Assessment of Allodynia Relief by Tissue-Protective Molecules in a Rat Model of Nerve Injury-Induced Neuropathic Pain

  • Maarten Swartjes
  • Marieke Niesters
  • Albert Dahan
Part of the Methods in Molecular Biology book series (MIMB, volume 982)


Neuropathic pain following nerve injury is a chronic disease characterized by allodynia and hyperalgesia of either mechanical or thermal origin. The mechanism underlying this disease is poorly understood leading to pharmacologic and physiotherapeutic control that is often insufficient. In this chapter, we describe a method to induce nerve injury in rats to create a robust animal model for studying neuropathic pain. Additionally we describe a method to follow up on animals in the process of testing treatments for efficacy in alleviating allodynia by testing for both mechanical and thermal allodynia with reproducible results.

Key words

Neuropathic pain Allodynia Spared nerve injury ARA290 Erythropoietin Erythro­poietin derivative 


  1. 1.
    Baron R, Binder A, Wasner G (2010) Neuropathic pain. Diagnosis, pathophysiological mechanisms, and treatment. Lancet Neurol 9:807–819PubMedCrossRefGoogle Scholar
  2. 2.
    Breivik H, Collett B, Ventafridda V, Cohen R, Gallacher D (2006) Survey of chronic pain in Europe: Prevalence, impact on daily life, and treatment. Eur J Pain 10:287–333PubMedCrossRefGoogle Scholar
  3. 3.
    Kuner R (2010) Central mechanisms of pathological pain. Nat Med 16:1258–1266PubMedCrossRefGoogle Scholar
  4. 4.
    Tanga FY, Raghavendra V, DeLeo JA (2007) Quantitative real-time RT-PCR assessment of spinal microglial and astrocytic activation markers in a rat model of neuropathic pain. Neurochem Int 45:397–407CrossRefGoogle Scholar
  5. 5.
    Brines M, Ghezzi P, Keenan S, Agnello D, De Lanorelle N, Cerami A (2000) Erythropoietin crosses the blood-brain barrier to protect against experimental brain injury. Proc Natl Acad Sci U S A 97:10531–10536CrossRefGoogle Scholar
  6. 6.
    Liao ZB, Zhi XG, Shi QH, He ZH (2008) Recombinant human erythropoietin administration protects cortical neurons from traumatic brain injury in rats. Eur J Neurol 15:140–149PubMedCrossRefGoogle Scholar
  7. 7.
    Campana MW, Myers RR (2003) Exogenous erythropoietin protects against dorsal root ganglion apoptosis and pain following peripheral nerve injury. Eur J Neurosci 18:1497–1506PubMedCrossRefGoogle Scholar
  8. 8.
    Sekiguchi Y, Kikuchi S, Myers RR, Campana WM (2003) Erythropoietin inhibits spinal neuronal apoptosis and pain following nerve root crush. Spine 28:2577–2584PubMedCrossRefGoogle Scholar
  9. 9.
    Keswani S, Buldanlioglu U, Fischer A, Reed N, Polley M, Liang H, Zhou C, Jack C, Leitz G, Hoke A (2004) A novel endogenous erythropoietin mediated pathway prevents axonal degeneration. Ann Neurol 56:815–826PubMedCrossRefGoogle Scholar
  10. 10.
    Campana WM, Li X, Shubayev VI, Angert M, Cai K, Myers RR (2006) Erythropoietin reduces Schwann cell TNF-a, Wallerian degeneration and pain-related behaviors after peripheral nerve injury. Eur J Neurosci 23:617–626PubMedCrossRefGoogle Scholar
  11. 11.
    Jia H, Feng X, Li W, Hu Y, Zeng Q, Liu J, Xu J (2009) Recombinant human erythropoietin attenuates spinal neuroimmune activation of neuropathic pain in rats. Ann Clin Lab Sci 39:84–91PubMedGoogle Scholar
  12. 12.
    Jia H, Jin Y, Ji Q, Hu Y, Zhou Z, Xu J, Yang J (2009) Effects of recombinant human erythropoietin on neuropathic pain and cerebral expressions of cytokines and nuclear factor-kappa B. Can J Aneasth 56:597–603CrossRefGoogle Scholar
  13. 13.
    Sasaki N, Sekiguchi M, Kikuchi S, Konno S (2011) Effects of asialo-erythropoietin on pain-related behavior and expression of phosphorylated-P38 MAP kinase and tumor necrosis factor-alpha induced by application of autologous nucleus pulposus on nerve root in rat. Spine 36:E86–E94PubMedCrossRefGoogle Scholar
  14. 14.
    Brines M, Patel NSA, Villa P, Brines C, Mennini T, De Paola M, Erbayraktar Z, Erbayraktar S, Sepodes B, Thiemermann C, Ghezzi P, Yamin M, Hand CC, Xie QW, Coleman T, Cerami A (2008) Nonerythro­poietic, tissue-protective peptides derived from the tertiary structure of erythropoietin. Proc Natl Acad Sci U S A 105:10925–10930PubMedCrossRefGoogle Scholar
  15. 15.
    Swartjes M, Morariu A, Niesters M, Brines M, Cerami A, Aarts L, Dahan A (2011) ARA290, a peptide derived from the tertiary structure of erythropoietin, produces long-term relief of neuropathic pain. An experimental study in rats and β-common receptor knockout mice. Anesthesiology 115:1084–1092PubMedCrossRefGoogle Scholar
  16. 16.
    Sigtermans M, van Hilten JJ, Bauer M, Arbous M, Marinus J, Sarton E, Dahan A (2009) Ketamine produces effective and long-term pain relief in patients with complex regional pain syndrome type 1. Pain 145:304–311PubMedCrossRefGoogle Scholar
  17. 17.
    Swartjes M, Morariu A, Niesters M, Aarts L, Dahan A (2011) Nonselective and NR2B-selective N-methyl-d-aspartic acid receptor antagonists produce antinociception and long-term relief of allodynia in acute and neuropathic pain. Anesthesiology 115:165–174PubMedCrossRefGoogle Scholar
  18. 18.
    Decosterd I, Woolf CJ (2000) Spared nerve injury: an animal model of persistent peripheral neuropathic pain. Pain 87:149–158PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2013

Authors and Affiliations

  • Maarten Swartjes
    • 1
  • Marieke Niesters
    • 1
  • Albert Dahan
    • 1
  1. 1.Department of AnesthesiologyLeiden University Medical CenterLeidenThe Netherlands

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