Skip to main content
SpringerLink
Log in

IL-1β Is Involved with the Generation of Pain in Experimental Autoimmune Encephalomyelitis

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Pain is one of the main symptoms of multiple sclerosis, a demyelinating disease of the central nervous system that affects millions of people worldwide. The experimental autoimmune encephalomyelitis (EAE) is considered an experimental model of multiple sclerosis, and besides motor weakness, hypernociception is one of the clinical signs of animals with EAE. In this study, we investigated the influence of some cytokines in the generation of the hypernociceptive response in a mouse model of EAE using MOG35–55. We measured some cytokines in the dorsal root ganglia (DRG), an important anatomical structure involved in pain. We found increased levels of the cytokines TNF-α, IL-1β, and Kc in DRGs of animals with EAE. We used the antibody IL-1ra to antagonize the effects of IL-1β, and animals presented a decrease in the hypernociceptive response. Thus, our results suggest that hypernociception in this experimental model of EAE may be a consequence of the increase in some cytokines in DRGs, especially IL-1β.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. McFarland HF, Martin R (2007) Multiple sclerosis: a complicated picture of autoimmunity. Nat Immunol 8(9):913–919

    Article  CAS  PubMed  Google Scholar 

  2. Siniscalchi A, Gallelli L, De Sarro G (2007) Drugs treatment of pain in multiple sclerosis. Curr Clin Pharmacol 2(3):227–233

    Article  CAS  PubMed  Google Scholar 

  3. Beard S, Hunn A, Wight J (2003) Treatments for spasticity and pain in multiple sclerosis: a systematic review. Health Technol Assess 7:1–124

    Article  Google Scholar 

  4. Foley PL, Vesterinen HM, Laird BJ, Sena ES, Colvin LA, Chandran S, MacLeod MR, Fallon MT (2013) Prevalence and natural history of pain in adults with multiple sclerosis: systematic review and meta-analysis. Pain 154(5):632–642

    Article  PubMed  Google Scholar 

  5. O’Connor AB et al (2008) Pain associated with multiple sclerosis: systematic review and proposed classification. Pain 137:96–111

    Article  PubMed  Google Scholar 

  6. Gold R, Linington C, Lassmann H (2006) Understanding pathogenesis and therapy of multiple sclerosis via animal models: 70 years of merits and culprits in experimental autoimmune encephalomyelitis research. Brain 129:1953–1971

    Article  PubMed  Google Scholar 

  7. Bettelli E, Oukka M, Kuchroo VK (2007) T(H)-17 cells in the circle of immunity and autoimmunity. Nat Immunol 8:345–350

    Article  CAS  PubMed  Google Scholar 

  8. Dos Santos AC, Roffê E, Arantes RM, Juliano L, Pesquero JL, Pesquero JB, Bader M, Teixeira MM et al (2008) Kinin B2 receptor regulates chemokines CCL2 and CCL5 expression and modulates leukocyte recruitment and pathology in experimental autoimmune encephalomyelitis (EAE) in mice. J Neuroinflammation 5:49

    Article  PubMed  PubMed Central  Google Scholar 

  9. Grace PM, Hutchinson MR, Maier SF, Watkins LR (2014) Pathological pain and the neuroimmune interface. Nat Rev Immunol 14(4):217–231

    Article  CAS  PubMed  Google Scholar 

  10. Sean Riminton D, Körner H, Strickland DH, Lemckert FA, Pollard JD, Sedgwick JD (1998) Challenging cytokine redundancy: inflammatory cell movement and clinical course of experimental autoimmune encephalomyelitis are normal in lymphotoxin-deficient, but not tumor necrosis factor-deficient, mice. J Exp Med 187(9):1517–1528

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Schiffenbauer J, Streit WJ, Butfiloski E, LaBow M, Edwards C 3rd, Moldawer LL (2000) The induction of EAE is only partially dependent on TNF receptor signaling but requires the IL-1 type I receptor. Clin Immunol 95(2):117–123

    Article  CAS  PubMed  Google Scholar 

  12. Cunha TM, Verri WA Jr, Valério DA, Guerrero AT, Nogueira LG, Vieira SM, Souza DG, Teixeira MM et al (2008) Role of cytokines in mediating mechanical hypernociception in a model of delayed-type hypersensitivity in mice. Eur J Pain 12(8):1059–1068

