The Korean Journal of Pain

The Korean Pain Society (대한통증학회)
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Immunological mechanism of postherpetic neuralgia and effect of pregabalin treatment on the mechanism: a prospective single-arm observational study

  • Mercan, Aysel (Department of Anesthesiology and Reanimation, Necmettin Erbakan University Meram Faculty of Medicine) ;
  • Uzun, Sema Tuncer (Division of Algology, Department of Anesthesiology and Reanimation, Necmettin Erbakan University Meram Faculty of Medicine) ;
  • Keles, Sevgi (Division of Pediatric Allergy and Immunology, Department of Pediatric Health, Necmettin Erbakan University Meram Faculty of Medicine) ;
  • Hacibeyoglu, Gulcin (Department of Anesthesiology and Reanimation, Necmettin Erbakan University Meram Faculty of Medicine) ;
  • Yilmaz, Resul (Department of Anesthesiology and Reanimation, Necmettin Erbakan University Meram Faculty of Medicine) ;
  • Reisli, Ruhiye (Division of Algology, Department of Anesthesiology and Reanimation, Necmettin Erbakan University Meram Faculty of Medicine)
  • Received : 2021.05.13
  • Accepted : 2021.07.09
  • Published : 2021.10.01
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Abstract

Background: Although neuropathic pain is a severe and common pain, its pathophysiology has not been elucidated yet. Studies in recent years have focused on the immune system's role in the pathogenesis of neuropathic pain. The aim of this study was to investigate the role of immunological mechanisms in neuropathic pain and the effect of pregabalin by measuring immunological marker levels in peripheral blood before and after pregabalin treatment in postherpetic neuralgia (PHN) patients with neuropathic pain. Methods: Forty patients diagnosed with PHN were included in the study. CD4, T follicular cells (Tfh: CD4+CXCR5+PD1+), Th17 (CD4+CCR6+ and CD4+IL17A+), regulatory T cells (Treg: CD4+ CD25+foxp3+), Th1 (CD4+ CXCR3+ and CD4+ IFN-γ+) and Th2 (CD4+ IL-4+) cell ratios were measured in peripheral blood samples before treatment and after 3 months of treatment. Results: When immunological marker and inflammation parameter levels were compared before and after treatment, the helper T cell ratio (CD3+, CD4+) was 30.28 ± 12.27% before treatment and 34.93 ± 11.70% after treatment, so there was a statistically significant increase (P = 0.028). Th17 was 4.75 ± 5.02% before treatment and 5.80 ± 3.13% after treatment, and there was a statistically significant increase (P = 0.036). Conclusions: Immunological mechanisms play an essential role in the pathogenesis of neuropathic pain, immunologically based treatment approach will be the critical point of treatment.

Keywords

Acknowledgement

We want to thank Professor Doctor Ismail Reisli and Seyma Celikbilek Celik for their support during our studies in the immunology laboratory.

