999) The changing sensitivity in the life of the nociceptor. Pain Suppl 6:S93–S102
Kourelis TV, Siegel RD (2012) Metformin and cancer: new applications for an old drug. Med Oncol 29:1314–1327
Laboureyras E, Chateauraynaud J, Richebe P, Simonnet G (2009) Long-term pain vulnerability after surgery in rats: prevention by nefopam, an analgesic with antihyperalgesic properties. Anesth Analg 109:623–631
Latremoliere A, Woolf CJ (2009) Central sensitization: a generator of pain hypersensitivity by central neural plasticity. J Pain 10:895–926
Light PE, Wallace CH, Dyck JR (2003) Constitutively active adenosine monophosphate-activated protein kinase regulates voltage-gated sodium channels in ventricular myocytes. Circulation 107:1962–1965
Lin AC, Holt CE (2008) Function and regulation of local axonal translation. Curr Opin Neurobiol 18:60–68
Liu YC, Berta T, Liu T, Tan PH, Ji RR (2012) Acute morphine induces matrix metalloproteinase-9 up-regulation in primary sensory neurons to mask opioid-induced analgesia in mice. Mol Pain 8:19
Liu J, Chen D, Liu P, He M, Li J, Li J, Hu L (2014) Discovery, synthesis, and structure-activity relationships of 20(S)-protopanaxadiol (PPD) derivatives as a novel class of AMPKalpha2beta1gamma1 activators. Eur J Med Chem 79:340–349
Loo L, Wright BD, Zylka MJ (2015) Lipid kinases as therapeutic targets for chronic pain. Pain 156(Suppl 1):S2–S10
Loram LC, Themistocleous AC, Fick LG, Kamerman PR (2007) The time course of inflammatory cytokine secretion in a rat model of postoperative pain does not coincide with the onset of mechanical hyperalgesia. Can J Physiol Pharmacol 85:613–620
Ma J, Yu H, Liu J, Chen Y, Wang Q, Xiang L (2015) Metformin attenuates hyperalgesia and allodynia in rats with painful diabetic neuropathy induced by Streptozotocin. Eur J Pharmacol 764:599–606
Maixner DW, Yan X, Gao M, Yadav R, Weng HR (2015) Adenosine monophosphate-activated protein kinase regulates interleukin-1 beta expression and glial glutamate transporter function in rodents with neuropathic pain. Anesthesiology 122:1401–1413
Manchikanti L, Vallejo R, Manchikanti KN, Benyamin RM, Datta S, Christo PJ (2011) Effectiveness of long-term opioid therapy for chronic non-cancer pain. Pain Physician 14:E133–E156
Mao-Ying QL, Kavelaars A, Krukowski K, Huo XJ, Zhou W, Price TJ, Cleeland C, Heijnen CJ (2014) The anti-diabetic drug metformin protects against chemotherapy-induced peripheral neuropathy in a mouse model. PLoS One 9, e100701
Martin KC, Barad M, Kandel ER (2000) Local protein synthesis and its role in synapse-specific plasticity. Curr Opin Neurobiol 10:587–592
Martin SW, Butcher AJ, Berrow NS, Richards MW, Paddon RE, Turner DJ, Dolphin AC, Sihra TS, Fitzgerald EM (2006) Phosphorylation sites on calcium channel alpha1 and beta subunits regulate ERK-dependent modulation of neuronal N-type calcium channels. Cell Calcium 39:275–292
Martinez-Outschoorn UE, Trimmer C, Lin Z, Whitaker-Menezes D, Chiavarina B, Zhou J, Wang C, Pavlides S, Martinez-Cantarin MP, Capozza F, Witkiewicz AK, Flomenberg N, Howell A, Pestell RG, Caro J, Lisanti MP, Sotgia F (2010) Autophagy in cancer associated fibroblasts promotes tumor cell survival: Role of hypoxia, HIF1 induction and NFkappaB activation in the tumor stromal microenvironment. Cell Cycle 9:3515–3533
Massard C, Fizazi K, Gross-Goupil M, Escudier B (2010) Reflex sympathetic dystrophy in patients with metastatic renal cell carcinoma treated with Everolimus. Investig New Drugs 28:879–881
