Metabolic Brain Disease

, Volume 30, Issue 3, pp 645–658 | Cite as

Spinal cord injury induced neuropathic pain: Molecular targets and therapeutic approaches

  • Dominic Schomberg
  • Gurwattan Miranpuri
  • Tyler Duellman
  • Andrew Crowell
  • Raghu Vemuganti
  • Daniel Resnick
Review Article


Neuropathic pain, especially that resulting from spinal cord injury, is a tremendous clinical challenge. A myriad of biological changes have been implicated in producing these pain states including cellular interactions, extracellular proteins, ion channel expression, and epigenetic influences. Physiological consequences of these changes are varied and include functional deficits and pain responses. Developing therapies that effectively address the cause of these symptoms require a deeper knowledge of alterations in the molecular pathways. Matrix metalloproteinases and tissue inhibitors of metalloproteinases are two promising therapeutic targets. Matrix metalloproteinases interact with and influence many of the studied pain pathways. Gene expression of ion channels and inflammatory mediators clearly contributes to neuropathic pain. Localized and time dependent targeting of these proteins could alleviate and even prevent neuropathic pain from developing. Current therapeutic options for neuropathic pain are limited primarily to analgesics targeting the opioid pathway. Therapies directed at molecular targets are highly desirable and in early stages of development. These include transplantation of exogenously engineered cell populations and targeted gene manipulation. This review describes specific molecular targets amenable to therapeutic intervention using currently available delivery systems.


Spinal cord injury Neuropathic pain Matrix metalloproteinase TIMPs Gene therapy Somatic cell genomic editing 



The authors are thankful to Dr. Jay Yang, Professor, Department of Anesthesiology, University of Wisconsin School of Medicine and Public Health, Madison, WI for initial guidance to write this review. Scholarly assistance from Hung Tae Kim, Carrie Nacht, and Steven Siegel is duly acknowledged. All work was funded through the UW Madison Department of Neurological Surgery. The authors declare that they have no conflicts of interest. The manuscript does not contain clinical studies of patient data.


  1. Abdellatif AA et al (2006) Gene delivery to the spinal cord: Comparison between lentiviral, adenoviral, and retroviral vector delivery systems. J Neurosci Res 84:553–567. doi: 10.1002/jnr.20968 PubMedCentralPubMedGoogle Scholar
  2. Ahmed MM et al (2010) Cannabinoid subtype-2 receptors modulate the antihyperalgesic effect of WIN 55,212-2 in rats with neuropathic spinal cord injury pain. Spine J 10:1049–1054. doi: 10.1016/j.spinee.2010.08.015 PubMedGoogle Scholar
  3. Aldieri E, Atragene D, Bergandi L, Riganti C, Costamagna C, Bosia A, Ghigo D (2003) Artemisinin inhibits inducible nitric oxide synthase and nuclear factor NF-kB activation. FEBS Lett 552:141–144PubMedGoogle Scholar
  4. Al-Dosari MS, Gao X (2009) Nonviral gene delivery: Principle, limitations, and recent progress. AAPS J 11:671–681. doi: 10.1208/s12248-009-9143-y PubMedCentralPubMedGoogle Scholar
  5. Aley KO, Levine JD (2002) Different peripheral mechanisms mediate enhanced nociception in metabolic/toxic and traumatic painful peripheral neuropathies in the rat. Neuroscience 111:389–397PubMedGoogle Scholar
  6. Arai S et al (2008) Induction of inducible nitric oxide synthase and apoptosis by LPS and TNF-alpha in nasal microvascular endothelial cells. Acta Otolaryngol 128:78–85. doi: 10.1080/00016480701361962 PubMedGoogle Scholar
  7. Arkin MR, Wells JA (2004) Small-molecule inhibitors of protein-protein interactions: Progressing towards the dream Nature reviews. Drug Disc 3:301–317. doi: 10.1038/nrd1343 Google Scholar
  8. Barres BA (2008) The mystery and magic of glia: A perspective on their roles in health and disease. Neuron 60:430–440. doi: 10.1016/j.neuron.2008.10.013 PubMedGoogle Scholar
  9. Basbaum AI (1999) Spinal mechanisms of acute and persistent pain. Reg Anesth Pain Med 24:59–67PubMedGoogle Scholar
  10. Bhalala OG, Srikanth M, Kessler JA (2013) The emerging roles of microRNAs in CNS injuries. Nat Rev Neurol 9:328–339. doi: 10.1038/nrneurol.2013.67 PubMedCentralPubMedGoogle Scholar
  11. Bikkavilli RK, Malbon CC (2009) Mitogen-activated protein kinases and Wnt/beta-catenin signaling: Molecular conversations among signaling pathways. Commun Integr Biol 2:46–49PubMedCentralPubMedGoogle Scholar
  12. Bogdanove AJ, Voytas DF (2011) TAL effectors: customizable proteins for DNA targeting. Science 333:1843–1846. doi: 10.1126/science.1204094 PubMedGoogle Scholar
  13. Boivie J (1989) On central pain and central pain mechanisms. Pain 38:121–122PubMedGoogle Scholar
  14. Borregaard N, Sorensen OE, Theilgaard-Monch K (2007) Neutrophil granules: A library of innate immunity proteins. Trends Immunol 28:340–345. doi: 10.1016/ PubMedGoogle Scholar
  15. Boulenguez P et al (2010) Down-regulation of the potassium-chloride cotransporter KCC2 contributes to spasticity after spinal cord injury. Nat Med 16:302–307. doi: 10.1038/nm.2107 PubMedGoogle Scholar
  16. Bowery NG, Hudson AL, Price GW (1987) GABAA and GABAB receptor site distribution in the rat central nervous system. Neuroscience 20:365–383PubMedGoogle Scholar
  17. Brew K, Nagase H (2010) The tissue inhibitors of metalloproteinases (TIMPs): An ancient family with structural and functional diversity. Biochim Biophys Acta 1803:55–71. doi: 10.1016/j.bbamcr.2010.01.003 PubMedCentralPubMedGoogle Scholar
  18. Brew K, Dinakarpandian D, Nagase H (2000) Tissue inhibitors of metalloproteinases: Evolution, structure and function. Biochim Biophys Acta 1477:267–283PubMedGoogle Scholar
  19. Brewer KL, Nolan TA (2007) Spinal and supraspinal changes in tumor necrosis factor-alpha expression following excitotoxic spinal cord injury. J Mol Neurosci 31:13–21PubMedGoogle Scholar
  20. Broverman RL et al (1998) Changes in the expression of extracellular matrix (ECM) and matrix metalloproteinases (MMP) of proliferating rat parotid acinar cells. J Dent Res 77:1504–1514PubMedGoogle Scholar
