Early intervention of ERK activation in the spinal cord can block initiation of peripheral nerve injury-induced neuropathic pain in rats

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HAN Mei(Institute of Neurobiology, Institute of Brain Science and State Key Laboratory of Medical Neurobiology, Shanghai Medical College, Fudan University, Shanghai 200032, China)
HUANG Ru-Yi(Department of Life Science, Fudan University, Shanghai 200433, China)
DU Yi-Min(Department of Life Science, Fudan University, Shanghai 200433, China)
ZHAO Zhi-Qi(Institute of Neurobiology, Institute of Brain Science and State Key Laboratory of Medical Neurobiology, Shanghai Medical College, Fudan University, Shanghai 200032, China)
ZHANG Yu-Qiu(Institute of Neurobiology, Institute of Brain Science and State Key Laboratory of Medical Neurobiology, Shanghai Medical College, Fudan University, Shanghai 200032, China)
Journal Title:
Volume 63, Issue 02, 2011
Key Word:
allodynia;hyperalgesia;ERK-CREB signaling pathway;early intervention;spinal cord;rats

Abstract: The present study is to investigate whether the extracellular signal-regulated kinase (ERK) and cAMP response element binding protein (CREB) signaling pathway contributes to the initiation of chronic constriction injury (CCI)-induced neuropathic pain in rats. Mechanical allodynia was assessed by measuring the hindpaw withdrawal threshold in response to a calibrated series of von Frey hairs. Thermal hyperalgesia was assessed by measuring the latency of paw withdrawal in response to a radiant heat source. The expressions of phosphor-ERK (pERK) and phosphor-CREB (pCREB) were examined using Western blot analysis and immunohistochemistry. An early robust increase in the expression of pERK on the spinal cords ipsilateral to injury was observed on day 1 after CCI, when the CCl-induced behavioral hypersensitivity had not developed yet. Moreover, the upregulation of pERK expression in ip-silateral spinal cord was associated with the increase in pCREB expression in bilateral spinal cord. Intrathecal administration of mito-gen-activated protein kinase kinase (MEK) inhibitor U0126 before CCI can efficiently block and delay the CCl-induced mechanical allodynia and thermal hyperalgesia. These data suggest that activation of ERK and CREB in the spinal cord contributes to the initia-tion of peripheral nerve injury-induced pain hypersensitivity, and an early intervention strategy should be proposed.

  • [1]Millan MJ.The induction of pain:an integrative review.Prog Neurobiol 1999; 57(1):1-164.
  • [2]Woolf CJ.Evidence for a central component of post-injury pain hypersensitivity.Nature 1983; 306(5944):686-688.
  • [3]Laird J M,Bennett GJ.An electrophysiological study of dorsal horn neurons in the spinal cord of rats with an experimental peripheral neuropathy.J Neurophysiol 1993; 69(6):2072-2085.
  • [4]Dalai A,Tata M,Allegre G,Gekiere F,Bons N,Albe-Fessard D.Spontaneous activity of rat dorsal horn cells in spinal segments of sciatic projection following transection of sciatic nerve or of corresponding dorsal roots.Neuroscience 1999;94(1):217-228.
  • [5]Kohno T,Moore KA,Baba H,Woolf CJ.Peripheral nerve injury alters excitatory synaptic transmission in lamina Ⅱ of the rat dorsal horn.J Physio12003; 548(Pt 1):131-138.
  • [6]Woolf CJ,Mannion RJ.Neuropathic pain:aetiology,symptoms,mechanisms,and management.Lancet 1999;353(9168):1959-1964.
  • [7]Jensen TS,Baron R.Translation of symptoms and signs into mechanisms in neuropathic pain.Pain 2003; 102(1-2):1-8.
  • [8]Zimmermann M.Pathobiology of neuropthic pain.Eur J Pharmaco1 2001; 429(1-3):23-37.
  • [9]Boulton TG,Nye SH,Robbins DJ,Ip NY,Radziejewska E,Morgenbesser SD,DePinho RA,Panayotatos N,Cobb MH,Yancopoulos GD.ERKs:a family of protein-serine/threonine kinases that are activated and tyrosine phosphorylated in response to insulin and NGF.Cell 1991; 65(4):663-675.
  • [10]Rosen LB,Ginty DD,Weber MJ,Greenberg ME.Membrane depolarization and calcium influx stimulate MEK and MAP kinase via activation of Ras.Neuron 1994; 12(6):1207-1221.
  • [11]Impey S,Obrietan K,Storm DR.Making new connections:role of ERK/MAP kinase signaling in neuronal plasticity.Neuron 1999; 23(1):11-14.
  • [12]Sweatt JD.The neuronal MAP kinase cascade:a biochemical signal integration system subserving synaptic plasticity and memory.J Neurochem 2001; 76(1):1-10.