    Article  CAS  PubMed  Google Scholar 

  13. Begum F, Zhu W, Cortes C, MacNeil B, Namaka M (2013) Elevation of tumor necrosis factor α in dorsal root ganglia and spinal cord is associated with neuroimmune modulation of pain in an animal model of multiple sclerosis. J Neuroimmune Pharmacol 8(3):677–690

    Article  CAS  PubMed  Google Scholar 

  14. Thibault K, Calvino B, Pezet S (2011) Characterisation of sensory abnormalities observed in an animal model of multiple sclerosis: a behavioural and pharmacological study. Eur J Pain 15(3):231.e1-16

    Article  PubMed  Google Scholar 

  15. Rodrigues DH, Sachs D, Teixeira AL (2009) Mechanical hypernociception in experimental autoimmune encephalomyelitis. Arq Neuropsiquiatr 67(1):78–81

    Article  PubMed  Google Scholar 

  16. Olechowski CJ, Truong JJ, Kerr BJ (2009) Neuropathic pain behaviours in a chronic-relapsing model of experimental autoimmune encephalomyelitis (EAE). Pain 141(1–2):156–164

    Article  CAS  PubMed  Google Scholar 

  17. Aicher SA, Silverman MB, Winkler CW, Bebo BF Jr (2004) Hyperalgesia in an animal model of multiple sclerosis. Pain 110(3):560–570

    Article  CAS  PubMed  Google Scholar 

  18. Weaver A, Silva AG, Nuttall RK et al (2005) An elevated matrix metalloproteinase (MMP) in an animal model of multiple sclerosis is protective by affecting Th1/Th2 polarization. FASEB J 19:1668–1670

    CAS  PubMed  Google Scholar 

  19. Brundula V, Rewcastle NB, Metz LM, Bernard CC, Yong VW (2002) Targeting leukocyte MMPs and transmigration: minocycline as a potential therapy for multiple sclerosis. Brain 125:1297–1308

    Article  PubMed  Google Scholar 

  20. Coelho FM, Pinho V, Amaral FA et al (2008) The chemokine receptors CXCR1/2 modulate antigen-induced arthritis by regulating adhesion of neutrophils to the synovial microvasculature. Arthritis Rheum 58:2329–2337

    Article  PubMed  Google Scholar 

  21. Dos Santos AC, Roffê E, Arantes RM, Juliano L, Pesquero JL, Pesquero JB, Bader M, Teixeira MM et al (2008) Kinin B2 receptor regulates chemokines CCL2 and CCL5 expression and modulates leukocyte recruitment and pathology in experimental autoimmune encephalomyelitis (EAE) in mice. J Neuroinflammation 5:5–49

    Article  Google Scholar 

  22. Rodrigues DH, Vilela MC, Barcelos LS, Pinho V, Teixeira MM, Teixeira AL (2010) Absence of PI3Kgamma leads to increased leukocyte apoptosis and diminished severity of experimental autoimmune encephalomyelitis. J Neuroimmunol 222(1–2):90–94

    Article  CAS  PubMed  Google Scholar 

  23. Galic MA, Riazi K, Pittman QJ (2012) Cytokines and brain excitability. Front Neuroendocrinol 33(1):116–125

    Article  CAS  PubMed  Google Scholar 

  24. Wang J, Yu J, Ding CP, Han SP, Zeng XY, Wang JY (2015) Transforming growth factor-beta in the red nucleus plays antinociceptive effect under physiological and pathological pain conditions. Neuroscience 291:37–45

    Article  CAS  PubMed  Google Scholar 

  25. Sloane E, Ledeboer A, Seibert W, Coats B, van Strien M, Maier SF, Johnson KW, Chavez R et al (2009) Anti-inflammatory cytokine gene therapy decreases sensory and motor dysfunction in experimental multiple sclerosis: MOG-EAE behavioral and anatomical symptom treatment with cytokine gene therapy. Brain Behav Immun 23(1):92–100

    Article  CAS  PubMed  Google Scholar 

  26. Lisi L, Navarra P, Cirocchi R, Sharp A, Stigliano E, Feinstein DL, Dello Russo C (2012) Rapamycin reduces clinical signs and neuropathic pain in a chronic model of experimental autoimmune encephalomyelitis. J Neuroimmunol 243(1–2):43–51