  21. Burzynski SR (2005) Aging: Gene silencing or gene activation. Med Hypotheses 64:201–208. doi: 10.1016/j.mehy.2004.06.010 PubMedGoogle Scholar
  22. Busch SA et al (2011) Multipotent adult progenitor cells prevent macrophage-mediated axonal dieback and promote regrowth after spinal cord injury. J Neurosci Off J Soc Neurosci 31:944–953. doi: 10.1523/JNEUROSCI. 3566-10.2011 Google Scholar
  23. Buss A, Pech K, Kakulas BA, Martin D, Schoenen J, Noth J, Brook GA (2007) Matrix metalloproteinases and their inhibitors in human traumatic spinal cord injury. BMC Neurol 7:17. doi: 10.1186/1471-2377-7-17 PubMedCentralPubMedGoogle Scholar
  24. Butovsky O et al (2006) Microglia activated by IL-4 or IFN-gamma differentially induce neurogenesis and oligodendrogenesis from adult stem/progenitor cells. Mol Cell Neurosci 31:149–160. doi: 10.1016/j.mcn.2005.10.006 PubMedGoogle Scholar
  25. Cermak T et al (2011) Efficient design and assembly of custom TALEN and other TAL effector-based constructs for DNA targeting. Nucleic Acids Res 39:e82. doi: 10.1093/nar/gkr218 PubMedCentralPubMedGoogle Scholar
  26. Chang DI, Hosomi N, Lucero J, Heo JH, Abumiya T, Mazar AP, del Zoppo GJ (2003) Activation systems for latent matrix metalloproteinase-2 are upregulated immediately after focal cerebral ischemia. J Cereb Blood Flow Metab 23:1408–1419. doi: 10.1097/01.WCB.0000091765.61714.30 PubMedGoogle Scholar
  27. Chang N et al (2013) Genome editing with RNA-guided Cas9 nuclease in zebrafish embryos. Cell Res 23:465–472. doi: 10.1038/cr.2013.45 PubMedCentralPubMedGoogle Scholar
  28. Chatzipanteli K, Garcia R, Marcillo AE, Loor KE, Kraydieh S, Dietrich WD (2002) Temporal and segmental distribution of constitutive and inducible nitric oxide synthases after traumatic spinal cord injury: effect of aminoguanidine treatment. J Neurotrauma 19:639–651. doi: 10.1089/089771502753754109 PubMedGoogle Scholar
  29. Chen ZY, He CY, Ehrhardt A, Kay MA (2003) Minicircle DNA vectors devoid of bacterial DNA result in persistent and high-level transgene expression in vivo Molecular therapy. J Am Soc Gene Ther 8:495–500Google Scholar
  30. Chernov AV, Strongin AY (2011) Epigenetic regulation of matrix metalloproteinases and their collagen substrates in cancer. Biomol concepts 2:135–147. doi: 10.1515/BMC.2011.017 PubMedCentralPubMedGoogle Scholar
  31. Chicoine E, Esteve PO, Robledo O, Van Themsche C, Potworowski EF, St-Pierre Y (2002) Evidence for the role of promoter methylation in the regulation of MMP-9 gene expression. Biochem Biophys Res Commun 297:765–772PubMedGoogle Scholar
  32. Cho SW, Kim S, Kim JM, Kim JS (2013) Targeted genome engineering in human cells with the Cas9 RNA-guided endonuclease. Nat Biotechnol 31:230–232. doi: 10.1038/nbt.2507 PubMedGoogle Scholar
  33. Choi EM, Lee YS (2010) Luteolin suppresses IL-1beta-induced cytokines and MMPs production via p38 MAPK, JNK, NF-kappaB and AP-1 activation in human synovial sarcoma cell line, SW982. Food Chem Toxicol 48:2607–2611. doi: 10.1016/j.fct.2010.06.029 PubMedGoogle Scholar
  34. Christoph T, Schiene K, Englberger W, Parsons CG, Chizh BA (2006) The antiallodynic effect of NMDA antagonists in neuropathic pain outlasts the duration of the in vivo NMDA antagonism. Neuropharmacol 51:12–17. doi: 10.1016/j.neuropharm.2006.02.007 Google Scholar
  35. Cong L (2013) Multiplex genome engineering using CRISPR/Cas systems. Science 339:819–823. doi: 10.1126/science.1231143 PubMedCentralPubMedGoogle Scholar
  36. Conti A, Miscusi M, Cardali S, Germano A, Suzuki H, Cuzzocrea S, Tomasello F (2007) Nitric oxide in the injured spinal cord: Synthases cross-talk, oxidative stress and inflammation. Brain Res Rev 54:205–218PubMedGoogle Scholar
  37. Cortright DN, Szallasi A (2004) Biochemical pharmacology of the vanilloid receptor TRPV1. Eur J Biochem 271:1814–1819. doi: 10.1111/j.1432-1033.2004.04082.x PubMedGoogle Scholar
  38. Couture R, Harrisson M, Vianna RM, Cloutier F (2001) Kinin receptors in pain and inflammation. Eur J Pharmacol 429:161–176PubMedGoogle Scholar
  39. Cramer SW et al (2008) The role of cation-dependent chloride transporters in neuropathic pain following spinal cord injury. Mol Pain 4:36. doi: 10.1186/1744-8069-4-36 PubMedCentralPubMedGoogle Scholar
  40. Dayton RD, Wang DB, Klein RL (2012) The advent of AAV9 expands applications for brain and spinal cord gene delivery. Expert Opin Biol Ther 12:757–766. doi: 10.1517/14712598.2012.681463 PubMedCentralPubMedGoogle Scholar
  41. de Castro RC Jr, Burns CL, McAdoo DJ, Romanic AM (2000) Metalloproteinase increases in the injured rat spinal cord. NeuroReport 11:3551–3554PubMedGoogle Scholar
  42. Dery MA, Rousseau G, Benderdour M, Beaumont E (2009) Atorvastatin prevents early apoptosis after thoracic spinal cord contusion injury and promotes locomotion recovery. Neurosci Lett 453:73–76. doi: 10.1016/j.neulet.2009.01.062 PubMedGoogle Scholar
  43. Detloff MR, Fisher LC, McGaughy V, Longbrake EE, Popovich PG, Basso DM (2008) Remote activation of microglia and pro-inflammatory cytokines predict the onset and severity of below-level neuropathic pain after spinal cord injury in rats. Exp Neurol 212:337–347. doi: 10.1016/j.expneurol.2008.04.009 PubMedCentralPubMedGoogle Scholar
  44. Devor M (2006) Sodium channels and mechanisms of neuropathic pain. J Pain 7:S3–S12. doi: 10.1016/j.jpain.2005.09.006 PubMedGoogle Scholar
  45. Dickenson AH, Sullivan AF (1987) Evidence for a role of the NMDA receptor in the frequency dependent potentiation of deep rat dorsal horn nociceptive neurones following C fibre stimulation. Neuropharmacol 26:1235–1238Google Scholar
  46. Ding YH, Li J, Rafols JA, Ding Y (2004) Reduced brain edema and matrix metalloproteinase (MMP) expression by pre-reperfusion infusion into ischemic territory in rat. Neurosci Lett 372:35–39. doi: 10.1016/j.neulet.2004.09.010 PubMedGoogle Scholar
  47. DomBourian MG, Turner NA, Gerovac TA, Vemuganti R, Miranpuri GS, Türeyen K, Satriotomo I, Miletic V, Resnick DK (2006) B1 and TRPV-1 receptor genes and their relationship to hyperalgesia following spinal cord injury. Spine 31:2778–2782. doi: 10.1097/01.brs.0000245865.97424.b4
  48. Donnelly DJ, Popovich PG (2008) Inflammation and its role in neuroprotection, axonal regeneration and functional recovery after spinal cord injury. Exp Neurol 209:378–388. doi: 10.1016/j.expneurol.2007.06.009 PubMedCentralPubMedGoogle Scholar