McCormack FX et al (2011) Efficacy and safety of Sirolimus in Lymphangioleiomyomatosis. N Engl J Med 364(17):1595–1606
Melemedjian OK, Asiedu MN, Tillu DV, Peebles KA, Yan J, Ertz N, Dussor GO, Price TJ (2010) IL-6- and NGF-induced rapid control of protein synthesis and nociceptive plasticity via convergent signaling to the eIF4F complex. J Neurosci 30:15113–15123
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 (2011) Targeting adenosine monophosphate-activated protein kinase (AMPK) in preclinical models reveals a potential mechanism for the treatment of neuropathic pain. Mol Pain 7:70
Melemedjian OK, Khoutorsky A, Sorge RE, Yan J, Asiedu MN, Valdez A, Ghosh S, Dussor G, Mogil JS, Sonenberg N, Price TJ (2013a) mTORC1 inhibition induces pain via IRS-1-dependent feedback activation of ERK. Pain 154(7):1080–1091
Melemedjian OK, Yassine HN, Shy A, Price TJ (2013b) Proteomic and functional annotation analysis of injured peripheral nerves reveals ApoE as a protein upregulated by injury that is modulated by metformin treatment. Mol Pain 9:14
Melemedjian OK, Tillu DV, Asiedu MN, Mandell EK, Moy JK, Blute VM, Taylor CJ, Ghosh S, Price TJ (2013c) BDNF regulates atypical PKC at spinal synapses to initiate and maintain a centralized chronic pain state. Mol Pain 9:12
Melemedjian OK, Tillu DV, Moy JK, Asiedu MN, Mandell EK, Ghosh S, Dussor G, Price TJ (2014) Local translation and retrograde axonal transport of CREB regulates IL-6-induced nociceptive plasticity. Mol Pain 10:45
Memmott RM, Mercado JR, Maier CR, Kawabata S, Fox SD, Dennis PA (2010) Metformin prevents tobacco carcinogen--induced lung tumorigenesis. Cancer Prev Res (Phila) 3:1066–1076
Mika J (2008) Modulation of microglia can attenuate neuropathic pain symptoms and enhance morphine effectiveness. Pharmacol Rep 60:297–307
Mogil JS (2009) Animal models of pain: progress and challenges. Nat Rev Neurosci 10:283–294
Mohr E, Richter D (2000) Axonal mRNAs: functional significance in vertebrates and invertebrates. J Neurocytol 29:783–791
Molina MG, Diekmann F, Burgos D, Cabello M, Lopez V, Oppenheimer F, Navarro A, Campistol J (2008) Sympathetic dystrophy associated with sirolimus therapy. Transplantation 85:290–292. doi:10.1097/TP.1090b1013e3181601230
Nie H, Weng HR (2009) Glutamate transporters prevent excessive activation of NMDA receptors and extrasynaptic glutamate spillover in the spinal dorsal horn. J Neurophysiol 101:2041–2051
Nie H, Weng HR (2010) Impaired glial glutamate uptake induces extrasynaptic glutamate spillover in the spinal sensory synapses of neuropathic rats. J Neurophysiol 103:2570–2580
Norsted Gregory E, Codeluppi S, Gregory JA, Steinauer J, Svensson CI (2010) Mammalian target of rapamycin in spinal cord neurons mediates hypersensitivity induced by peripheral inflammation. Neuroscience 169:1392–1402
Obara I, Tochiki KK, Geranton SM, Carr FB, Lumb BM, Liu Q, Hunt SP (2011) Systemic inhibition of the mammalian target of rapamycin (mTOR) pathway reduces neuropathic pain in mice. Pain 152:2582–2595
Obara I, Geranton SM, Hunt SP (2012) Axonal protein synthesis: a potential target for pain relief? Curr Opin Pharmacol 12:42–48
Obata K, Noguchi K (2004) MAPK activation in nociceptive neurons and pain hypersensitivity. Life Sci 74:2643–2653
Obata K, Yamanaka H, Dai Y, Tachibana T, Fukuoka T, Tokunaga A, Yoshikawa H, Noguchi K (2003) Differential activation of extracellular signal-regulated protein kinase in primary afferent neurons regulates brain-derived neurotrophic factor expression after peripheral inflammation and nerve injury. J Neurosci 23:4117–4126
