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Seminars in Immunopathology

, Volume 40, Issue 3, pp 291–300 | Cite as

Neurogenic inflammation in fibromyalgia

  • Geoffrey LittlejohnEmail author
  • Emma Guymer
Review

Abstract

Fibromyalgia is a high impact chronic pain disorder with a well-defined and robust clinical phenotype. Key features include widespread pain and tenderness, high levels of sleep disturbance, fatigue, cognitive dysfunction and emotional distress. Abnormal processing of pain and other sensory input occurs in the brain, spinal cord and periphery and is related to the processes of central and peripheral sensitization. As such, fibromyalgia is deemed to be one of the central sensitivity syndromes. There is increasing evidence of neurogenically derived inflammatory mechanisms occurring in the peripheral tissues, spinal cord and brain in fibromyalgia. These involve a variety of neuropeptides, chemokines and cytokines with activation of both the innate and adaptive immune systems. This process results in several of the peripheral clinical features of fibromyalgia, such as swelling and dysesthesia, and may influence central symptoms, such as fatigue and changes in cognition. In turn, emotional and stress-related physiological mechanisms are seen as upstream drivers of neurogenic inflammation in fibromyalgia.

Keywords

Fibromyalgia Neurogenic Inflammation Neuropeptides Cytokines Chemokines Brain Pain 

References

  1. 1.
    Branco JC, Bannwarth B, Failde I, Abello Carbonell J, Blotman F, Spaeth M, Saraiva F, Nacci F, Thomas E, Caubere JP, Le Lay K, Taieb C, Matucci-Cerinic M (2010) Prevalence of fibromyalgia: a survey in five European countries. Semin Arthritis Rheum 39(6):448–453.  https://doi.org/10.1016/j.semarthrit.2008.12.003 CrossRefPubMedGoogle Scholar
  2. 2.
    Gerdle B, Bjork J, Coster L, Henriksson K, Henriksson C, Bengtsson A (2008) Prevalence of widespread pain and associations with work status: a population study. BMC Musculoskelet Disord 9:102.  https://doi.org/10.1186/1471-2474-9-102 CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Clauw DJ (2014) Fibromyalgia: a clinical review. JAMA 311(15):1547–1555.  https://doi.org/10.1001/jama.2014.3266 CrossRefPubMedGoogle Scholar
  4. 4.
    Theoharides TC, Tsilioni I, Arbetman L, Panagiotidou S, Stewart JM, Gleason RM, Russell IJ (2015) Fibromyalgia syndrome in need of effective treatments. J Pharmacol Exp Ther 355(2):255–263.  https://doi.org/10.1124/jpet.115.227298 CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Haviland MG, Morton KR, Oda K, Fraser GE (2010) Traumatic experiences, major life stressors, and self-reporting a physician-given fibromyalgia diagnosis. Psychiatry Res 177(3):335–341.  https://doi.org/10.1016/j.psychres.2009.08.017 CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Van Houdenhove B, Egle U, Luyten P (2005) The role of life stress in fibromyalgia. Curr Rheumatol Rep 7(5):365–370CrossRefPubMedGoogle Scholar
  7. 7.
    Helme RD, Littlejohn GO, Weinstein C (1987) Neurogenic flare responses in chronic rheumatic pain syndromes. Clin Exp Neurol 23:91–94PubMedGoogle Scholar
  8. 8.
    Clauw DJ, Arnold LM, McCarberg BH, FibroCollaborative (2011) The science of fibromyalgia. Mayo Clin Proc 86(9):907–911.  https://doi.org/10.4065/mcp.2011.0206 CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Thiagarajah AT, Guymer E, Leech M, Littlejohn G (2014) The relationship between fibromyalgia, stress and depression. Int J Clin Rheum 9(4):371–384CrossRefGoogle Scholar
  10. 10.
    Littlejohn G (2014) Fibromyalgia: honing fibromyalgia diagnosis. Nat Rev Rheumatol 10(5):267–269.  https://doi.org/10.1038/nrrheum.2014.48 CrossRefPubMedGoogle Scholar
  11. 11.
    Wolfe F, Smythe HA, Yunus MB, Bennett RM, Bombardier C, Goldenberg DL, Tugwell P, Campbell SM, Abeles M, Clark P, Fam AG, Farber SJ, Fiechtner JJ, Michael Franklin C, Gatter RA, Hamaty D, Lessard J, Lichtbroun AS, Masi AT, Mccain GA, John Reynolds W, Romano TJ, Jon Russell I, Sheon RP (1990) The American College of Rheumatology 1990 criteria for the classification of fibromyalgia. Report of the multicenter criteria committee. Arthritis Rheum 33(2):160–172CrossRefPubMedGoogle Scholar
  12. 12.