  49. Doyle EL, Booher NJ, Standage DS, Voytas DF, Brendel VP, Vandyk JK, Bogdanove AJ (2012) TAL Effector-Nucleotide Targeter (TALE-NT) 2.0: Tools for TAL effector design and target prediction. Nucleic Acids Res 40:W117–122. doi: 10.1093/nar/gks608 PubMedCentralPubMedGoogle Scholar
  50. Duellman T, Warren CL, Peissig P, Wynn M, Yang J (2012) Matrix metalloproteinase-9 genotype as a potential genetic marker for abdominal aortic aneurysm. Circ Cardiovasc Genet 5:529–537. doi: 10.1161/CIRCGENETICS.112.963082 PubMedCentralPubMedGoogle Scholar
  51. Duellman T, Warren C, Yang J (2014) Single nucleotide polymorphism-specific regulation of matrix metalloproteinase-9 by multiple miRNAs targeting the coding exon. Nucleic Acids Res. doi: 10.1093/nar/gku197 PubMedCentralPubMedGoogle Scholar
  52. Dziembowska M, Wlodarczyk J (2012) MMP9: A novel function in synaptic plasticity. Int J Biochem Cell Biol 44:709–713. doi: 10.1016/j.biocel.2012.01.023 PubMedGoogle Scholar
  53. Dzwonek J, Rylski M, Kaczmarek L (2004) Matrix metalloproteinases and their endogenous inhibitors in neuronal physiology of the adult brain. FEBS Lett 567:129–135. doi: 10.1016/j.febslet.2004.03.070 PubMedGoogle Scholar
  54. Eaton MJ, Martinez MA, Karmally S (1999) A single intrathecal injection of GABA permanently reverses neuropathic pain after nerve injury. Brain Res 835:334–339PubMedGoogle Scholar
  55. Ehrhart J et al (2005) Stimulation of cannabinoid receptor 2 (CB2) suppresses microglial activation. J Neuroinflammation 2:29. doi: 10.1186/1742-2094-2-29 PubMedCentralPubMedGoogle Scholar
  56. Esposito E, Genovese T, Caminiti R, Bramanti P, Meli R, Cuzzocrea S (2008) Melatonin regulates matrix metalloproteinases after traumatic experimental spinal cord injury. J Pineal Res 45:149–156. doi: 10.1111/j.1600-079X.2008.00569.x PubMedGoogle Scholar
  57. Estella C, Herrer I, Atkinson SP, Quinonero A, Martinez S, Pellicer A, Simon C (2012) Inhibition of histone deacetylase activity in human endometrial stromal cells promotes extracellular matrix remodelling and limits embryo invasion. PLoS ONE 7:e30508. doi: 10.1371/journal.pone.0030508 PubMedCentralPubMedGoogle Scholar
  58. Fairbanks CA et al (2000) Agmatine reverses pain induced by inflammation, neuropathy, and spinal cord injury. Proc Natl Acad Sci U S A 97:10584–10589PubMedCentralPubMedGoogle Scholar
  59. Federici T et al (2012) Robust spinal motor neuron transduction following intrathecal delivery of AAV9 in pigs. Gene Ther 19:852–859. doi: 10.1038/gt.2011.130 PubMedGoogle Scholar
  60. Fehlings MG, Wilson JR, O’Higgins M (2012) Introduction: Spinal cord injury at the cutting edge of clinical translation: a focus issue collaboration between NACTN and AOSpine. N Am J Neurosurg Spine 17:1–3. doi: 10.3171/2012.6.AOSPINE12632 Google Scholar
  61. Feldblum S, Arnaud S, Simon M, Rabin O, D’Arbigny P (2000) Efficacy of a new neuroprotective agent, gacyclidine, in a model of rat spinal cord injury. J Neurotrauma 17:1079–1093PubMedGoogle Scholar
  62. Ferreira J, Beirith A, Mori MA, Araujo RC, Bader M, Pesquero JB, Calixto JB (2005) Reduced nerve injury-induced neuropathic pain in kinin B1 receptor knock-out mice. J Neurosci 25:2405–2412. doi: 10.1523/JNEUROSCI. 2466-04.2005 PubMedGoogle Scholar
  63. Fleming JC (2006) The cellular inflammatory response in human spinal cords after injury. Brain 129:3249–3269. doi: 10.1093/brain/awl296 PubMedGoogle Scholar
  64. Fleming J, Ginn SL, Weinberger RP, Trahair TN, Smythe JA, Alexander IE (2001) Adeno-associated virus and lentivirus vectors mediate efficient and sustained transduction of cultured mouse and human dorsal root ganglia sensory neurons. Human Gene Ther 12:77–86. doi: 10.1089/104303401450997 Google Scholar
  65. Foust KD, Nurre E, Montgomery CL, Hernandez A, Chan CM, Kaspar BK (2009) Intravascular AAV9 preferentially targets neonatal neurons and adult astrocytes. Nat Biotechnol 27:59–65. doi: 10.1038/nbt.1515 PubMedCentralPubMedGoogle Scholar
  66. Franz S, Weidner N, Blesch A (2012) Gene therapy approaches to enhancing plasticity and regeneration after spinal cord injury. Exp Neurol 235:62–69. doi: 10.1016/j.expneurol.2011.01.015 PubMedCentralPubMedGoogle Scholar
  67. Fujimoto M et al (2008) Tissue inhibitor of metalloproteinases protect blood–brain barrier disruption in focal cerebral ischemia. J Cereb Blood Flow Metab 28:1674–1685. doi: 10.1038/jcbfm.2008.59 PubMedGoogle Scholar
  68. Fujioka H, Dairyo Y, Yasunaga K, Emoto K (2012) Neural functions of matrix metalloproteinases: plasticity, neurogenesis, and disease Biochem Res Int 2012:789083 doi:10.1155/2012/789083Google Scholar
  69. Gavva NR, Tamir R, Klionsky L, Norman MH, Louis JC, Wild KD, Treanor JJ (2005) Proton activation does not alter antagonist interaction with the capsaicin-binding pocket of TRPV1. Mol Pharmacol 68:1524–1533. doi: 10.1124/mol.105.015727 PubMedGoogle Scholar
  70. Genda Y, Arai M, Ishikawa M, Tanaka S, Okabe T, Sakamoto A (2013) microRNA changes in the dorsal horn of the spinal cord of rats with chronic constriction injury: A TaqMan(R) low density array study. Int J Mol Med 31:129–137. doi: 10.3892/ijmm.2012.1163 PubMedGoogle Scholar
  71. Gilroy DW, Tomlinson A, Willoughby DA (1998) Differential effects of inhibition of isoforms of cyclooxygenase (COX-1, COX-2) in chronic inflammation. Inflamm Res 47:79–85PubMedGoogle Scholar
  72. Gimenez-Mila M, Busquets C, Ojeda A, Fauli A, Moreno LA, Videla S (2014) Neuropathic pain with features of complex regional syndrome in the upper extremity after herpes zoster. Pain Pract 14:158–161. doi: 10.1111/papr.12028 PubMedGoogle Scholar
  73. Giovanini MA, Reier PJ, Eskin TA, Wirth E, Anderson DK (1997) Characteristics of human fetal spinal cord grafts in the adult rat spinal cord: influences of lesion and grafting conditions. Exp Neurol 148:523–543. doi: 10.1006/exnr.1997.6703 PubMedGoogle Scholar
  74. Gordon EJ, Rao S, Pollard JW, Nutt SL, Lang RA, Harvey NL (2010) Macrophages define dermal lymphatic vessel calibre during development by regulating lymphatic endothelial cell proliferation. Dev 137:3899–3910. doi: 10.1242/dev.050021 Google Scholar