Obata K, Yamanaka H, Dai Y, Mizushima T, Fukuoka T, Tokunaga A, Noguchi K (2004a) Differential activation of MAPK in injured and uninjured DRG neurons following chronic constriction injury of the sciatic nerve in rats. Eur J Neurosci 20:2881–2895
Obata K, Yamanaka H, Kobayashi K, Dai Y, Mizushima T, Katsura H, Fukuoka T, Tokunaga A, Noguchi K (2004b) Role of mitogen-activated protein kinase activation in injured and intact primary afferent neurons for mechanical and heat hypersensitivity after spinal nerve ligation. J Neurosci 24:10211–10222
Ouyang J, Parakhia RA, Ochs RS (2011) Metformin activates AMP kinase through inhibition of AMP deaminase. J Biol Chem 286:1–11
Pang T, Zhang ZS, Gu M, Qiu BY, Yu LF, Cao PR, Shao W, Su MB, Li JY, Nan FJ, Li J (2008) Small molecule antagonizes autoinhibition and activates AMP-activated protein kinase in cells. J Biol Chem 283:16051–16060
Pavlides S, Tsirigos A, Migneco G, Whitaker-Menezes D, Chiavarina B, Flomenberg N, Frank PG, Casimiro MC, Wang C, Pestell RG, Martinez-Outschoorn UE, Howell A, Sotgia F, Lisanti MP (2010) The autophagic tumor stroma model of cancer: Role of oxidative stress and ketone production in fueling tumor cell metabolism. Cell Cycle 9:3485–3505
Perl ER (1996) Cutaneous polymodal receptors: characteristics and plasticity. Prog Brain Res 113:21–37
Pinto PR, McIntyre T, Ferrero R, Almeida A, Araujo-Soares V (2013) Risk factors for moderate and severe persistent pain in patients undergoing total knee and hip arthroplasty: a prospective predictive study. PLoS One 8, e73917
Piomelli D, Hohmann AG, Seybold V, Hammock BD (2014) A lipid gate for the peripheral control of pain. J Neurosci 34:15184–15191
Piper M, Holt C (2004) RNA translation in axons. Annu Rev Cell Dev Biol 20:505–523
Pop-Busui RLJ, Lopes N, Jones TL, BARI 2D Investigators (2009) Prevalence of diabetic peripheral neuropathy and relation to glycemic control therapies at baseline in the BARI 2D cohort. J Peripher Nerv Syst 14:1–13
Poulikakos PI, Solit DB (2011) Resistance to MEK inhibitors: should we co-target upstream? Sci Signal 4:pe16
Price TJ, Dussor G (2013) AMPK: An emerging target for modification of injury-induced pain plasticity. Neurosci Lett 557 Pt A:9–18
Price TJ, Geranton SM (2009) Translating nociceptor sensitivity: the role of axonal protein synthesis in nociceptor physiology. Eur J Neurosci 29:2253–2263
Price TJ, Inyang KE (2015) Commonalities between pain and memory mechanisms and their meaning for understanding chronic pain. In: Price TJ, Dussor G (eds) Molecular biology of pain, progress in molecular and translational science. Elsevier: Amsterdam. Prog Mol Biol Transl Sci.131:409–34
Price TJ, Rashid MH, Millecamps M, Sanoja R, Entrena JM, Cervero F (2007) Decreased nociceptive sensitization in mice lacking the fragile X mental retardation protein: role of mGluR1/5 and mTOR. J Neurosci 27:13958–13967
Price TJ, Das V, Dussor G (2016) Adenosine monophosphate-activated protein kinase (AMPK) activators for the prevention, treatment and potential reversal of pathological pain. Curr Drug Targets 17(8):908–920
Pyronnet S, Imataka H, Gingras AC, Fukunaga R, Hunter T, Sonenberg N (1999) Human eukaryotic translation initiation factor 4G (eIF4G) recruits mnk1 to phosphorylate eIF4E. EMBO J 18:270–279