  • [13]Impey S,Obrietan K,Wong ST,Poser S,Yano S,Wayman G,Deloulme JC,Chan G,Storm DR.Cross talk between ERK and PKA is required for Ca2+ stimulation of CREB-dependent transcription and ERK nuclear translocation.Neuron 1998; 21(4):869-883.
  • [14]Obrietan K,Impey S,Smith D,Athos J,Storm DR.Circadian regulation of cAMP response element-mediated gene expression in the suprachiasmatic nuclei.J Biol Chem 1999;274(25):17748-17756.
  • [15]Ji RR,Baba H,Brenner GJ,WoolfCJ.Nociceptive-specific activation of ERK in spinal neurons contributes to pain hypersensitivity.Nat Neurosci 1999; 2(12):1114-1119.
  • [16]Karim F,Wang CC,Gereau RWt.Metabotropic glutamate receptor subtypes I and 5 are activators of extracellular signal-regulated kinase signaling required for inflammatory pain in mice.J Neurosci 2001; 21 (11):3771-3779.
  • [17]Woolf C J,Salter MW.Neuronal plasticity:increasing the gain in pain.Science 2000; 288(5472):1765-1769.
  • [18]Ji RR,Kohno T,Moore KA,Woolf CJ.Central sensitization and LTP:do pain and memory share similar mechanisms?Trends Neurosci 2003; 26(12):696-705.
  • [19]Ji RR,Befort K,Brenner GJ,Woolf CJ.ERK MAP kinase activation in superficial spinal cord neurons induces prodynorphin and NK-I upregulation and contributes to persistent inflammatory pain hypersensitivity.J Neurosci 2002;22(2):478-485.
  • [20]Galan A,Lopez-Garcia JA,Cervero F,Laird JM.Activation of spinal extracellular signaling-regulated kinase-1 and -2 by intraplantar earrageenan in rodents.Neurosci Lett 2002;322(1):37-40.
  • [21]Dai Y,Iwata K,Fukuoka T,Kondo E,Tokunaga A,Yamanaka H,Tachibana T,Liu Y,Noguchi K.Phosphorylation of extracellular signal-regulated kinase in primary afferent neurons by noxious stimuli and its involvement in peripheral sensitization.J Neurosci 2002; 22(17):7737-7745.
  • [22]Cruz CD,Nero FL,Castro-Lopes J,McMahon SB,Cruz F.Inhibition of ERK phosphorylation decreases nociceptive behaviour in monoarthritic rats.Pain 2005; 116(3):411-419.
  • [23]Xu Q,Garraway SM,Weyerbacher AR,Shin S J,Inturrisi CE.Activation of the neuronal extracellular signal-regulated kinase 2 in the spinal cord dorsal horn is required for complete Freund's adjuvant-induced pain hypersensitivity.J Neurosci 2008; 28(52):14087-14096.
  • [24]Kiguchi N,Maeda T,Kobayashi Y,Fukazawa Y,Kishioka S.Activation of extracellular signal-regulated kinase in sciatic nerve contributes to neuropathic pain after partial sciatic nerve ligation in mice.Anesth Analg 2009; 109(4):1305-1311.
  • [25]Ma W,Quirion R.Partial sciatic nerve ligation induces increase in the phosphorylation of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) in astrocytes in the lumbar spinal dorsal horn and the gracile nucleus.Pain 2002; 99(1-2):175-184.
  • [26]Zhuang ZY,Gerner P,Woolf C J,Ji RR.ERK is sequentially activated in neurons,microglia,and astrocytes by spinal nerve ligation and contributes to mechanical allodynia in this neuropathic pain model.Pain 2005; 114(1-2):149-159.
  • [27]Ciruela A,Dixon AK,Bramwell S,Gonzalez MI,Pinnock RD,Lee K.Identification of MEKI as a novel target for the treatment ofneuropathic pain.Br J Pharmacol 2003; 138(5):751-756.
  • [28]Song XS,Cao JL,Xu YB,He JI-I,Zhang LC,Zeng YM.Activation of ERK/CREB pathway in spinal cord contributes to chronic constrictive injury-induced neuropathic pain in rats.Acta Pharmacol Sin 2005; 26(7):789-798.
  • [29]Karim F,Hu H J,Adwanikar H,Kaplan D,Gereau RWt.Impaired inflammatory pain and thermal hyperalgesia in miceexpressing neuron-specific dominant negative mitogen activated protein kinase kinase (MEK).Mol Pain 2006; 2:2.
  • [30]Zhao P,Waxman SG,Hains BC.Extracellular signal-regulated kinase-regulated microglia-neuron signaling by prostaglandin E2 contributes to pain after spinal cord injury.J Neurosci 2007; 27(9):2357-2368.
  • [31]Bennett GJ,Xie YK.A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man.Pain 1988; 33(1):87-107.
  • [32]Ji RR,Gereau RWt,Malcangio M,Strichartz GR.MAP kinase and pain.Brain Res Rev 2009; 60(1):135-148.