  75. Gordy C, Pua H, Sempowski GD, He YW (2011) Regulation of steady-state neutrophil homeostasis by macrophages. Blood 117:618–629. doi: 10.1182/blood-2010-01-265959 PubMedCentralPubMedGoogle Scholar
  76. Grant A, Amadesi S, Bunnett NW (2007) Protease-Activated Receptors: Mechanisms by Which Proteases Sensitize TRPV Channels to Induce Neurogenic Inflammation and Pain doi:NBK5243 [bookaccession]Google Scholar
  77. Guindon J, Hohmann AG (2008) Cannabinoid CB2 receptors: A therapeutic target for the treatment of inflammatory and neuropathic pain. Br J Pharmacol 153:319–334. doi: 10.1038/sj.bjp.0707531 PubMedCentralPubMedGoogle Scholar
  78. Gunthorpe MJ, Benham CD, Randall A, Davis JB (2002) The diversity in the vanilloid (TRPV) receptor family of ion channels. Trends Pharmacol Sci 23:183–191PubMedGoogle Scholar
  79. Gwak YS, Hulsebosch CE (2011) GABA and central neuropathic pain following spinal cord injury. Neuropharmacol 60:799–808. doi: 10.1016/j.neuropharm.2010.12.030 Google Scholar
  80. Gwak YS, Tan HY, Nam TS, Paik KS, Hulsebosch CE, Leem JW (2006) Activation of spinal GABA receptors attenuates chronic central neuropathic pain after spinal cord injury. J Neurotrauma 23:1111–1124. doi: 10.1089/neu.2006.23.1111 PubMedGoogle Scholar
  81. Hackanson B, Guo Y, Lubbert M (2005) The silence of the genes: epigenetic disturbances in haematopoietic malignancies. Expert Opin Ther Targets 9:45–61. doi: 10.1517/14728222.9.1.45 PubMedGoogle Scholar
  82. Hains BC, Waxman SG (2006) Activated microglia contribute to the maintenance of chronic pain after spinal cord injury. J Neurosci 26:4308–4317. doi: 10.1523/JNEUROSCI.0003-06.2006 PubMedGoogle Scholar
  83. Hasbargen T, Ahmed MM, Miranpuri G, Li L, Kahle KT, Resnick D, Sun D (2010) Role of NKCC1 and KCC2 in the development of chronic neuropathic pain following spinal cord injury. Ann N Y Acad Sci 1198:168–172. doi: 10.1111/j.1749-6632.2010.05462.x PubMedGoogle Scholar
  84. Hirai T (2012) Intrathecal shRNA-AAV9 inhibits target protein expression in the spinal cord and dorsal root ganglia of adult mice. Human Gene Ther Methods 23:119–127. doi: 10.1089/hgtb.2012.035 Google Scholar
  85. Hu J, Van den Steen PE, Sang QX, Opdenakker G (2007a) Matrix metalloproteinase inhibitors as therapy for inflammatory and vascular diseases. Nat Rev Drug Discov 6:480–498. doi: 10.1038/nrd2308 PubMedGoogle Scholar
  86. Hu P, Bembrick AL, Keay KA, McLachlan EM (2007b) Immune cell involvement in dorsal root ganglia and spinal cord after chronic constriction or transection of the rat sciatic nerve. Brain Behav Immun 21:599–616. doi: 10.1016/j.bbi.2006.10.013 PubMedGoogle Scholar
  87. Hu JR, Lv GH, Yin BL (2013a) Altered microRNA expression in the ischemic-reperfusion spinal cord with atorvastatin therapy. J Pharmacol Sci 121:343–346PubMedGoogle Scholar
  88. Hu JZ, Huang JH, Zeng L, Wang G, Cao M, Lu HB (2013b) Anti-apoptotic effect of MicroRNA-21 after contusion spinal cord injury in rats. J Neurotrauma 30:1349–1360. doi: 10.1089/neu.2012.2748 PubMedCentralPubMedGoogle Scholar
  89. Hwang JH, Yaksh TL (1997) The effect of spinal GABA receptor agonists on tactile allodynia in a surgically-induced neuropathic pain model in the rat. Pain 70:15–2PubMedGoogle Scholar
  90. Hwang WY et al (2013) Efficient genome editing in zebrafish using a CRISPR-Cas system. Nat Biotechnol 31:227–229. doi: 10.1038/nbt.2501 PubMedCentralPubMedGoogle Scholar
  91. Hyun JK, Kim HW (2010) Clinical and experimental advances in regeneration of spinal cord injury. J Tissue Eng 2010:650–857. doi: 10.4061/2010/650857 Google Scholar
  92. Ibrahim MM et al (2003) Activation of CB2 cannabinoid receptors by AM1241 inhibits experimental neuropathic pain: pain inhibition by receptors not present in the CNS. Proc Natl Acad Sci U S A 100:10529–10533. doi: 10.1073/pnas.1834309100 PubMedCentralPubMedGoogle Scholar
  93. Imamura K, Inoue H (2012) Research on neurodegenerative diseases using induced pluripotent stem cells Psychogeriatrics. Off J Jpn Psychogeriatr Soc 12:115–119. doi: 10.1111/j.1479-8301.2011.00394.x Google Scholar
  94. Iskandar BJ et al (2004) Folic acid supplementation enhances repair of the adult central nervous system. Ann Neurol 56:221–227. doi: 10.1002/ana.20174 PubMedGoogle Scholar
  95. Iskandar BJ et al (2010) Folate regulation of axonal regeneration in the rodent central nervous system through DNA methylation. J Clin Invest 120:1603–1616. doi: 10.1172/JCI40000 PubMedCentralPubMedGoogle Scholar
  96. Janssens S, Lijnen HR (2006) What has been learned about the cardiovascular effects of matrix metalloproteinases from mouse models? Cardiovasc Res 69:585–594. doi: 10.1016/j.cardiores.2005.12.010 PubMedGoogle Scholar
  97. Jee MK, Jung JS, Choi JI, Jang JA, Kang KS, Im YB, Kang SK (2012a) MicroRNA 486 is a potentially novel target for the treatment of spinal cord injury. Brain J Neurol 135:1237–1252. doi: 10.1093/brain/aws047 Google Scholar
  98. Jee MK, Jung JS, Im YB, Jung SJ, Kang SK (2012b) Silencing of miR20a is crucial for Ngn1-mediated neuroprotection in injured spinal cord. Hum Gene Ther 23:508–520. doi: 10.1089/hum.2011.121 PubMedGoogle Scholar
  99. Jin J, Cai L, Liu ZM, Zhou XS (2013) miRNA-218 inhibits osteosarcoma cell migration and invasion by down-regulating of TIAM1, MMP2 and MMP9. Asian Pac J Cancer Prev 14:3681–3684PubMedGoogle Scholar
  100. Jinek M, Chylinski K, Fonfara I, Hauer M, Doudna JA, Charpentier E (2012) A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science 337:816–821. doi: 10.1126/science.1225829 PubMedGoogle Scholar
  101. Kaneko F et al (2004) Down-regulation of matrix-invasive potential of human liver cancer cells by type I interferon and a histone deacetylase inhibitor sodium butyrate. Int J Oncol 24:837–845PubMedGoogle Scholar
  102. Kawasaki Y et al (2008) Distinct roles of matrix metalloproteases in the early- and late-phase development of neuropathic pain. Nat Med 14:331–336. doi: 10.1038/nm1723 PubMedCentralPubMedGoogle Scholar
  103. Kay MA, He CY, Chen ZY (2010) A robust system for production of minicircle DNA vectors. Nat Biotechnol 28:1287–1289. doi: 10.1038/nbt.1708 PubMedCentralPubMedGoogle Scholar
