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Upregulation of Inflammatory Mediators in a Model of Chronic Pain after Spinal Cord Injury

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Abstract

Chronic neuropathic pain is a disabling condition observed in large number of individuals following spinal cord injury (SCI). Recent progress points to an important role of neuroinflammation in the pathogenesis of central neuropathic pain. The focus of the present study is to investigate the role of proinflammatory molecules IL-1β, TNF-α, MCP-1, MMP-9 and TIMP-1 in chronic neuropathic pain in a rodent model of SCI. Rats were subjected to spinal cord contusion using a controlled linear motor device with an injury epicenter at T10. The SCI rats had severe impairment in locomotor function at 7 days post-injury as assessed by the BBB score. The locomotor scores showed significant improvement starting at day 14 and thereafter showed no further improvement. The Hargreaves’ test was used to assess thermal hyperalgesia for hindpaw, forepaw and tail. A significant reduction in withdrawal latency was observed for forepaw and tail of SCI rats at days 21 and 28, indicating the appearance of thermal hyperalgesia. Changes in expression of mRNAs for IL-1β, TNF-α, MCP-1, MMP-9 and TIMP-1 were assessed using real-time polymerase chain reaction in spinal cord including the injury epicenter along with regions above and below the level of lesion at day 28 post-injury. A significant increase was observed in the expression of MCP-1, TNF-α, TIMP-1 and IL-1β in the injury epicenter, whereas only TIMP-1 was upregulated in the area below the injury epicenter. The results of the study suggest that prolonged upregulation of inflammatory mediators might be involved in chronic neuropathic pain in SCI, and that TIMP-1 may play a role in maintenance of chronic below level pain.

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Abbreviations

IL-1β:

Interleukin 1 beta

MCP-1:

Monocyte chemotactic protein-1

MMP-9:

Matrix metalloproteinase 9

TIMP-1:

Tissue inhibitor of metalloproteinase 1

TNF-α:

Tumor necrosis factor-alpha

References

  1. Sekhon LHS, Fehlings MG (2001) Epidemiology, demographics, and pathophysiology of acute spinal cord injury. Spine 26(24S):S2–S12

    Article  PubMed  CAS  Google Scholar 

  2. Deumens R, Joosten EA, Waxman SG, Hains BC (2008) Locomotor dysfunction and pain: the scylla and charybdis of fiber sprouting after spinal cord injury. Mol Neurobiol 37:52–63

    Article  PubMed  CAS  Google Scholar 

  3. Judith AT, Diana DC, Catherine AW, Catherine BM (2001) Chronic pain associated with spinal cord injuries: a community survey. Arch Phys Med Rehabil 82:501–509

    Article  Google Scholar 

  4. Finnerup NB, Johannesen IL, Sindrup SH, Bach FW, Jensen TS (2001) Pain and dysesthesia in patients with spinal cord injury: a postal survey. Spinal Cord 39:256–262

    Article  PubMed  CAS  Google Scholar 

  5. Gwak YS, Crown ED, Unabia GC, Hulsebosch CE (2008) Propentofylline attenuates allodynia, glial activation and modulates GABAergic tone after spinal cord injury in the rat. Pain 138:410–422

    Article  PubMed  CAS  Google Scholar 

  6. Anderson KD (2004) Targeting recovery: priorities of the spinal cord-injured population. J Neurotrauma 21:1371–1383

    Article  PubMed  Google Scholar 

  7. Woolf CJ, Mannion RJ (1999) Neuropathic pain: aetiology, symptoms, mechanisms, and management. Lancet 353:1959–1964

    Article  PubMed  CAS  Google Scholar 

  8. Dworkin RH, Backonja M, Rowbotham MC, Allen RR, Argoff CR, Bennett GJ et al (2003) Advances in neuropathic pain: diagnosis, mechanisms, and treatment recommendations. Arch Neurol 60:1524–1534

    Article  PubMed  Google Scholar 

  9. Milligan ED, Watkins LR (2009) Pathological and protective roles of glia in chronic pain. Nat Rev Neurosci 10:23–36

    Article  PubMed  CAS  Google Scholar 

  10. Moalem G, Tracey DJ (2006) Immune and inflammatory mechanisms in neuropathic pain. Brain Res Rev 51:240–264

    Article  PubMed  CAS  Google Scholar 

  11. Hulsebosch CE (2008) Gliopathy ensures persistent inflammation and chronic pain after spinal cord injury. Exp Neurol 214:6–9