    Wolfe F, Clauw DJ, Fitzcharles MA, Goldenberg DL, Katz RS, Mease P, Russell AS, Russell IJ, Winfield JB, Yunus MB (2010) The American College of Rheumatology preliminary diagnostic criteria for fibromyalgia and measurement of symptom severity. Arthritis Care Res 62(5):600–610.  https://doi.org/10.1002/acr.20140 CrossRefGoogle Scholar
  13. 13.
    Wolfe F, Clauw DJ, Fitzcharles MA, Goldenberg DL, Hauser W, Katz RS, Mease P, Russell AS, Russell IJ, Winfield JB (2011) Fibromyalgia criteria and severity scales for clinical and epidemiological studies: a modification of the ACR preliminary diagnostic criteria for fibromyalgia. J Rheumatol 38(6):1113–1122.  https://doi.org/10.3899/jrheum.100594 CrossRefPubMedGoogle Scholar
  14. 14.
    Wolfe F, Clauw DJ, Fitzcharles MA, Goldenberg DL, Hauser W, Katz RL, Mease PJ, Russell AS, Russell IJ, Walitt B (2016) 2016 revisions to the 2010/2011 fibromyalgia diagnostic criteria. Semin Arthritis Rheum 46(3):319–329.  https://doi.org/10.1016/j.semarthrit.2016.08.012 CrossRefPubMedGoogle Scholar
  15. 15.
    Yunus MB (2015) Editorial review: an update on central sensitivity syndromes and the issues of nosology and psychobiology. Curr Rheumatol Rev 11(2):70–85CrossRefPubMedGoogle Scholar
  16. 16.
    Yunus MB (2007) Fibromyalgia and overlapping disorders: the unifying concept of central sensitivity syndromes. Semin Arthritis Rheum 36(6):339–356.  https://doi.org/10.1016/j.semarthrit.2006.12.009 CrossRefPubMedGoogle Scholar
  17. 17.
    Napadow V, Kim J, Clauw DJ, Harris RE (2012) Decreased intrinsic brain connectivity is associated with reduced clinical pain in fibromyalgia. Arthritis Rheum 64(7):2398–2403.  https://doi.org/10.1002/art.34412 CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Jensen KB, Loitoile R, Kosek E, Petzke F, Carville S, Fransson P, Marcus H, Williams SC, Choy E, Mainguy Y, Vitton O, Gracely RH, Gollub R, Ingvar M, Kong J (2012) Patients with fibromyalgia display less functional connectivity in the brain’s pain inhibitory network. Mol Pain 8:32.  https://doi.org/10.1186/1744-8069-8-32 CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Harris RE, Sundgren PC, Craig AD, Kirshenbaum E, Sen A, Napadow V, Clauw DJ (2009) Elevated insular glutamate in fibromyalgia is associated with experimental pain. Arthritis Rheum 60(10):3146–3152.  https://doi.org/10.1002/art.24849 CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Vaeroy H, Helle R, Forre O, Kass E, Terenius L (1988) Elevated CSF levels of substance P and high incidence of Raynaud phenomenon in patients with fibromyalgia: new features for diagnosis. Pain 32(1):21–26CrossRefPubMedGoogle Scholar
  21. 21.
    Russell IJ, Orr MD, Littman B, Vipraio GA, Alboukrek D, Michalek JE, Lopez Y, MacKillip F (1994) Elevated cerebrospinal fluid levels of substance P in patients with the fibromyalgia syndrome. Arthritis Rheum 37(11):1593–1601CrossRefPubMedGoogle Scholar
  22. 22.
    Giovengo SL, Russell IJ, Larson AA (1999) Increased concentrations of nerve growth factor in cerebrospinal fluid of patients with fibromyalgia. J Rheumatol 26(7):1564–1569PubMedGoogle Scholar
  23. 23.
    Sarchielli P, Mancini ML, Floridi A, Coppola F, Rossi C, Nardi K, Acciarresi M, Pini LA, Calabresi P (2007) Increased levels of neurotrophins are not specific for chronic migraine: evidence from primary fibromyalgia syndrome. J Pain 8(9):737–745.  https://doi.org/10.1016/j.jpain.2007.05.002 CrossRefPubMedGoogle Scholar
  24. 24.