  104. Kim HT et al. (2013) Thermal hyperalgesia assessment for rats after spinal cord injury: developing a valid and useful pain index The spine journal : official journal of the North American Spine Society doi:10.1016/j.spinee.2013.09.051Google Scholar
  105. King SN, Hanson SE, Chen X, Kim J, Hematti P, Thibeault SL (2013) In vitro characterization of macrophage interaction with mesenchymal stromal cell-hyaluronan hydrogel constructs Journal of biomedical materials research Part A doi:10.1002/jbm.a.34746Google Scholar
  106. Knerlich-Lukoschus F, Noack M, von der Ropp-Brenner B, Lucius R, Mehdorn HM, Held-Feindt J (2011) Spinal Cord Injuries Induce Changes of CB1 Cannabinoid Receptor and C-C Chemokine Expression in Brain Areas Underlying Circuitry of Chronic Pain Conditions J Neurotrauma doi:10.1089/neu.2010.1652Google Scholar
  107. Kobayashi H, Chattopadhyay S, Kato K, Dolkas J, Kikuchi S, Myers RR, Shubayev VI (2008) MMPs initiate Schwann cell-mediated MBP degradation and mechanical nociception after nerve damage. Mol Cell Neurosci 39:619–627. doi: 10.1016/j.mcn.2008.08.008 PubMedCentralPubMedGoogle Scholar
  108. Kontkanen O, Lakso M, Koponen E, Wong G, Castren E (2000) Molecular effects of the psychotropic NMDA receptor antagonist MK-801 in the rat entorhinal cortex: Increases in AP-1 DNA binding activity and expression of Fos and Jun family members. Ann N Y Acad Sci 911:73–82PubMedGoogle Scholar
  109. Kuljaca S, Liu T, Tee AE, Haber M, Norris MD, Dwarte T, Marshall GM (2007) Enhancing the anti-angiogenic action of histone deacetylase inhibitors. Mol Cancer 6:68. doi: 10.1186/1476-4598-6-68 PubMedCentralPubMedGoogle Scholar
  110. Kumru H, Vidal J, Kofler M, Portell E, Valls-Sole J (2010) Alterations in excitatory and inhibitory brainstem interneuronal circuits after severe spinal cord injury. J Neurotrauma 27:721–728. doi: 10.1089/neu.2009.1089 PubMedGoogle Scholar
  111. Lauer-Fields JL, Whitehead JK, Li S, Hammer RP, Brew K, Fields GB (2008) Selective modulation of matrix metalloproteinase 9 (MMP-9) functions via exosite inhibition. J Biol Chem 283:20087–20095. doi: 10.1074/jbc.M801438200 PubMedCentralPubMedGoogle Scholar
  112. Lee KH et al (2010) Inhibition of histone deacetylase activity down-regulates urokinase plasminogen activator and matrix metalloproteinase-9 expression in gastric cancer. Mol Cell Biochem 343:163–171. doi: 10.1007/s11010-010-0510-x PubMedGoogle Scholar
  113. Lee HK, Ahmed MM, King KC, Miranpuri GS, Kahle KT, Resnick DK, Sun D (2013a) Persistent phosphorylation of NKCC1 and WNK1 in the epicenter of the spinal cord following contusion injury The spine journal : official journal of the North American Spine Society doi: 10.1016/j.spinee.2013.06.100
  114. Lee S, Ashizawa AT, Kim KS, Falk DJ, Notterpek L (2013b) Liposomes to target peripheral neurons and Schwann cells. PLoS ONE 8:e78724. doi: 10.1371/journal.pone.0078724 PubMedCentralPubMedGoogle Scholar
  115. Li J, Ramenaden ER, Peng J, Koito H, Volpe JJ, Rosenberg PA (2008) Tumor necrosis factor alpha mediates lipopolysaccharide-induced microglial toxicity to developing oligodendrocytes when astrocytes are presen. J Neurosci 28:5321–5330. doi: 10.1523/JNEUROSCI.3995-07.2008 PubMedCentralPubMedGoogle Scholar
  116. Liebner S et al (2008) Wnt/beta-catenin signaling controls development of the blood–brain barrier. J Cell Biol 183:409–417. doi: 10.1083/jcb.200806024 PubMedCentralPubMedGoogle Scholar
  117. Liu NK, Xu XM (2011) MicroRNA in central nervous system trauma and degenerative disorders. Physiol Genomics 43:571–580. doi: 10.1152/physiolgenomics.00168.2010 PubMedCentralPubMedGoogle Scholar
  118. Liu NK, Wang XF, Lu QB, Xu XM (2009) Altered microRNA expression following traumatic spinal cord injury. Exp Neurol 219:424–429. doi: 10.1016/j.expneurol.2009.06.015 PubMedCentralPubMedGoogle Scholar
  119. Lu KT, Wu CY, Yen HH, Peng JH, Wang CL, Yang YL (2007) Bumetanide administration attenuated traumatic brain injury through IL-1 overexpression. Neurol Res 29:404–409. doi: 10.1179/016164107X204738 PubMedGoogle Scholar
  120. Mackay-Sim A, St John JA (2011) Olfactory ensheathing cells from the nose: Clinical application in human spinal cord injuries. Exp Neurol 229:174–180. doi: 10.1016/j.expneurol.2010.08.025 PubMedGoogle Scholar
  121. Madathil SK, Nelson PT, Saatman KE, Wilfred BR (2011) MicroRNAs in CNS injury: Potential roles and therapeutic implications. Bioessays News Rev Mol Cell Dev Biol 33:21–26. doi: 10.1002/bies.201000069 Google Scholar
  122. Mason MR et al (2010) Comparison of AAV serotypes for gene delivery to dorsal root ganglion neurons. Mol Ther J Am Soc Gene Ther 18:715–724. doi: 10.1038/mt.2010.19 Google Scholar
  123. Mathiesen O, Imbimbo BP, Hilsted KL, Fabbri L, Dahl JB (2006) CHF3381, a N-methyl-D-aspartate receptor antagonist and monoamine oxidase-A inhibitor, attenuates secondary hyperalgesia in a human pain model. J Pain 7:565–574. doi: 10.1016/j.jpain.2006.02.004 PubMedGoogle Scholar
  124. Mayo MW, Denlinger CE, Broad RM, Yeung F, Reilly ET, Shi Y, Jones DR (2003) Ineffectiveness of histone deacetylase inhibitors to induce apoptosis involves the transcriptional activation of NF-kappa B through the Akt pathway. J Biol Chem 278:18980–18989. doi: 10.1074/jbc.M211695200 PubMedGoogle Scholar
  125. Mayrhofer P, Schleef M, Jechlinger W (2009) Use of minicircle plasmids for gene therapy. Methods Mol Biol 542:87–104. doi: 10.1007/978-1-59745-561-9_4 PubMedGoogle Scholar
  126. Michaluk P, Kaczmarek L (2007) Matrix metalloproteinase-9 in glutamate-dependent adult brain function and dysfunction. Cell Death Differ 14:1255–1258. doi: 10.1038/sj.cdd.4402141 PubMedGoogle Scholar
  127. Mitmaker EJ (2011) Modulation of matrix metalloproteinase activity in human thyroid cancer cell lines using demethylating agents and histone deacetylase inhibitors. Surgery 149:504–511. doi: 10.1016/j.surg.2010.10.007 PubMedGoogle Scholar
  128. Morgado C, Pereira-Terra P, Cruz CD, Tavares I (2011) Minocycline completely reverses mechanical hyperalgesia in diabetic rats through microglia-induced changes in the expression of the potassium chloride co-transporter 2 (KCC2) at the spinal cord. Diab Obes Metab 13:150–159. doi: 10.1111/j.1463-1326.2010.01333.x Google Scholar