    Article  PubMed  CAS  Google Scholar 

  12. Chang HT (2007) Subacute human spinal cord contusion: few lymphocytes and many macrophages. Spinal Cord 45:174–182

    Article  PubMed  CAS  Google Scholar 

  13. 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

    Article  PubMed  CAS  Google Scholar 

  14. McKay SM, Brooks DJ, Hu P, McLachlan EM (2007) Distinct types of microglial activation in white and grey matter of rat lumbosacral cord after mid-thoracic spinal transection. J Neuropathol Exp Neurol 66:698–710

    Article  PubMed  Google Scholar 

  15. Zhao P, Waxman SG, Hains BC (2007) Modulation of thalamic nociceptive processing after spinal cord injury through remote activation of thalamic microglia by cysteine cysteine chemokine ligand 21. J Neurosci 27:8893–8902

    Article  PubMed  CAS  Google Scholar 

  16. Guo W, Wang H, Watanabe M, Shimizu K, Zou S, LaGraize SC et al (2007) Glial-cytokine-neuronal interactions underlying the mechanisms of persistent pain. J Neurosci 27:6006–6018

    Article  PubMed  CAS  Google Scholar 

  17. Mika J (2008) Modulation of microglia can attenuate neuropathic pain symptoms and enhance morphine effectiveness. Pharmacol Rep 60:297–307

    PubMed  CAS  Google Scholar 

  18. Chattopadhyay S, Myers RR, Janes J, Shubayev V (2007) Cytokine regulation of MMP-9 in peripheral glia: implications for pathological processes and pain in injured nerve. Brain, Behavior, Immun 21:561–568

    Article  CAS  Google Scholar 

  19. Alexander JK, Popovich PG (2009) Neuroinflammation in spinal cord injury: therapeutic targets for neuroprotection and regeneration. Prog Brain Res 175:125–137

    Article  PubMed  CAS  Google Scholar 

  20. Tan AM, Zhao P, Waxman SG, Hains BC (2009) Early microglial inhibition preemptively mitigates chronic pain development after experimental spinal cord injury. J Rehabil Res Dev 46:123–133

    Article  PubMed  Google Scholar 

  21. Ramu J, Bockhorst KH, Mogatadakala KV, Narayana PA (2006) Functional magnetic resonance imaging in rodents: methodology and application to spinal cord injury. J Neurosci Res 84:1235–1244

    Article  PubMed  CAS  Google Scholar 

  22. Bilgen M (2005) A new device for experimental modeling of central nervous system injuries. Neurorehabil Neural Repair 19:219–226

    Article  PubMed  Google Scholar 

  23. Basso DM, Beattie MS, Bresnahan JC (1995) A sensitive and reliable locomotor rating scale for open field testing in rats. J Neurotrauma 12:1–21

    Article  PubMed  CAS  Google Scholar 

  24. Pfaffl MW, Horgan GW, Dempfle L (2002) Relative expression software tool (REST) for group-wise comparison and statistical analysis of relative expression results in real-time PCR. Nucleic Acids Res 30:e36

    Article  PubMed  Google Scholar 

  25. Yamamotova A, Sramkova T, Rokyta R (2010) Intensity of pain and biochemical changes in blood plasma in spinal cord trauma. Spinal Cord 48:21–26

    Article  PubMed  CAS  Google Scholar 

  26. Gwak YS, Hains BC, Johnson KM, Hulsebosch CE (2004) Locomotor recovery and mechanical hyperalgesia following spinal cord injury depend on age at time of injury in rat. Neurosci Lett 362:232–235

    Article  PubMed  CAS  Google Scholar 

  27. 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

    Article  PubMed  CAS  Google Scholar 

  28. Menetski J, Mistry S, Lu M, Mudgett JS, Ransohoff RM, Demartino JA et al (2007) Mice overexpressing chemokine ligand 2 (CCL2) in astrocytes display enhanced nociceptive responses. Neuroscience 149:706–714

    Article  PubMed  CAS  Google Scholar 

  29. Zhang J, Shi XQ, Echeverry S, Mogil JS, De Koninck Y, Rivest S (2007) Expression of CCR2 in both resident and bone marrow-derived microglia plays a critical role in neuropathic pain. J Neurosci 27:12396–12406

    Article  PubMed  CAS  Google Scholar 

  30. Gao YJ, Zhang L, Samad OA, Suter MR, Yasuhiko K, Xu ZZ et al (2009) JNK-induced MCP-1 production in spinal cord astrocytes contributes to central sensitization and neuropathic pain. J Neurosci 29:4096–4108