    Article  CAS  PubMed  Google Scholar 

  27. Melanson M, Miao P, Eisenstat D, Gong Y, Gu X, Au K, Zhu W, Begum F et al (2009) Experimental autoimmune encephalomyelitis-induced upregulation of tumor necrosis factor-alpha in the dorsal root ganglia. Mult Scler 15(10):1135–1145

    Article  CAS  PubMed  Google Scholar 

  28. Matsuki T, Nakae S, Sudo K, Horai R, Iwakura Y (2006) Abnormal T cell activation caused by the imbalance of the IL-1/IL-1R antagonist system is responsible for the development of experimental autoimmune encephalomyelitis. Int Immunol 18(2):399–407

    Article  CAS  PubMed  Google Scholar 

  29. Sim YB, Park SH, Kang YJ, Jung JS, Ryu OH, Choi MG, Suh HW (2012) Interleukin-1β (IL-1β) increases pain behavior and the blood glucose level: possible involvement of sympathetic nervous system. Pharmacol Biochem Behav 102(1):170–176

    Article  CAS  PubMed  Google Scholar 

  30. Binshtok AM, Wang H, Zimmermann K, Amaya F, Vardeh D, Shi L, Brenner GJ, Ji RR et al (2008) Nociceptors are interleukin-1beta sensors. J Neurosci 28:14062–14073

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Caterina MJ, Leffler A, Malmberg AB, Martin WJ, Trafton J, Petersen-Zeitz KR, Koltzenburg M, Basbaum AI et al (2000) Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science 14 288(5464):306–313

    CAS  Google Scholar 

  32. Cummins TR, Sheets PL, Waxman SG (2007) The roles of sodium channels in nociception: implications for mechanisms of pain. Pain 131(3):243–257

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Hwang SW, Cho H, Kwak J, Lee SY, Kang CJ, Jung J, Cho S, Min KH et al (2000) Direct activation of capsaicin receptors by products of lipoxygenases: endogenous capsaicin-like substances. Proc Natl Acad Sci U S A 97(11):6155–6160

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Ji RR, Samad TA, Jin SX, Schmoll R, Woolf CJ (2002) p38 MAPK activation by NGF in primary sensory neurons after inflammation increases TRPV1 levels and maintains heat hyperalgesia. Neuron 36(1):57–68

    Article  CAS  PubMed  Google Scholar 

  35. Jarvis MF, Honore P, Shieh CC et al (2007) A-803467, a potent and selective Nav1.8 sodium channel blocker, attenuates neuropathic and inflammatory pain in the rat. Proc Natl Acad Sci U S A 104(20):8520–8525

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Basic and Health Sciences, Universidade Federal de Juiz de Fora—campus Governador Valadares, de Juiz de Fora, Brazil

    David Henrique Rodrigues

  2. Translational Psychoneuroimmunology Group, Laboratory of Immunopharmacology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil

    David Henrique Rodrigues, Aline Silva Miranda & Antônio Lúcio Teixeira

  3. Department of Biochemistry, Universidade Federal de Minas Gerais, Belo Horizonte, MG, 31270-901, Brazil

    David Henrique Rodrigues, Bruno Pereira Leles, Vivian Vasconcelos Costa, Daniel Cisalpino, Dawidson Assis Gomes, Danielle Glória de Souza & Antônio Lúcio Teixeira

Authors
  1. David Henrique Rodrigues
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bruno Pereira Leles
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Vivian Vasconcelos Costa
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Aline Silva Miranda
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Daniel Cisalpino
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Dawidson Assis Gomes
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Danielle Glória de Souza
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Antônio Lúcio Teixeira
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David Henrique Rodrigues.

Ethics declarations

Funding

This work was funded by Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq).

Conflict of Interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rodrigues, D.H., Leles, B.P., Costa, V.V. et al. IL-1β Is Involved with the Generation of Pain in Experimental Autoimmune Encephalomyelitis. Mol Neurobiol 53, 6540–6547 (2016). https://doi.org/10.1007/s12035-015-9552-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-015-9552-0

Keywords

Search

Navigation