References

  1. Toth C, Lander J, Wiebe S. The prevalence and impact of chronic pain with neuropathic pain symptoms in the general population. Pain Med 2009; 10: 918-29. https://doi.org/10.1111/j.1526-4637.2009.00655.x
  2. Tian L, Ma L, Kaarela T, Li Z. Neuroimmune crosstalk in the central nervous system and its significance for neurological diseases. J Neuroinflammation 2012; 9: 155. https://doi.org/10.1186/1742-2094-9-155
  3. Calvo M, Dawes JM, Bennett DL. The role of the immune system in the generation of neuropathic pain. Lancet Neurol 2012; 11: 629-42. https://doi.org/10.1016/S1474-4422(12)70134-5
  4. Campbell JN, Meyer RA. Mechanisms of neuropathic pain. Neuron 2006; 52: 77-92. https://doi.org/10.1016/j.neuron.2006.09.021
  5. Feldman EL, Callaghan BC, Pop-Busui R, Zochodne DW, Wright DE, Bennett DL, et al. Diabetic neuropathy. Nat Rev Dis Primers 2019; 5: 41. https://doi.org/10.1038/s41572-019-0092-1
  6. Johnson RW, Rice AS. Clinical practice. Postherpetic neuralgia. N Engl J Med 2014; 371: 1526-33. https://doi.org/10.1056/NEJMcp1403062
  7. Opstelten W, McElhaney J, Weinberger B, Oaklander AL, Johnson RW. The impact of varicella zoster virus: chronic pain. J Clin Virol 2010; 48 Suppl 1: S8-13. https://doi.org/10.1016/S1386-6532(10)70003-2
  8. Hadley GR, Gayle JA, Ripoll J, Jones MR, Argoff CE, Kaye RJ, et al. Post-herpetic neuralgia: a review. Curr Pain Headache Rep 2016; 20: 17. https://doi.org/10.1007/s11916-016-0548-x
  9. Yawn BP, Saddier P, Wollan PC, St Sauver JL, Kurland MJ, Sy LS. A population-based study of the incidence and complication rates of herpes zoster before zoster vaccine introduction. Mayo Clin Proc 2007; 82: 1341-9. https://doi.org/10.4065/82.11.1341
  10. Drolet M, Brisson M, Schmader K, Levin M, Johnson R, Oxman M, et al. Predictors of postherpetic neuralgia among patients with herpes zoster: a prospective study. J Pain 2010; 11: 1211-21. https://doi.org/10.1016/j.jpain.2010.02.020
  11. Bayat A, Burbelo PD, Browne SK, Quinlivan M, Martinez B, Holland SM, et al. Anti-cytokine autoantibodies in postherpetic neuralgia. J Transl Med 2015; 13: 333. https://doi.org/10.1186/s12967-015-0695-6
  12. Luchting B, Rachinger-Adam B, Heyn J, Hinske LC, Kreth S, Azad SC. Anti-inflammatory T-cell shift in neuropathic pain. J Neuroinflammation 2015; 12: 12. https://doi.org/10.1186/s12974-014-0225-0
  13. Kiguchi N, Kobayashi D, Saika F, Matsuzaki S, Kishioka S. Pharmacological regulation of neuropathic pain driven by inflammatory macrophages. Int J Mol Sci 2017; 18: 2296. https://doi.org/10.3390/ijms18112296
  14. Zhu SM, Liu YM, An ED, Chen QL. Influence of systemic immune and cytokine responses during the acute phase of zoster on the development of postherpetic neuralgia. J Zhejiang Univ Sci B 2009; 10: 625-30. https://doi.org/10.1631/jzus.B0920049
  15. Kim CF, Moalem-Taylor G. Interleukin-17 contributes to neuroinflammation and neuropathic pain following peripheral nerve injury in mice. J Pain 2011; 12: 370-83. https://doi.org/10.1016/j.jpain.2010.08.003
  16. Hung AL, Lim M, Doshi TL. Targeting cytokines for treatment of neuropathic pain. Scand J Pain 2017; 17: 287-93. https://doi.org/10.1016/j.sjpain.2017.08.002
  17. Lees JG, Duffy SS, Perera CJ, Moalem-Taylor G. Depletion of Foxp3+ regulatory T cells increases severity of mechanical allodynia and significantly alters systemic cytokine levels following peripheral nerve injury. Cytokine 2015; 71: 207-14. https://doi.org/10.1016/j.cyto.2014.10.028
  18. Xing Q, Hu D, Shi F, Chen F. Role of regulatory T cells in patients with acute herpes zoster and relationship to postherpetic neuralgia. Arch Dermatol Res 2013; 305: 715-22. https://doi.org/10.1007/s00403-013-1367-0
  19. Ji RR, Chamessian A, Zhang YQ. Pain regulation by nonneuronal cells and inflammation. Science 2016; 354: 572-7. https://doi.org/10.1126/science.aaf8924
  20. Ren K, Dubner R. Interactions between the immune and nervous systems in pain. Nat Med 2010; 16: 1267-76. https://doi.org/10.1038/nm.2234
  21. Davoli-Ferreira M, de Lima KA, Fonseca MM, Guimaraes RM, Gomes FI, Cavallini MC, et al. Regulatory T cells counteract neuropathic pain through inhibition of the Th1 response at the site of peripheral nerve injury. Pain 2020; 161: 1730-43. https://doi.org/10.1097/j.pain.0000000000001879
  22. Moalem G, Xu K, Yu L. T lymphocytes play a role in neuropathic pain following peripheral nerve injury in rats. Neuroscience 2004; 129: 767-77. https://doi.org/10.1016/j.neuroscience.2004.08.035