Ramalho TC, Rocha M, da Cunha EF, Freitas MP (2009) The search for new COX-2 inhibitors: a review of 2002–2008 patents. Expert Opin Ther Pat 19:1193–1228
Reichling DB, Levine JD (2009) Critical role of nociceptor plasticity in chronic pain. Trends Neurosci 32:611–618
Roy Chowdhury SK, Smith DR, Saleh A, Schapansky J, Marquez A, Gomes S, Akude E, Morrow D, Calcutt NA, Fernyhough P (2012) Impaired adenosine monophosphate-activated protein kinase signalling in dorsal root ganglia neurons is linked to mitochondrial dysfunction and peripheral neuropathy in diabetes. Brain 135:1751–1766
Ruangsri S, Lin A, Mulpuri Y, Lee K, Spigelman I, Nishimura I (2011) Relationship of axonal voltage-gated sodium channel 1.8 (NaV1.8) mRNA accumulation to sciatic nerve injury-induced painful neuropathy in rats. J Biol Chem 286:39836–39847
Russe OQ, Moser CV, Kynast KL, King TS, Stephan H, Geisslinger G, Niederberger E (2013) Activation of the AMP-activated protein kinase reduces inflammatory nociception. J Pain 14:1330–1340
Sahbaie P, Sun Y, Liang DY, Shi XY, Clark JD (2014) Curcumin treatment attenuates pain and enhances functional recovery after incision. Anesth Analg 118:1336–1344
Sale MJ, Cook SJ (2014) Intrinsic and acquired resistance to MEK1/2 inhibitors in cancer. Biochem Soc Trans 42:776–783
Schrader LA, Birnbaum SG, Nadin BM, Ren Y, Bui D, Anderson AE, Sweatt JD (2006) ERK/MAPK regulates the Kv4.2 potassium channel by direct phosphorylation of the pore-forming subunit. Am J Physiol Cell Physiol 290:C852–C861
Schuman EM, Dynes JL, Steward O (2006) Synaptic regulation of translation of dendritic mRNAs. J Neurosci 26:7143–7146
Sehgal N, Colson J, Smith HS (2013) Chronic pain treatment with opioid analgesics: benefits versus harms of long-term therapy. Expert Rev Neurother 13:1201–1220
Serra J, Bostock H, Sola R, Aleu J, Garcia E, Cokic B, Navarro X, Quiles C (2012) Microneurographic identification of spontaneous activity in C-nociceptors in neuropathic pain states in humans and rats. Pain 153:42–55
Shih MH, Kao SC, Wang W, Yaster M, Tao YX (2012) Spinal cord NMDA receptor-mediated activation of mammalian target of rapamycin is required for the development and maintenance of bone cancer-induced pain hypersensitivities in rats. J Pain 13:338–349
Siddiqui N, Sonenberg N (2015) Signalling to eIF4E in cancer. Biochem Soc Trans 43:763–772
Sisignano M, Parnham MJ, Geisslinger G (2016) Drug repurposing for the development of novel analgesics. Trends Pharmacol Sci 37(3):172–183
Smith B, Ang D (2015) Metformin: potential analgesic? Pain Med 16(12):2256–2260
Sonenberg N (2008) eIF4E, the mRNA cap-binding protein: from basic discovery to translational research. Biochem Cell Biol 86:178–183
Song H, Han Y, Pan C, Deng X, Dai W, Hu L, Jiang C, Yang Y, Cheng Z, Li F, Zhang G, Wu X, Liu W (2015) Activation of adenosine monophosphate-activated protein kinase suppresses neuroinflammation and ameliorates bone cancer pain: involvement of inhibition on mitogen-activated protein kinase. Anesthesiology 123:1170–1185
Sorensen L, Molyneaux L, Yue DK (2006) The relationship among pain, sensory loss, and small nerve fibers in diabetes. Diabetes Care 29:883–887
Spasic MR, Callaerts P, Norga KK (2009) AMP-activated protein kinase (AMPK) molecular crossroad for metabolic control and survival of neurons. Neuroscientist 15:309–316
Stamboulian S, Choi JS, Ahn HS, Chang YW, Tyrrell L, Black JA, Waxman SG, Dib-Hajj SD (2010) ERK1/2 mitogen-activated protein kinase phosphorylates sodium channel Na(v)1.7 and alters its gating properties. J Neurosci 30:1637–1647