    Vaeroy H, Sakurada T, Forre O, Kass E, Terenius L (1989) Modulation of pain in fibromyalgia (fibrositis syndrome): cerebrospinal fluid (CSF) investigation of pain related neuropeptides with special reference to calcitonin gene related peptide (CGRP). J Rheumatol Suppl 19:94–97PubMedGoogle Scholar
  25. 25.
    Reynolds WJ, Chiu B, Inman RD (1988) Plasma substance P levels in fibrositis. J Rheumatol 15(12):1802–1803PubMedGoogle Scholar
  26. 26.
    Tsilioni I, Russell IJ, Stewart JM, Gleason RM, Theoharides TC (2016) Neuropeptides CRH, SP, HK-1, and inflammatory cytokines IL-6 and TNF are increased in serum of patients with fibromyalgia syndrome, implicating mast cells. J Pharmacol Exp Ther 356(3):664–672.  https://doi.org/10.1124/jpet.115.230060 CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Kadetoff D, Lampa J, Westman M, Andersson M, Kosek E (2012) Evidence of central inflammation in fibromyalgia-increased cerebrospinal fluid interleukin-8 levels. J Neuroimmunol 242(1–2):33–38.  https://doi.org/10.1016/j.jneuroim.2011.10.013 CrossRefPubMedGoogle Scholar
  28. 28.
    Kosek E, Martinsen S, Gerdle B, Mannerkorpi K, Lofgren M, Bileviciute-Ljungar I, Fransson P, Schalling M, Ingvar M, Ernberg M, Jensen KB (2016) The translocator protein gene is associated with symptom severity and cerebral pain processing in fibromyalgia. Brain Behav Immun 58:218–227.  https://doi.org/10.1016/j.bbi.2016.07.150 CrossRefPubMedGoogle Scholar
  29. 29.
    Backryd E, Tanum L, Lind AL, Larsson A, Gordh T (2017) Evidence of both systemic inflammation and neuroinflammation in fibromyalgia patients, as assessed by a multiplex protein panel applied to the cerebrospinal fluid and to plasma. J Pain Res 10:515–525.  https://doi.org/10.2147/JPR.S128508 CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Rea K, Dinan TG, Cryan JF (2016) The microbiome: a key regulator of stress and neuroinflammation. Neurobiol Stress 4:23–33.  https://doi.org/10.1016/j.ynstr.2016.03.001 CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Lyon P, Cohen M, Quintner J (2011) An evolutionary stress-response hypothesis for chronic widespread pain (fibromyalgia syndrome). Pain Med 12(8):1167–1178.  https://doi.org/10.1111/j.1526-4637.2011.01168.x CrossRefPubMedGoogle Scholar
  32. 32.
    Geracioti TD Jr, Carpenter LL, Owens MJ, Baker DG, Ekhator NN, Horn PS, Strawn JR, Sanacora G, Kinkead B, Price LH, Nemeroff CB (2006) Elevated cerebrospinal fluid substance p concentrations in posttraumatic stress disorder and major depression. Am J Psychiatry 163(4):637–643.  https://doi.org/10.1176/appi.ajp.163.4.637 CrossRefPubMedGoogle Scholar
  33. 33.
    Xanthos DN, Sandkuhler J (2014) Neurogenic neuroinflammation: inflammatory CNS reactions in response to neuronal activity. Nat Rev Neurosci 15(1):43–53.  https://doi.org/10.1038/nrn3617 CrossRefPubMedGoogle Scholar
  34. 34.
    Garate I, Garcia-Bueno B, Madrigal JL, Bravo L, Berrocoso E, Caso JR, Mico JA, Leza JC (2011) Origin and consequences of brain toll-like receptor 4 pathway stimulation in an experimental model of depression. J Neuroinflammation 8:151.  https://doi.org/10.1186/1742-2094-8-151 CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Rosenkranz MA, Davidson RJ, Maccoon DG, Sheridan JF, Kalin NH, Lutz A (2013) A comparison of mindfulness-based stress reduction and an active control in modulation of neurogenic inflammation. Brain Behav Immun 27(1):174–184.  https://doi.org/10.1016/j.bbi.2012.10.013 CrossRefPubMedGoogle Scholar
  36. 36.