    Article  PubMed  CAS  Google Scholar 

  31. Liu SQ, Ma YG, Peng H, Fan L (2005) Monocyte chemoattractant protein-1 level in serum of patients with acute spinal cord injury. Chin J Traumatol 8:216–219

    PubMed  CAS  Google Scholar 

  32. Bhangoo S, Ren D, Miller RJ, Henry KJ, Lineswala J, Hamdouchi C et al (2007) Delayed functional expression of neuronal chemokine receptors following focal nerve demyelination in the rat: a mechanism for the development of chronic sensitization of peripheral nociceptors. Mol Pain 3:38

    Article  PubMed  Google Scholar 

  33. Knerlich-Lukoschus F, Juraschek M, Blomer U, Lucius R, Mehdorn HM, Held-Feindt J (2008) Force-dependent development of neuropathic central pain and time-related CCL2/CCR2 expression after graded spinal cord contusion injuries of the rat. J Neurotrauma 25:427–448

    Article  PubMed  Google Scholar 

  34. White FA, Feldman P, Miller RJ (2009) Chemokine signaling and the management of neuropathic pain. Mol Interv 9:188–195

    Article  PubMed  CAS  Google Scholar 

  35. Ji R-R, Xu Z-Z, Wang X, Lo EH (2009) Matrix metalloprotease regulation of neuropathic pain. Trends Pharmacol Sci 30:336–340

    Article  PubMed  CAS  Google Scholar 

  36. Kawasaki Y, Xu ZZ, Wang X, Park JY, Zhuang ZY, Tan PH et al (2008) Distinct roles of matrix metalloproteases in the early- and late-phase development of neuropathic pain. Nat Med 14:331–336

    Article  PubMed  CAS  Google Scholar 

  37. Goussev S, Hsu JY, Lin Y, Tjoa T, Maida N, Werb Z et al (2003) Differential temporal expression of matrix metalloproteinases after spinal cord injury: relationship to revascularization and wound healing. J Neurosurg 99:188–197

    PubMed  CAS  Google Scholar 

  38. Tejima E, Guo S, Murata Y, Arai K, Lok J, van Leyen K et al (2009) Neuroprotective effects of over-expressing tissue inhibitor of metalloproteinase TIMP-1. J Neurotrauma 26:1935–1941

    Article  PubMed  Google Scholar 

  39. Stetler-Stevenson WG (2008) Tissue inhibitors of metalloproteinases in cell signaling: metalloproteinase-independent biological activities. Sci Signal 1:re6

    Article  PubMed  Google Scholar 

  40. Chirco R, Liu XW, Jung KK, Kim HR (2006) Novel functions of TIMPs in cell signaling. Cancer Metastasis Rev 25:99–113

    Article  PubMed  CAS  Google Scholar 

  41. Davies AL, Hayes KC, Dekaban GA (2007) Clinical correlates of elevated serum concentrations of cytokines and autoantibodies in patients with spinal cord injury. Arch Phys Med Rehabil 88:1384–1393

    Article  PubMed  Google Scholar 

  42. Nakagawa T (2010) Spinal astrocytes as therapeutic targets for pathological pain. J Pharmacol Sci 114:347–353

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The financial assistance provided by the Steve Palermo Endowment and the National Institute of Health (P30-HD02528) is acknowledged.

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Authors and Affiliations

  1. Steve Palermo Nerve Regeneration Laboratory, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS, 66160, USA

    Rajat Sandhir, Eugene Gregory & Nancy E. J. Berman

  2. Department of Anatomy and Cell Biology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS, 66160, USA

    Rajat Sandhir, Eugene Gregory & Nancy E. J. Berman

  3. Department of Neurosurgery, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS, 66160, USA

    Nancy E. J. Berman

  4. Hoglund Brain Imaging Center, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS, 66160, USA

    Yong-Yue He

Authors
  1. Rajat Sandhir
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  2. Eugene Gregory
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  3. Yong-Yue He
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  4. Nancy E. J. Berman
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Correspondence to Nancy E. J. Berman.

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Sandhir, R., Gregory, E., He, YY. et al. Upregulation of Inflammatory Mediators in a Model of Chronic Pain after Spinal Cord Injury. Neurochem Res 36, 856–862 (2011). https://doi.org/10.1007/s11064-011-0414-5

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