  23. Draleau K, Maddula S, Slaiby A, Nutile-McMenemy N, De Leo J, Cao L. Phenotypic identification of spinal cord-infiltrating CD4+ T lymphocytes in a murine model of neuropathic pain. J Pain Relief 2014; Suppl 3: 003.
  24. Sah DW, Ossipo MH, Porreca F. Neurotrophic factors as novel therapeutics for neuropathic pain. Nat Rev Drug Discov 2003; 2: 460-72. https://doi.org/10.1038/nrd1107
  25. Kobayashi Y, Kiguchi N, Fukazawa Y, Saika F, Maeda T, Kishioka S. Macrophage-T cell interactions mediate neuropathic pain through the glucocorticoid-induced tumor necrosis factor ligand system. J Biol Chem 2015; 290: 12603-13. https://doi.org/10.1074/jbc.M115.636506
  26. Kiguchi N, Kobayashi Y, Saika F, Sakaguchi H, Maeda T, Kishioka S. Peripheral interleukin-4 ameliorates inflammatory macrophage-dependent neuropathic pain. Pain 2015; 156: 684-93. https://doi.org/10.1097/j.pain.0000000000000097
  27. Hao S, Mata M, Glorioso JC, Fink DJ. HSV-mediated expression of interleukin-4 in dorsal root ganglion neurons reduces neuropathic pain. Mol Pain 2006; 2: 6. https://doi.org/10.1186/1744-8069-2-6
  28. Sorge RE, Mapplebeck JC, Rosen S, Beggs S, Taves S, Alexander JK, et al. Different immune cells mediate mechanical pain hypersensitivity in male and female mice. Nat Neurosci 2015; 18: 1081-3. https://doi.org/10.1038/nn.4053
  29. Austin PJ, Kim CF, Perera CJ, Moalem-Taylor G. Regulatory T cells attenuate neuropathic pain following peripheral nerve injury and experimental autoimmune neuritis. Pain 2012; 153: 1916-31. https://doi.org/10.1016/j.pain.2012.06.005
  30. Langley RG, Elewski BE, Lebwohl M, Reich K, Griffiths CE, Papp K, et al. Secukinumab in plaque psoriasis--results of two phase 3 trials. N Engl J Med 2014; 371: 326-38. https://doi.org/10.1056/NEJMoa1314258
  31. Attal N, Cruccu G, Baron R, Haanpaa M, Hansson P, Jensen TS, et al. EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision. Eur J Neurol 2010; 17: 1113-e88. https://doi.org/10.1111/j.1468-1331.2010.02999.x
  32. Tesfaye S, Boulton AJ, Dyck PJ, Freeman R, Horowitz M, Kempler P, et al. Diabetic neuropathies: update on definitions, diagnostic criteria, estimation of severity, and treatments. Diabetes Care 2010; 33: 2285-93. https://doi.org/10.2337/dc10-1303
  33. Kanazi G, Johnson R, Dworkin R. Treatment of postherpetic neuralgia-an update. J Peripher Nerv Syst 2000; 5: 250.
  34. Gulec H, Babayigit M, Kutuk S, Sahap M, Tutal Z, Kurtay A, et al. Combination treatment of post-herpetic neuralgia. J Contemp Med 2014; 4(2 EK): 100-37.
  35. Higa K, Noda B, Manabe H, Sato S, Dan K. T-lymphocyte subsets in otherwise healthy patients with herpes zoster and relationships to the duration of acute herpetic pain. Pain 1992; 51: 111-8. https://doi.org/10.1016/0304-3959(92)90015-4
  36. Asanuma H, Sharp M, Maecker HT, Maino VC, Arvin AM. Frequencies of memory T cells specific for varicella-zoster virus, herpes simplex virus, and cytomegalovirus by intracellular detection of cytokine expression. J Infect Dis 2000; 181: 859-66. https://doi.org/10.1086/315347
  37. Austin PJ, Moalem-Taylor G. The neuro-immune balance in neuropathic pain: involvement of inflammatory immune cells, immune-like glial cells and cytokines. J Neuroimmunol 2010; 229: 26-50. https://doi.org/10.1016/j.jneuroim.2010.08.013
  38. Kohm AP, McMahon JS, Podojil JR, Begolka WS, DeGutes M, Kasprowicz DJ, et al. Cutting Edge: anti-CD25 monoclonal antibody injection results in the functional inactivation, not depletion, of CD4+CD25+ T regulatory cells. J Immunol 2006; 176: 3301-5. https://doi.org/10.4049/jimmunol.176.6.3301
  39. Suntharalingam G, Perry MR, Ward S, Brett SJ, Castello-Cortes A, Brunner MD, et al. Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N Engl J Med 2006; 355: 1018-28. https://doi.org/10.1056/NEJMoa063842
  40. Abdel-Moneim A, Bakery HH, Allam G. The potential pathogenic role of IL-17/Th17 cells in both type 1 and type 2 diabetes mellitus. Biomed Pharmacother 2018; 101: 287-92. https://doi.org/10.1016/j.biopha.2018.02.103
  41. Noma N, Khan J, Chen IF, Markman S, Benoliel R, Hadlaq E, et al. Interleukin-17 levels in rat models of nerve damage and neuropathic pain. Neurosci Lett 2011; 493: 86-91. https://doi.org/10.1016/j.neulet.2011.01.079
  42. Kleinschnitz C, Hofstetter HH, Meuth SG, Braeuninger S, Sommer C, Stoll G. T cell infiltration after chronic constriction injury of mouse sciatic nerve is associated with interleukin-17 expression. Exp Neurol 2006; 200: 480-5. https://doi.org/10.1016/j.expneurol.2006.03.014