    Lentz MJ, Landis CA, Rothermel J, Shaver JL (1999) Effects of selective slow wave sleep disruption on musculoskeletal pain and fatigue in middle aged women. J Rheumatol 26(7):1586–1592PubMedGoogle Scholar
  37. 37.
    Zhu B, Dong Y, Xu Z, Gompf HS, Ward SA, Xue Z, Miao C, Zhang Y, Chamberlin NL, Xie Z (2012) Sleep disturbance induces neuroinflammation and impairment of learning and memory. Neurobiol Dis 48(3):348–355.  https://doi.org/10.1016/j.nbd.2012.06.022 CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Malin K, Littlejohn GO (2016) Psychological factors mediate key symptoms of fibromyalgia through their influence on stress. Clin Rheumatol 35(9):2353–2357.  https://doi.org/10.1007/s10067-016-3315-9 CrossRefPubMedGoogle Scholar
  39. 39.
    Milligan ED, Watkins LR (2009) Pathological and protective roles of glia in chronic pain. Nat Rev Neurosci 10(1):23–36.  https://doi.org/10.1038/nrn2533 CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Watkins LR, Maier SF (2005) Immune regulation of central nervous system functions: from sickness responses to pathological pain. J Intern Med 257(2):139–155.  https://doi.org/10.1111/j.1365-2796.2004.01443.x CrossRefPubMedGoogle Scholar
  41. 41.
    Desmeules JA, Cedraschi C, Rapiti E, Baumgartner E, Finckh A, Cohen P, Dayer P, Vischer TL (2003) Neurophysiologic evidence for a central sensitization in patients with fibromyalgia. Arthritis Rheum 48(5):1420–1429.  https://doi.org/10.1002/art.10893 CrossRefPubMedGoogle Scholar
  42. 42.
    Cagnie B, Coppieters I, Denecker S, Six J, Danneels L, Meeus M (2014) Central sensitization in fibromyalgia? A systematic review on structural and functional brain MRI. Semin Arthritis Rheum 44(1):68–75.  https://doi.org/10.1016/j.semarthrit.2014.01.001 CrossRefPubMedGoogle Scholar
  43. 43.
    Sluka KA, Clauw DJ (2016) Neurobiology of fibromyalgia and chronic widespread pain. Neuroscience 338:114–129.  https://doi.org/10.1016/j.neuroscience.2016.06.006 CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Kosek E, Hansson P (1997) Modulatory influence on somatosensory perception from vibration and heterotopic noxious conditioning stimulation (HNCS) in fibromyalgia patients and healthy subjects. Pain 70(1):41–51CrossRefPubMedGoogle Scholar
  45. 45.
    Julien N, Goffaux P, Arsenault P, Marchand S (2005) Widespread pain in fibromyalgia is related to a deficit of endogenous pain inhibition. Pain 114(1–2):295–302.  https://doi.org/10.1016/j.pain.2004.12.032 CrossRefPubMedGoogle Scholar
  46. 46.
    Harris RE, Clauw DJ, Scott DJ, McLean SA, Gracely RH, Zubieta JK (2007) Decreased central mu-opioid receptor availability in fibromyalgia. J Neurosci 27(37):10000–10006.  https://doi.org/10.1523/JNEUROSCI.2849-07.2007 CrossRefPubMedGoogle Scholar
  47. 47.
    Woolf CJ (2011) Central sensitization: implications for the diagnosis and treatment of pain. Pain 152(3 Suppl):S2–S15.  https://doi.org/10.1016/j.pain.2010.09.030
  48. 48.
    Roche S, Gabelle A, Lehmann S (2008) Clinical proteomics of the cerebrospinal fluid: towards the discovery of new biomarkers. Proteomics Clin Appl 2(3):428–436.  https://doi.org/10.1002/prca.200780040 CrossRefPubMedGoogle Scholar
  49. 49.
    Lewis T (1927) The blood vessels of the human skin and their responses. Shaw and Sons, LondonGoogle Scholar
  50. 50.
    Wallengren J, Moller H (1986) The effect of capsaicin on some experimental inflammations in human skin. Acta Derm Venereol 66(5):375–380PubMedGoogle Scholar
  51. 51.
    Holzer P (1998) Neurogenic vasodilatation and plasma leakage in the skin. Gen Pharmacol 30(1):5–11CrossRefPubMedGoogle Scholar
  52. 52.
    Schmelz M, Michael K, Weidner C, Schmidt R, Torebjork HE, Handwerker HO (2000) Which nerve fibers mediate the axon reflex flare in human skin? Neuroreport 11(3):645–648CrossRefPubMedGoogle Scholar
  53. 53.