  • [33]Riccio A,Pierchala BA,Ciarallo CL,Ginty DD.An NGFTrkA-mediated retrograde signal to transcription factor CREB in sympathetic neurons.Science 1997; 277(5329):1097-1100.
  • [34]Riccio A,Alan S,Davenport CM,Blendy JA,Ginty DD.Mediation by a CREB family transcription factor of NGF-dependent survival of sympathetic neurons.Science 1999;286(5448):2358-2361.
  • [35]Ji RR,Strichartz G.Cell signaling and the genesis of neuropathic pain.Sci STKE 2004; 2004(252):reE14.
  • [36]Pang XY,Liu T,Jiang F,Ji YH.Activation of spinal ERK signaling pathway contributes to pain-related responses induced by scorpion Buthus martensi Karch venom.Toxicon 2008; 51(6):994-1007.
  • [37]Crown ED,Ye Z,Johnson KM,Xu GY,McAdoo DJ,Hulsebosch CE.Increases in the activated forms of ERK 1/2,p38 MAPK,and CREB are correlated with the expression of atlevel mechanical allodynia following spinal cord injury.Exp Neurol 2006; 199(2):397-407.
  • [38]Kawasaki Y,Kohno T,Ji RR.Different effects of opioid and cannabinoid receptor agonists on C-fiber-induced extracelluIar signal-regulated kinase activation in dorsal horn neurons in normal and spinal nerve-ligated rats.J Pharmacol Exp Ther 2006; 316(2):601-607.
  • [39]Obata K,Yamanaka H,Kobayashi K,Dai Y,Mizushima T,Katsura H,Fukuoka T,Tokunaga A,Noguchi K.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 2004;24(45):10211-10222.
  • [40]Yu YQ,Chen J.Activation of spinal extracellular signalingregulated kinases by intraplantar melittin injection.Neurosci Lett 2005; 381(1-2):194-198.
  • [41]onze BE,Ginty DD.Function and regulation of CREB family transcription factors in the nervous system.Neuron 2002; 35(4):605-623.
  • [42]Lee KM,Jeon SM,Cho HJ.Interleukin-6 induces microglial CX3CR1 expression in the spinal cord after peripheral nerve injury through the activation of p38 MAPK.Eur J Pain 2010; 14(7):682.e1-682.e12.
  • [43]Wen YR,Suter MR,Ji RR,Yeh GC,Wu YS,Wang KC,Kohno T,Sun WZ,Wang CC.Activation of p38 mitogen-activated protein kinase in spinal microglia contributes to incision-induced mechanical allodynia.Anesthesiology 2009;110(1):155-165.
  • [44]Cui XY,Dai Y,Wang SL,Yamanaka H,Kobayashi K,Obata K,Chert J,Noguchi K.Differential activation of p38 and extracellular signal-regulated kinase in spinal cord in a model of bee venom-induced inflammation and hyperalgesia.MolPain 2008; 4:17.
  • [45]Jin SX,Zhuang ZY,Woolf CJ,Ji RR.p38 mitogen-activated protein kinase is activated after a spinal nerve ligation in spinal cord microglia and dorsal root ganglion neurons and contributes to the generation of neuropathic pain.J Neurosci 2003; 23(10):4017-4022.
  • [46]Wen YR,Suter MR,Kawasaki Y,Huang J,Pertin M,Kohno T,Berde CB,Decosterd I,Ji RR.Nerve conduction blockade in the sciatic nerve prevents but does not reverse the activation of p38 mitogen-activated protein kinase in spinal microglia in the rat spared nerve injury model.Anesthesiology 2007; 107(2):312-321.
  • [47]Clark AK,Yip PK,Grist J,Gentry C,Staniland AA,Marchand F,Dehvari M,Wotherspoon G,Winter J,Ullah J,Bevan S,Malcangio M.Inhibition of spinal microglial cathepsin S for the reversal of neuropathic pain.Proc Natl Acad Sci U S A 2007; 100(25):10655-10660.
  • [48]Hains BC,Waxman SG.Activated microglia contribute to the maintenance of chronic pain after spinal cord injury.J Neurosci 2006; 26(16):4308-4317.
  • [49]Miiligan ED,Twining C,Chacur M,Biedenkapp J,O'Connor K,Poole S,Tracey K,Martin D,Maier SF,Watkins LR.Spinal glia and proinflammatory cytokines mediate mirror-image neuropathic pain in rats.J Neurosci 2003; 23(3):1026-1040.
  • [50]Tsuda M,Mizokoshi A,Shigemoto-Mogami Y,Koizumi S,Inoue K.Activation of p38 mitogen-activated protein kinase in spinal hyperactive microglia contributes to pain hypersensitivity following peripheral nerve injury.Glia 2004; 45(1):89-95.
  • [51]Ji RR,Rupp F.Phosphorylation of transcription factor CREB in rat spinal cord after formalin-induced hyperalgesia:relationship to c-los induction.J Neurosci 1997; 17(5):1776-1785.
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