Sukhodub A, Jovanovic S, Du Q, Budas G, Clelland AK, Shen M, Sakamoto K, Tian R, Jovanovic A (2007) AMP-activated protein kinase mediates preconditioning in cardiomyocytes by regulating activity and trafficking of sarcolemmal ATP-sensitive K(+) channels. J Cell Physiol 210:224–236
Sun J, Liu S, Mata M, Fink DJ, Hao S (2012) Transgene-mediated expression of tumor necrosis factor soluble receptor attenuates morphine tolerance in rats. Gene Ther 19:101–108
Sun Y, Sahbaie P, Liang D, Li W, Clark JD (2014) Opioids enhance CXCL1 expression and function after incision in mice. J Pain 15:856–866
Sutton MA, Schuman EM (2005) Local translational control in dendrites and its role in long-term synaptic plasticity. J Neurobiol 64:116–131
Taylor A, Westveld AH, Szkudlinska M, Guruguri P, Annabi E, Patwardhan A, Price TJ, Yassine HN (2013) The use of metformin is associated with decreased lumbar radiculopathy pain. J Pain Res 6:755–763
Thakor DK, Lin A, Matsuka Y, Meyer EM, Ruangsri S, Nishimura I, Spigelman I (2009) Increased peripheral nerve excitability and local NaV1.8 mRNA up-regulation in painful neuropathy. Mol Pain 5:14
Tillu DV, Melemedjian OK, Asiedu MN, Qu N, De Felice M, Dussor G, Price TJ (2012) Resveratrol engages AMPK to attenuate ERK and mTOR signaling in sensory neurons and inhibits incision-induced acute and chronic pain. Mol Pain 8:5
Tripodi F, Pagliarin R, Fumagalli G, Bigi A, Fusi P, Orsini F, Frattini M, Coccetti P (2012) Synthesis and biological evaluation of 1,4-diaryl-2-azetidinones as specific anticancer agents: activation of adenosine monophosphate activated protein kinase and induction of apoptosis. J Med Chem 55:2112–2124
Vicier C, Dieci MV, Andre F (2013) New strategies to overcome resistance to mammalian target of rapamycin inhibitors in breast cancer. Curr Opin Oncol 25:587–593
Walters ET, Moroz LL (2009) Molluscan memory of injury: evolutionary insights into chronic pain and neurological disorders. Brain Behav Evol 74:206–218
Watkins LR, Hutchinson MR, Johnston IN, Maier SF (2005) Glia: novel counter-regulators of opioid analgesia. Trends Neurosci 28:661–669
Willis DE, Twiss JL (2006) The evolving roles of axonally synthesized proteins in regeneration. Curr Opin Neurobiol 16:111–118
Willis D, Li KW, Zheng JQ, Chang JH, Smit AB, Kelly T, Merianda TT, Sylvester J, van Minnen J, Twiss JL (2005) Differential transport and local translation of cytoskeletal, injury-response, and neurodegeneration protein mRNAs in axons. J Neurosci 25:778–791
Willis DE, Xu M, Donnelly CJ, Tep C, Kendall M, Erenstheyn M, English AW, Schanen NC, Kirn-Safran CB, Yoon SO, Bassell GJ, Twiss JL (2011) Axonal localization of transgene mRNA in mature PNS and CNS neurons. J Neurosci 31:14481–14487
Witzig TE, Geyer SM, Ghobrial I, Inwards DJ, Fonseca R, Kurtin P, Ansell SM, Luyun R, Flynn PJ, Morton RF, Dakhil SR, Gross H, Kaufmann SH (2005) Phase II trial of single-agent temsirolimus (CCI-779) for relapsed mantle cell lymphoma. J Clin Oncol 23:5347–5356
Woolf CJ (2011) Central sensitization: implications for the diagnosis and treatment of pain. Pain 152:S2–S15
Woolf CJ, Costigan M (1999) Transcriptional and posttranslational plasticity and the generation of inflammatory pain. Proc Natl Acad Sci U S A 96:7723–7730
Woolf CJ, Salter MW (2000) Neuronal plasticity: increasing the gain in pain. Science 288:1765–1769
Woolf CJ, Walters ET (1991) Common patterns of plasticity contributing to nociceptive sensitization in mammals and Aplysia. Trends Neurosci 14:74–78