    Chiu IM, von Hehn CA, Woolf CJ (2012) Neurogenic inflammation and the peripheral nervous system in host defense and immunopathology. Nat Neurosci 15(8):1063–1067.  https://doi.org/10.1038/nn.3144 CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Littlejohn GO, Weinstein C, Helme RD (1987) Increased neurogenic inflammation in fibrositis syndrome. J Rheumatol 14(5):1022–1025PubMedGoogle Scholar
  55. 55.
    Yunus M, Masi AT, Calabro JJ, Miller KA, Feigenbaum SL (1981) Primary fibromyalgia (fibrositis): clinical study of 50 patients with matched normal controls. Semin Arthritis Rheum 11(1):151–171CrossRefPubMedGoogle Scholar
  56. 56.
    Hauser W, Hayo S, Biewer W, Gesmann M, Kuhn-Becker H, Petzke F, von Wilmoswky H, Langhorst J (2010) Diagnosis of fibromyalgia syndrome—a comparison of Association of the Medical Scientific Societies in Germany, survey, and American College of Rheumatology criteria. Clin J Pain 26(6):505–511.  https://doi.org/10.1097/AJP.0b013e3181d92a6c CrossRefPubMedGoogle Scholar
  57. 57.
    Littlejohn G, Granges G (1995) The relationship between vertebral dysfunction and clinical features of fibromyalgia syndrome. J Orthopedic Rheum 8:97–105Google Scholar
  58. 58.
    Pay S, Calguneri M, Caliskaner Z, Dinc A, Apras S, Ertenli I, Kiraz S, Cobankara V (2000) Evaluation of vascular injury with proinflammatory cytokines, thrombomodulin and fibronectin in patients with primary fibromyalgia. Nagoya J Med Sci 63(3–4):115–122PubMedGoogle Scholar
  59. 59.
    Caro XJ (1984) Immunofluorescent detection of IgG at the dermal-epidermal junction in patients with apparent primary fibrositis syndrome. Arthritis Rheum 27(10):1174–1179CrossRefPubMedGoogle Scholar
  60. 60.
    Birklein F, Schmelz M (2008) Neuropeptides, neurogenic inflammation and complex regional pain syndrome (CRPS). Neurosci Lett 437(3):199–202.  https://doi.org/10.1016/j.neulet.2008.03.081 CrossRefPubMedGoogle Scholar
  61. 61.
    Blanco I, Beritze N, Arguelles M, Carcaba V, Fernandez F, Janciauskiene S, Oikonomopoulou K, de Serres FJ, Fernandez-Bustillo E, Hollenberg MD (2010) Abnormal overexpression of mastocytes in skin biopsies of fibromyalgia patients. Clin Rheumatol 29(12):1403–1412.  https://doi.org/10.1007/s10067-010-1474-7 CrossRefPubMedGoogle Scholar
  62. 62.
    Enestrom S, Bengtson A, Lindstrom F, Johan K (1990) Attachment of IgG to dermal extracellular matrix in patients with fibromyalgia. Clin Exp Rheumatol 8(2):127–135PubMedGoogle Scholar
  63. 63.
    Enestrom S, Bengtsson A, Frodin T (1997) Dermal IgG deposits and increase of mast cells in patients with fibromyalgia—relevant findings or epiphenomena? Scand J Rheumatol 26(4):308–313CrossRefPubMedGoogle Scholar
  64. 64.
    Caro XJ, Wolfe F, Johnston WH, Smith AL (1986) A controlled and blinded study of immunoreactant deposition at the dermal-epidermal junction of patients with primary fibrositis syndrome. J Rheumatol 13(6):1086–1092PubMedGoogle Scholar
  65. 65.
    Caro XJ (1986) Immunofluorescent studies of skin in primary fibrositis syndrome. Am J Med 81(3A):43–49CrossRefPubMedGoogle Scholar
  66. 66.
    Rodriguez-Pinto I, Agmon-Levin N, Howard A, Shoenfeld Y (2014) Fibromyalgia and cytokines. Immunol Lett 161(2):200–203.  https://doi.org/10.1016/j.imlet.2014.01.009 CrossRefPubMedGoogle Scholar
  67. 67.