  129. Mulvey MR et al. (2013) Confirming neuropathic pain in cancer patients: Applying the NeuPSIG grading system in clinical practice and clinical research Pain doi: 10.1016/j.pain.2013.11.010
  130. Nagase H, Visse R, Murphy G (2006) Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc Res 69:562–573. doi: 10.1016/j.cardiores.2005.12.002 PubMedGoogle Scholar
  131. Nakamura M, Okano H (2013) Cell transplantation therapies for spinal cord injury focusing on induced pluripotent stem cells. Cell Res 23:70–80. doi: 10.1038/cr.2012.171 PubMedCentralPubMedGoogle Scholar
  132. Nimmerjahn A, Kirchhoff F, Helmchen F (2005) Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308:1314–1318. doi: 10.1126/science.1110647 PubMedGoogle Scholar
  133. Noble LJ, Donovan F, Igarashi T, Goussev S, Werb Z (2002) Matrix metalloproteinases limit functional recovery after spinal cord injury by modulation of early vascular events. J Neurosci Off J Soc Neuroscie 22:7526–7535Google Scholar
  134. Noda M et al (2007) Neuroprotective role of bradykinin because of the attenuation of pro-inflammatory cytokine release from activated microglia. J Neurochem 101:397–410. doi: 10.1111/j.1471-4159.2006.04339.x PubMedGoogle Scholar
  135. Ogier C (2006) Matrix metalloproteinase-2 (MMP-2) regulates astrocyte motility in connection with the actin cytoskeleton and integrins. Glia 54:272–284. doi: 10.1002/glia.20349 PubMedGoogle Scholar
  136. Olson JK, Miller SD (2004) Microglia initiate central nervous system innate and adaptive immune responses through multiple TLRs. J Immuno 173:3916–3924Google Scholar
  137. Oshita K, Inoue A, Tang HB, Nakata Y, Kawamoto M, Yuge O (2005) CB(1) cannabinoid receptor stimulation modulates transient receptor potential vanilloid receptor 1 activities in calcium influx and substance P Release in cultured rat dorsal root ganglion cells. J Pharmacol Sci 97:377–385PubMedGoogle Scholar
  138. Pang XY, Liu T, Jiang F, Ji YH (2008) ctivation of spinal ERK signaling pathway contributes to pain-related responses induced by scorpion. Buthus martensi Karch venom Toxicon 51:994–1007. doi: 10.1016/j.toxicon.2008.01.005 Google Scholar
  139. Park SW, Yi JH, Miranpuri G, Satriotomo I, Bowen K, Resnick DK, Vemuganti R (2007) Thiazolidinedione class of peroxisome proliferator-activated receptor gamma agonists prevents neuronal damage, motor dysfunction, myelin loss, neuropathic pain, and inflammation after spinal cord injury in adult rats. J Pharmacol Exp Ther 320:1002–1012. doi: 10.1124/jpet.106.113472 PubMedGoogle Scholar
  140. Parks WC, Wilson CL, Lopez-Boado YS (2004) Matrix metalloproteinases as modulators of inflammation and innate immunity. Nature reviews Immunology 4:617–629. doi: 10.1038/nri1418 PubMedGoogle Scholar
  141. Patel S, Naeem S, Kesingland A, Froestl W, Capogna M, Urban L, Fox A (2001) The effects of GABA(B) agonists and gabapentin on mechanical hyperalgesia in models of neuropathic and inflammatory pain in the rat. Pain 90:217–226PubMedGoogle Scholar
  142. Pineau I, Lacroix S (2007) Proinflammatory cytokine synthesis in the injured mouse spinal cord: Multiphasic expression pattern and identification of the cell types involved. J Comp Neurol 500:267–285. doi: 10.1002/cne.21149 PubMedGoogle Scholar
  143. Pitcher MH, Price TJ, Entrena JM, Cervero F (2007) Spinal NKCC1 blockade inhibits TRPV1-dependent referred allodynia. Mol Pain 3:17. doi: 10.1186/1744-8069-3-17 PubMedCentralPubMedGoogle Scholar
  144. Pol O, Murtra P, Caracuel L, Valverde O, Puig MM, Maldonado R (2006) Expression of opioid receptors and c-fos in CB1 knockout mice exposed to neuropathic pain. Neuropharmacology 50:123–132. doi: 10.1016/j.neuropharm.2005.11.002 PubMedGoogle Scholar
  145. Popovich PG, Wei P, Stokes BT (1997) Cellular inflammatory response after spinal cord injury in Sprague–Dawley and Lewis rats. J Comp Neurol 377:443–464. doi: 10.1002/(SICI)1096-9861(19970120)377:3<443::AID-CNE10>3.0.CO;2-S PubMedGoogle Scholar
  146. Popovich PG, Guan Z, McGaughy V, Fisher L, Hickey WF, Basso DM (2002) The neuropathological and behavioral consequences of intraspinal microglial/macrophage activation. J Neuropathol Exp Neurol 61:623–633PubMedGoogle Scholar
  147. Pradeepkumar Singh L, Kundu P, Ganguly K, Mishra A, Swarnakar S (2007) Novel role of famotidine in downregulation of matrix metalloproteinase-9 during protection of ethanol-induced acute gastric ulcer. Free Radic Biol Med 43:289–299. doi: 10.1016/j.freeradbiomed.2007.04.027 PubMedGoogle Scholar
  148. Price TJ, Cervero F, Gold MS, Hammond DL, Prescott SA (2009) Chloride regulation in the pain pathway. Brain Res Rev 60:149–170. doi: 10.1016/j.brainresrev.2008.12.015 PubMedCentralPubMedGoogle Scholar
  149. Qi LS, Larson MH, Gilbert LA, Doudna JA, Weissman JS, Arkin AP, Lim WA (2013) Repurposing CRISPR as an RNA-guided platform for sequence-specific control of gene expression. Cell 152:1173–1183. doi: 10.1016/j.cell.2013.02.022 PubMedCentralPubMedGoogle Scholar
  150. Quartilho A, Mata HP, Ibrahim MM, Vanderah TW, Porreca F, Makriyannis A, Malan TP Jr (2003) Inhibition of inflammatory hyperalgesia by activation of peripheral CB2 cannabinoid receptors. Anesthesiology 99:955–960PubMedGoogle Scholar
  151. Racz I et al (2008a) Interferon-gamma is a critical modulator of CB(2) cannabinoid receptor signaling during neuropathic pain. J Neurosci 28:12136–12145. doi: 10.1523/JNEUROSCI. 3402-08.2008 PubMedCentralPubMedGoogle Scholar
  152. Racz I et al (2008b) Crucial role of CB(2) cannabinoid receptor in the regulation of central immune responses during neuropathic pain. J Neurosci 28:12125–12135. doi: 10.1523/JNEUROSCI. 3400-08.2008 PubMedCentralPubMedGoogle Scholar
  153. Rajpal S, Gerovac TA, Turner NA, Tilghman JI, Allcock BK, McChesney SL, Miranpuri GS, Park SW, Resnick DK (2007) Antihyperalgesic effects of vanilloid-1 and bradykinin-1 receptor antagonists following spinal cord injury in rats. J Neurosurg Spine 6:420–424. doi: 10.3171/spi.2007.6.5.420
  154. Ramer R, Hinz B (2008) Inhibition of cancer cell invasion by cannabinoids via increased expression of tissue inhibitor of matrix metalloproteinases-1. J Natl Cancer Inst 100:59–69. doi: 10.1093/jnci/djm268 PubMedGoogle Scholar
  155. Ratan RR, Noble M (2009) Novel multi-modal strategies to promote brain and spinal cord injury recovery Stroke. J Cereb Circ 40:S130–132. doi: 10.1161/STROKEAHA.108.534933 Google Scholar