Wu C, Boustany L, Liang H, Brennan TJ (2007) Nerve growth factor expression after plantar incision in the rat. Anesthesiology 107:128–135
Wu C, Erickson MA, Xu J, Wild KD, Brennan TJ (2009) Expression profile of nerve growth factor after muscle incision in the rat. Anesthesiology 110:140–149
Xiao B, Sanders MJ, Carmena D, Bright NJ, Haire LF, Underwood E, Patel BR, Heath RB, Walker PA, Hallen S, Giordanetto F, Martin SR, Carling D, Gamblin SJ (2013) Structural basis of AMPK regulation by small molecule activators. Nat Commun 4:3017
Xu J, Brennan TJ (2009) Comparison of skin incision vs. skin plus deep tissue incision on ongoing pain and spontaneous activity in dorsal horn neurons. Pain 144:329–339
Xu JT, Zhao X, Yaster M, Tao YX (2010) Expression and distribution of mTOR, p70S6K, 4E-BP1, and their phosphorylated counterparts in rat dorsal root ganglion and spinal cord dorsal horn. Brain Res 1336:46–57
Xu Q, Fitzsimmons B, Steinauer J, Neill AO, Newton AC, Hua XY, Yaksh TL (2011) Spinal phosphinositide 3-kinase-akt-Mammalian target of rapamycin signaling cascades in inflammation-induced hyperalgesia. J Neurosci 31:2113–2124
Xu JT, Zhao JY, Zhao X, Ligons D, Tiwari V, Atianjoh FE, Lee CY, Liang L, Zang W, Njoku D, Raja SN, Yaster M, Tao YX (2014) Opioid receptor-triggered spinal mTORC1 activation contributes to morphine tolerance and hyperalgesia. J Clin Invest 124:592–603
Yoshida H, Bao L, Kefaloyianni E, Taskin E, Okorie U, Hong M, Dhar-Chowdhury P, Kaneko M, Coetzee WA (2012) AMP-activated protein kinase connects cellular energy metabolism to KATP channel function. J Mol Cell Cardiol 52:410–418
Yu S, Shen G, Khor TO, Kim JH, Kong AN (2008) Curcumin inhibits Akt/mammalian target of rapamycin signaling through protein phosphatase-dependent mechanism. Mol Cancer Ther 7:2609–2620
Zahn PK, Subieta A, Park SS, Brennan TJ (2004) Effect of blockade of nerve growth factor and tumor necrosis factor on pain behaviors after plantar incision. J Pain 5:157–163
Zhang LN, Xu L, Zhou HY, Wu LY, Li YY, Pang T, Xia CM, Qiu BY, Gu M, Dong TC, Li JY, Shen JK, Li J (2013) Novel small-molecule AMP-activated protein kinase allosteric activator with beneficial effects in db/db mice. PLoS One 8, e72092
Zhao CM, Guo RX, Hu F, Meng JL, Mo LQ, Chen PX, Liao XX, Cui Y, Feng JQ (2012) Spinal MCP-1 contributes to the development of morphine antinociceptive tolerance in rats. Am J Med Sci 344:473–479
Zheng JQ, Kelly TK, Chang B, Ryazantsev S, Rajasekaran AK, Martin KC, Twiss JL (2001) A functional role for intra-axonal protein synthesis during axonal regeneration from adult sensory neurons. J Neurosci 21:9291–9303
Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, Wu M, Ventre J, Doebber T, Fujii N, Musi N, Hirshman MF, Goodyear LJ, Moller DE (2001) Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 108:1167–1174
Acknowledgements
This work was supported by NIH grants R01NS065926 (TJP), R01GM102575 (TJP and GD), and The University of Texas STARS program (TJP and GD).
The authors declare no conflicts of interest.
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Asiedu, M.N., Dussor, G., Price, T.J. (2016). Targeting AMPK for the Alleviation of Pathological Pain. In: Cordero, M., Viollet, B. (eds) AMP-activated Protein Kinase. Experientia Supplementum, vol 107. Springer, Cham. https://doi.org/10.1007/978-3-319-43589-3_11
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