    Generaal E, Vogelzangs N, Macfarlane GJ, Geenen R, Smit JH, Dekker J, Penninx BW (2014) Basal inflammation and innate immune response in chronic multisite musculoskeletal pain. Pain 155(8):1605–1612.  https://doi.org/10.1016/j.pain.2014.05.007 CrossRefPubMedGoogle Scholar
  68. 68.
    Uceyler N, Hauser W, Sommer C (2011) Systematic review with meta-analysis: cytokines in fibromyalgia syndrome. BMC Musculoskelet Disord 12:245.  https://doi.org/10.1186/1471-2474-12-245 CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Mendieta D, De la Cruz-Aguilera DL, Barrera-Villalpando MI, Becerril-Villanueva E, Arreola R, Hernandez-Ferreira E, Perez-Tapia SM, Perez-Sanchez G, Garces-Alvarez ME, Aguirre-Cruz L, Velasco-Velazquez MA, Pavon L (2016) IL-8 and IL-6 primarily mediate the inflammatory response in fibromyalgia patients. J Neuroimmunol 290:22–25.  https://doi.org/10.1016/j.jneuroim.2015.11.011 CrossRefPubMedGoogle Scholar
  70. 70.
    Gerdle B, Ghafouri B, Ghafouri N, Backryd E, Gordh T (2017) Signs of ongoing inflammation in female patients with chronic widespread pain: a multivariate, explorative, cross-sectional study of blood samples. Medicine 96(9):e6130.  https://doi.org/10.1097/MD.0000000000006130 CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Ranzolin A, Duarte AL, Bredemeier M, da Costa Neto CA, Ascoli BM, Wollenhaupt-Aguiar B, Kapczinski F, Xavier RM (2016) Evaluation of cytokines, oxidative stress markers and brain-derived neurotrophic factor in patients with fibromyalgia—a controlled cross-sectional study. Cytokine 84:25–28.  https://doi.org/10.1016/j.cyto.2016.05.011 CrossRefPubMedGoogle Scholar
  72. 72.
    Littlejohn G (2015) Neurogenic neuroinflammation in fibromyalgia and complex regional pain syndrome. Nat Rev Rheumatol 11(11):639–648.  https://doi.org/10.1038/nrrheum.2015.100 CrossRefPubMedGoogle Scholar
  73. 73.
    Behm FG, Gavin IM, Karpenko O, Lindgren V, Gaitonde S, Gashkoff PA, Gillis BS (2012) Unique immunologic patterns in fibromyalgia. BMC Clin Pathol 12:25.  https://doi.org/10.1186/1472-6890-12-25 CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Christidis N, Ghafouri B, Larsson A, Palstam A, Mannerkorpi K, Bileviciute-Ljungar I, Lofgren M, Bjersing J, Kosek E, Gerdle B, Ernberg M (2015) Comparison of the levels of pro-inflammatory cytokines released in the vastus lateralis muscle of patients with fibromyalgia and healthy controls during contractions of the quadriceps muscle—a microdialysis study. PLoS One 10(12):e0143856.  https://doi.org/10.1371/journal.pone.0143856 CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Heijmans-Antonissen C, Wesseldijk F, Munnikes RJ, Huygen FJ, van der Meijden P, Hop WC, Hooijkaas H, Zijlstra FJ (2006) Multiplex bead array assay for detection of 25 soluble cytokines in blister fluid of patients with complex regional pain syndrome type 1. Mediat Inflamm 2006(1):28398–28398.  https://doi.org/10.1155/MI/2006/28398 CrossRefGoogle Scholar
  76. 76.
    Huygen FJ, De Bruijn AG, De Bruin MT, Groeneweg JG, Klein J, Zijlstra FJ (2002) Evidence for local inflammation in complex regional pain syndrome type 1. Mediat Inflamm 11(1):47–51.  https://doi.org/10.1080/09629350210307 CrossRefGoogle Scholar
  77. 77.
    Munnikes RJ, Muis C, Boersma M, Heijmans-Antonissen C, Zijlstra FJ, Huygen FJ (2005) Intermediate stage complex regional pain syndrome type 1 is unrelated to proinflammatory cytokines. Mediat Inflamm 2005(6):366–372.  https://doi.org/10.1155/MI.2005.366 CrossRefGoogle Scholar
  78. 78.
    Martinez-Martinez LA, Mora T, Vargas A, Fuentes-Iniestra M, Martinez-Lavin M (2014) Sympathetic nervous system dysfunction in fibromyalgia, chronic fatigue syndrome, irritable bowel syndrome, and interstitial cystitis: a review of case-control studies. J Clin Rheumatol 20(3):146–150.  https://doi.org/10.1097/RHU.0000000000000089 CrossRefPubMedGoogle Scholar
  79. 79.