  156. Reichard JF, Puga A (2010) Effects of arsenic exposure on DNA methylation and epigenetic gene regulation. Epigenomics 2:87–104. doi: 10.2217/epi.09.45 PubMedCentralPubMedGoogle Scholar
  157. Resnick DK, Graham SH, Dixon CE, Marion DW (1998) Role of cyclooxygenase 2 in acute spinal cord injury. J Neurotrauma 15:1005–1013PubMedGoogle Scholar
  158. Resnick DK, Schmitt C, Miranpuri GS, Dhodda VK, Isaacson J, Vemuganti R (2004) Molecular evidence of repair and plasticity following spinal cord injury. NeuroReport 15:837–839PubMedGoogle Scholar
  159. Reunanen N, Li SP, Ahonen M, Foschi M, Han J, Kahari VM (2002) Activation of p38 alpha MAPK enhances collagenase-1 (matrix metalloproteinase (MMP)-1) and stromelysin-1 (MMP-3) expression by mRNA stabilization. J Biol Chem 277:32360–32368. doi: 10.1074/jbc.M204296200 PubMedGoogle Scholar
  160. Rhee JS, Coussens LM (2002) RECKing MMP function: implications for cancer development. Trends Cell Biol 12:209–211PubMedGoogle Scholar
  161. Rosell A, Cuadrado E, Ortega-Aznar A, Hernandez-Guillamon M, Lo EH, Montaner J (2008) MMP-9-positive neutrophil infiltration is associated to blood–brain barrier breakdown and basal lamina type IV collagen degradation during hemorrhagic transformation after human ischemic stroke. Stroke 39:1121–1126. doi: 10.1161/STROKEAHA.107.500868 PubMedGoogle Scholar
  162. Rosenberg GA et al (2001) Immunohistochemistry of matrix metalloproteinases in reperfusion injury to rat brain: activation of MMP-9 linked to stromelysin-1 and microglia in cell cultures. Brain Res 893:104–112PubMedGoogle Scholar
  163. Sanjana NE, Cong L, Zhou Y, Cunniff MM, Feng G, Zhang F (2012) A transcription activator-like effector toolbox for genome engineering. Nat Protoc 7:171–192. doi: 10.1038/nprot.2011.431 PubMedCentralPubMedGoogle Scholar
  164. Sato J, Perl ER (1991) Adrenergic excitation of cutaneous pain receptors induced by peripheral nerve injury. Science 251:1608–1610PubMedGoogle Scholar
  165. Schafers M, Svensson CI, Sommer C, Sorkin LS (2003) Tumor necrosis factor-alpha induces mechanical allodynia after spinal nerve ligation by activation of p38 MAPK in primary sensory neurons. J Neurosci 23:2517–2521PubMedGoogle Scholar
  166. Schipke CG, Boucsein C, Ohlemeyer C, Kirchhoff F, Kettenmann H (2002) Astrocyte Ca2+ waves trigger responses in microglial cells in brain slices. FASEB J 16:255–257. doi: 10.1096/fj.01-0514fje PubMedGoogle Scholar
  167. Schomberg D, Olson JK (2012) Immune responses of microglia in the spinal cord: Contribution to pain states. Exp Neurol 234:262–270. doi: 10.1016/j.expneurol.2011.12.021 PubMedGoogle Scholar
  168. Schwartz M, Yoles E (2006) Immune-based therapy for spinal cord repair: Autologous macrophages and beyond. J Neurotrauma 23:360–370. doi: 10.1089/neu.2006.23.360 PubMedGoogle Scholar
  169. Senju S et al (2011) Generation of dendritic cells and macrophages from human induced pluripotent stem cells aiming at cell therapy. Gene Ther 18:874–883. doi: 10.1038/gt.2011.22 PubMedGoogle Scholar
  170. Sharma HS, Badgaiyan RD, Alm P, Mohanty S, Wiklund L (2005) Neuroprotective effects of nitric oxide synthase inhibitors in spinal cord injury-induced pathophysiology and motor functions: An experimental study in the rat. Ann N Y Acad Sci 1053:422–434. doi: 10.1196/annals.1344.037 PubMedGoogle Scholar
  171. Shechter R, Raposo C, London A, Sagi I, Schwartz M (2011) The glial scar-monocyte interplay: A pivotal resolution phase in spinal cord repair. PLoS ONE 6:e27969. doi: 10.1371/journal.pone.0027969 PubMedCentralPubMedGoogle Scholar
  172. Sommer C, Petrausch S, Lindenlaub T, Toyka KV (1999) Neutralizing antibodies to interleukin 1-receptor reduce pain associated behavior in mice with experimental neuropathy. Neurosci Lett 270:25–28PubMedGoogle Scholar
  173. Sorkin LS, Puig S, Jones DL (1998) Spinal bicuculline produces hypersensitivity of dorsal horn neurons: Effects of excitatory amino acid antagonists. Pain 77:181–190PubMedGoogle Scholar
  174. Spinal cord gene therapy (2000) Nature biotechnology 18:915Google Scholar
  175. Stella N (2004) Cannabinoid signaling in glial cells. Glia 48:267–277. doi: 10.1002/glia.20084 PubMedGoogle Scholar
  176. Streit WJ (2001) Microglia and macrophages in the developing CNS. Neurotoxicology 22:619–624PubMedGoogle Scholar
  177. Strickland ER, Hook MA, Balaraman S, Huie JR, Grau JW, Miranda RC (2011) MicroRNA dysregulation following spinal cord contusion: implications for neural plasticity and repair. Neurosci 186:146–160. doi: 10.1016/j.neuroscience.2011.03.063 Google Scholar
  178. Sung YH, Baek IJ, Seong JK, Kim JS, Lee HW (2012) Mouse genetics: Catalogue and scissors. BMB Rep 45:686–692PubMedCentralPubMedGoogle Scholar
  179. Swarnakar S, Mishra A, Ganguly K, Sharma AV (2007) Matrix metalloproteinase-9 activity and expression is reduced by melatonin during prevention of ethanol-induced gastric ulcer in mice. J Pineal Res 43:56–64. doi: 10.1111/j.1600-079X.2007.00443.x PubMedGoogle Scholar
  180. Thomas JA et al (2011) Macrophage therapy for murine liver fibrosis recruits host effector cells improving fibrosis, regeneration, and function. Hepatology 53:2003–2015. doi: 10.1002/hep.24315 PubMedGoogle Scholar
  181. Tong L, Smyth D, Kerr C, Catterall J, Richards CD (2004) Mitogen-activated protein kinases Erk1/2 and p38 are required for maximal regulation of TIMP-1 by oncostatin M in murine fibroblasts. Cell Signal 16:1123–1132. doi: 10.1016/j.cellsig.2004.03.003 PubMedGoogle Scholar
  182. Van den Steen PE et al (2006) The hemopexin and O-glycosylated domains tune gelatinase B/MMP-9 bioavailability via inhibition and binding to cargo receptors. J Biol Chem 281:18626–18637. doi: 10.1074/jbc.M512308200 PubMedGoogle Scholar
  183. Verge GM, Milligan ED, Maier SF, Watkins LR, Naeve GS, Foster AC (2004) Fractalkine (CX3CL1) and fractalkine receptor (CX3CR1) distribution in spinal cord and dorsal root ganglia under basal and neuropathic pain conditions. Eur J Neurosci 20:1150–1160. doi: 10.1111/j.1460-9568.2004.03593.x PubMedGoogle Scholar
  184. Vranken JH (2009) Mechanisms and treatment of neuropathic pain Cent Nerv Syst Agents. Med Chem 9:71–78Google Scholar