    Lerma C, Martinez A, Ruiz N, Vargas A, Infante O, Martinez-Lavin M (2011) Nocturnal heart rate variability parameters as potential fibromyalgia biomarker: correlation with symptoms severity. Arthritis Res Ther 13(6):R185.  https://doi.org/10.1186/ar3513 CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Lerma C, Martinez-Martinez LA, Ruiz N, Vargas A, Infante O, Martinez-Lavin M (2016) Fibromyalgia beyond reductionism. Heart rhythm fractal analysis to assess autonomic nervous system resilience. Scand J Rheumatol 45(2):151–157.  https://doi.org/10.3109/03009742.2015.1055299 CrossRefPubMedGoogle Scholar
  81. 81.
    Dawson LF, Phillips JK, Finch PM, Inglis JJ, Drummond PD (2011) Expression of alpha1-adrenoceptors on peripheral nociceptive neurons. Neuroscience 175:300–314.  https://doi.org/10.1016/j.neuroscience.2010.11.064 CrossRefPubMedGoogle Scholar
  82. 82.
    Maestroni GJ (2006) Sympathetic nervous system influence on the innate immune response. Ann N Y Acad Sci 1069:195–207.  https://doi.org/10.1196/annals.1351.017 CrossRefPubMedGoogle Scholar
  83. 83.
    Kosek E, Altawil R, Kadetoff D, Finn A, Westman M, Le Maitre E, Andersson M, Jensen-Urstad M, Lampa J (2015) Evidence of different mediators of central inflammation in dysfunctional and inflammatory pain—interleukin-8 in fibromyalgia and interleukin-1 beta in rheumatoid arthritis. J Neuroimmunol 280:49–55.  https://doi.org/10.1016/j.jneuroim.2015.02.002 CrossRefPubMedPubMedCentralGoogle Scholar
  84. 84.
    Uceyler N, Zeller D, Kahn AK, Kewenig S, Kittel-Schneider S, Schmid A, Casanova-Molla J, Reiners K, Sommer C (2013) Small fibre pathology in patients with fibromyalgia syndrome. Brain 136(Pt 6):1857–1867.  https://doi.org/10.1093/brain/awt053 CrossRefPubMedGoogle Scholar
  85. 85.
    de Tommaso M, Nolano M, Iannone F, Vecchio E, Ricci K, Lorenzo M, Delussi M, Girolamo F, Lavolpe V, Provitera V, Stancanelli A, Lapadula G, Livrea P (2014) Update on laser-evoked potential findings in fibromyalgia patients in light of clinical and skin biopsy features. J Neurol 261(3):461–472.  https://doi.org/10.1007/s00415-013-7211-9 CrossRefPubMedGoogle Scholar
  86. 86.
    Giannoccaro MP, Donadio V, Incensi A, Avoni P, Liguori R (2014) Small nerve fiber involvement in patients referred for fibromyalgia. Muscle Nerve 49(5):757–759.  https://doi.org/10.1002/mus.24156 CrossRefPubMedGoogle Scholar
  87. 87.
    Kosmidis ML, Koutsogeorgopoulou L, Alexopoulos H, Mamali I, Vlachoyiannopoulos PG, Voulgarelis M, Moutsopoulos HM, Tzioufas AG, Dalakas MC (2014) Reduction of Intraepidermal nerve fiber density (IENFD) in the skin biopsies of patients with fibromyalgia: a controlled study. J Neurol Sci 347(1–2):143–147.  https://doi.org/10.1016/j.jns.2014.09.035 CrossRefPubMedGoogle Scholar
  88. 88.
    Oaklander AL, Herzog ZD, Downs HM, Klein MM (2013) Objective evidence that small-fiber polyneuropathy underlies some illnesses currently labeled as fibromyalgia. Pain 154(11):2310–2316.  https://doi.org/10.1016/j.pain.2013.06.001 CrossRefPubMedGoogle Scholar
  89. 89.
    Caro XJ, Winter EF (2015) The role and importance of small fiber neuropathy in fibromyalgia pain. Curr Pain Headache Rep 19(12):55.  https://doi.org/10.1007/s11916-015-0527-7 CrossRefPubMedGoogle Scholar
  90. 90.
    Doppler K, Rittner HL, Deckart M, Sommer C (2015) Reduced dermal nerve fiber diameter in skin biopsies of patients with fibromyalgia. Pain 156(11):2319–2325.  https://doi.org/10.1097/j.pain.0000000000000285 CrossRefPubMedGoogle Scholar
  91. 91.
    Caro XJ, Winter EF (2014) Evidence of abnormal epidermal nerve fiber density in fibromyalgia: clinical and immunologic implications. Arthritis Rheumatol 66(7):1945–1954.  https://doi.org/10.1002/art.38662 CrossRefPubMedGoogle Scholar
  92. 92.
    Leinders M, Doppler K, Klein T, Deckart M, Rittner H, Sommer C, Uceyler N (2016) Increased cutaneous miR-let-7d expression correlates with small nerve fiber pathology in patients with fibromyalgia syndrome. Pain 157(11):2493–2503.  https://doi.org/10.1097/j.pain.0000000000000668 CrossRefPubMedGoogle Scholar
  93. 93.
    Serra J, Collado A, Sola R, Antonelli F, Torres X, Salgueiro M, Quiles C, Bostock H (2014) Hyperexcitable C nociceptors in fibromyalgia. Ann Neurol 75(2):196–208.  https://doi.org/10.1002/ana.24065 CrossRefPubMedGoogle Scholar
  94. 94.
    Kim SH, Kim DH, Oh DH, Clauw DJ (2008) Characteristic electron microscopic findings in the skin of patients with fibromyalgia: preliminary study. Clin Rheumatol 27(2):219–223.  https://doi.org/10.1007/s10067-007-0739-2 CrossRefPubMedGoogle Scholar
  95. 95.
    Ramirez M, Martinez-Martinez LA, Hernandez-Quintela E, Velazco-Casapia J, Vargas A, Martinez-Lavin M (2015) Small fiber neuropathy in women with fibromyalgia. An in vivo assessment using corneal confocal bio-microscopy. Semin Arthritis Rheum 45(2):214–219.  https://doi.org/10.1016/j.semarthrit.2015.03.003 CrossRefPubMedGoogle Scholar
  96. 96.
    Watson NF, Buchwald D, Goldberg J, Noonan C, Ellenbogen RG (2009) Neurologic signs and symptoms in fibromyalgia. Arthritis Rheum 60(9):2839–2844.  https://doi.org/10.1002/art.24772 CrossRefPubMedPubMedCentralGoogle Scholar
  97. 97.
    Harte S, Clauw D, Hayes JM, Feldman EL, St Charles IC, Watson CJ (2017) Reduced intraepidermal nerve fiber density after a sustained increase in insular glutamate: a proof-of-concept study examining the pathogenesis of small fiber pathology in fibromyalgia. Pain Rep 2(e590):1–6Google Scholar
  98. 98.
    Staud R, Nagel S, Robinson ME, Price DD (2009) Enhanced central pain processing of fibromyalgia patients is maintained by muscle afferent input: a randomized, double-blind, placebo-controlled study. Pain 145(1–2):96–104.  https://doi.org/10.1016/j.pain.2009.05.020 CrossRefPubMedPubMedCentralGoogle Scholar
  99. 99.
    Baron R, Hans G, Dickenson AH (2013) Peripheral input and its importance for central sensitization. Ann Neurol 74(5):630–636.  https://doi.org/10.1002/ana.24017 CrossRefPubMedGoogle Scholar
  100. 100.
    Grover S, Srivastava A, Lee R, Tewari AK, Te AE (2011) Role of inflammation in bladder function and interstitial cystitis. Ther Adv Urol 3(1):19–33.  https://doi.org/10.1177/1756287211398255 CrossRefPubMedPubMedCentralGoogle Scholar
  101. 101.
    Malhotra R (2016) Understanding migraine: potential role of neurogenic inflammation. Ann Indian Acad Neurol 19(2):175–182.  https://doi.org/10.4103/0972-2327.182302 CrossRefPubMedPubMedCentralGoogle Scholar
  102. 102.
    Feng B, La JH, Schwartz ES, Gebhart GF (2012) Irritable bowel syndrome: methods, mechanisms, and pathophysiology. Neural and neuro-immune mechanisms of visceral hypersensitivity in irritable bowel syndrome. Am J Physiol Gastrointest Liver Physiol 302(10):G1085–G1098.  https://doi.org/10.1152/ajpgi.00542.2011 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Departments of MedicineMonash University, and Rheumatology, MonashHealthMelbourneAustralia

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