  185. Wang Y, Liu C, Guo QL, Yan JQ, Zhu XY, Huang CS, Zou WY (2011) Intrathecal 5-azacytidine inhibits global DNA methylation and methyl- CpG-binding protein 2 expression and alleviates neuropathic pain in rats following chronic constriction injury. Brain Res 1418:64–69. doi: 10.1016/j.brainres.2011.08.040 PubMedGoogle Scholar
  186. Watkins LR, Wiertelak EP, Goehler LE, Smith KP, Martin D, Maier SF (1994) Characterization of cytokine-induced hyperalgesia. Brain Res 654:15–26PubMedGoogle Scholar
  187. Wei H, Wang C, Zhang C, Li P, Wang F, Zhang Z (2010) Comparative profiling of microRNA expression between neural stem cells and motor neurons in embryonic spinal cord in rat. Int J Dev Neurosci Off J Int Soc Dev Neurosci 28:545–551. doi: 10.1016/j.ijdevneu.2010.04.007 Google Scholar
  188. White FA, Bhangoo SK, Miller RJ (2005) Chemokines: integrators of pain and inflammation. Nat Rev Drug Discov 4:834–844. doi: 10.1038/nrd1852 PubMedCentralPubMedGoogle Scholar
  189. Wolf G, Gabay E, Tal M, Yirmiya R, Shavit Y (2006) Genetic impairment of interleukin-1 signaling attenuates neuropathic pain, autotomy, and spontaneous ectopic neuronal activity, following nerve injury in mice. Pain 120:315–324. doi: 10.1016/j.pain.2005.11.011 PubMedGoogle Scholar
  190. Wu Y (2013) Correction of a genetic disease in mouse via use of CRISPR-Cas9. Cell Stem Cell 13:659–662. doi: 10.1016/j.stem.2013.10.016 PubMedGoogle Scholar
  191. Wu B, Crampton SP, Hughes CC (2007a) Wnt signaling induces matrix metalloproteinase expression and regulates T cell transmigration. Immun 26:227–239. doi: 10.1016/j.immuni.2006.12.007 Google Scholar
  192. Wu CY et al (2007b) Clinicopathological significance of MMP-2 and TIMP-2 genotypes in gastric cancer. Eur J Cancer 43:799–808. doi: 10.1016/j.ejca.2006.10.022 PubMedGoogle Scholar
  193. Xu W, Li P, Qin K, Wang X, Jiang X (2012) miR-124 regulates neural stem cells in the treatment of spinal cord injury. Neurosci Lett 529:12–17. doi: 10.1016/j.neulet.2012.09.025 PubMedGoogle Scholar
  194. Yan W et al (2011) Identification of MMP-9 specific microRNA expression profile as potential targets of anti-invasion therapy in glioblastoma multiforme. Brain Res 1411:108–115. doi: 10.1016/j.brainres.2011.07.002 PubMedGoogle Scholar
  195. Yao L, Yao S, Daly W, Hendry W, Windebank A, Pandit A (2012) Non-viral gene therapy for spinal cord regeneration. Drug Disc Today 17:998–1005. doi: 10.1016/j.drudis.2012.05.009 Google Scholar
  196. Yezierski RP (1996) Pain following spinal cord injury: the clinical problem and experimental studies. Pain 68:185–194PubMedGoogle Scholar
  197. Yong VW, Power C, Forsyth P, Edwards DR (2001) Metalloproteinases in biology and pathology of the nervous system. Nat Rev Neurosci 2:502–511. doi: 10.1038/35081571 PubMedGoogle Scholar
  198. Yong VW, Agrawal SM, Stirling DP (2007) Targeting MMPs in acute and chronic neurological conditions Neurotherapeutics. J Am Soc Exp NeuroTher 4:580–589. doi: 10.1016/j.nurt.2007.07.005 Google Scholar
  199. Yoshimura M, Yonehara N (2006) Alteration in sensitivity of ionotropic glutamate receptors and tachykinin receptors in spinal cord contribute to development and maintenance of nerve injury-evoked neuropathic pain. Neurosci Res 56:21–28. doi: 10.1016/j.neures.2006.04.015 PubMedGoogle Scholar
  200. Yu Y, Matsuyama Y, Nakashima S, Yanase M, Kiuchi K, Ishiguro N (2004) Effects of MPSS and a potent iNOS inhibitor on traumatic spinal cord injury. NeuroReport 15:2103–2107PubMedGoogle Scholar
  201. Yu F, Kamada H, Niizuma K, Endo H, Chan PH (2008) Induction of mmp-9 expression and endothelial injury by oxidative stress after spinal cord injury. J Neurotrauma 25:184–195. doi: 10.1089/neu.2007.0438 PubMedCentralPubMedGoogle Scholar
  202. Yune TY et al (2003) Increased production of tumor necrosis factor-alpha induces apoptosis after traumatic spinal cord injury in rats. J Neurotrauma 20:207–219. doi: 10.1089/08977150360547116 PubMedGoogle Scholar
  203. Zhang H (2011) Matrix metalloproteinase-9 and stromal cell-derived factor-1 act synergistically to support migration of blood-borne monocytes into the injured spinal cord. J Neuroscie Off J Soc Neurosci 31:15894–15903. doi: 10.1523/JNEUROSCI.3943-11.2011 Google Scholar
  204. Zhang M, Martin BR, Adler MW, Razdan RK, Ganea D, Tuma RF (2008) Modulation of the balance between cannabinoid CB(1) and CB(2) receptor activation during cerebral ischemic/reperfusion injury. Neuroscience 152:753–760. doi: 10.1016/j.neuroscience.2008.01.022 PubMedCentralPubMedGoogle Scholar
  205. Zhang X, Chen G, Xue Q, Yu B (2010) Early changes of beta-Catenins and Menins in spinal cord dorsal horn after peripheral nerve injury. Cell Mol Neurobiol 30:885–890. doi: 10.1007/s10571-010-9517-9 PubMedGoogle Scholar
  206. Zhang H, Chang M, Hansen CN, Basso DM, Noble-Haeusslein LJ (2011) Role of matrix metalloproteinases and therapeutic benefits of their inhibition in spinal cord injury Neurotherapeutics. J Am Soc Exp NeuroTher 8:206–220. doi: 10.1007/s13311-011-0038-0 Google Scholar
  207. Zhao P, Waxman SG, Hains BC (2007) Extracellular signal-regulated kinase-regulated microglia-neuron signaling by prostaglandin E2 contributes to pain after spinal cord injury. J Neurosci 27:2357–2368. doi: 10.1523/JNEUROSCI. 0138-07.2007 PubMedGoogle Scholar
  208. Zufferey R, Dull T, Mandel RJ, Bukovsky A, Quiroz D, Naldini L, Trono D (1998) Self-inactivating lentivirus vector for safe and efficient in vivo gene delivery. J Virol 72:9873–9880PubMedCentralPubMedGoogle Scholar
  209. Zuo Q, Xu JJ (2011) [Specific expression of microRNA in different tissues of nervous system and expression changes in nerve regeneration] Sheng li ke xue jin zhan [Progress in physiology] 42:261-268Google Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Dominic Schomberg
    • 1
  • Gurwattan Miranpuri
    • 1
  • Tyler Duellman
    • 2
  • Andrew Crowell
    • 1
  • Raghu Vemuganti
    • 1
  • Daniel Resnick
    • 1
  1. 1.Department of Neurological SurgeryUniversity of Wisconsin School of Medicine and Public HealthMadisonUSA
  2. 2.Molecular and Cellular Pharmacology Training ProgramUniversity of Wisconsin-MadisonMadisonUSA

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