Skip to main content

Advertisement

Log in

Possible Molecular Mediators Involved and Mechanistic Insight into Fibromyalgia and Associated Co-morbidities

  • Review
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Fibromyalgia is a chronic complex syndrome of non-articulate origin characterized by musculoskeletal pain, painful tender points, sleep problems and co-morbidities including depression, migraine. The etiopathogenesis of fibromyalgia is complex, variable and remains inconclusive. The etiological factors that have been defined include stress, genetic predisposition and environmental components. As per the reports of the American College of Rheumatology (ACR) the prevalence of fibromyalgia varies from 2 to 22% among the general population with poor diagnostic features primarily pain. Fibromyalgia encompasses a spectrum of co-morbid conditions with multifarious pathogenesis. The highly prevalent manifestations of fibromyalgia include heterogeneous pain and aches. Biochemical and neurobiological elements of fibromyalgia include neurotransmitters, hypothalamic pituitary adrenal axis (HPA axis), inflammatory cytokines, monoaminergic pathway, opioid peptides, sex hormones, nerve growth factor (NGF) and local free radical insult. An imbalance in the serotonergic system is the major underlying etiological factor that has been explored most widely. Owing to complex interplay of diverse pathophysiological pathways, overlapping co-morbidities such as depression have been clinically observed. Therapeutic management of fibromyalgia involves both non pharmacological and pharmacological measures. The current review presents various dysregulations and their association with symptoms of fibromyalgia along with their underlying neurobiological aspects.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Yunus MB, Dailey JW, Aldag JC, Masi AT, Jobe PC (1992) Plasma tryptophan and other amino acids in primary fibromyalgia: a controlled study. J Rheumatol 19:90–94

    CAS  PubMed  Google Scholar 

  2. Waylonis GW, Heck W (1992) Fibromyalgia syndrome. New associations. Am J Phys Med Rehabil 71:343–348

    Article  CAS  PubMed  Google Scholar 

  3. Kaplan KH, Goldenberg DL, Galvin-Nadeau M (1993) The impact of a meditation-based stress reduction program on fibromyalgia. Gen Hosp Psychiatry 15:284–289

    Article  CAS  PubMed  Google Scholar 

  4. Rizzi M, Radovanovic D, Santus P, Airoldi A, Frassanito F, Vanni S, Cristiano A, Masala IF, Sarzi-Puttini P (2017) Influence of autonomic nervous system dysfunction in the genesis of sleep disorders in fibromyalgia patients. Clin Exp Rheumatol 105:74–80

    Google Scholar 

  5. Tunks E, Crook J, Norman G, Kalaher S (1988) Tender points in fibromyalgia. Pain 34:11–19

    Article  CAS  PubMed  Google Scholar 

  6. 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 60:3146–3152

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Russell IJ, Vaeroy H, Javors M, Nyberg F (1992) Cerebrospinal fluid biogenic amine metabolites in fibromyalgia/fibrositis syndrome and rheumatoid arthritis. Arthritis Rheum 35:550–556

    Article  CAS  PubMed  Google Scholar 

  8. Hernandez-Leon A, De la Luz-Cuellar YE, Granados-Soto V, González-Trujano ME, Fernández-Guasti A (2018) Sex differences and estradiol involvement in hyperalgesia and allodynia in an experimental model of fibromyalgia. Horm Behav 97:39–46

    Article  CAS  PubMed  Google Scholar 

  9. Neyal M, Yimenicioglu F, Aydeniz A, Taskin A, Saglam S, Cekmen M, Neyal A, Gursoy S, Erel O, Balat A (2013) Plasma nitrite levels, total antioxidant status, total oxidant status, and oxidative stress index in patients with tension-type headache and fibromyalgia. Clin Neurol Neurosurg 115:736–740

    Article  PubMed  Google Scholar 

  10. Panerai AE, Vecchiet J, Panzeri P, Meroni P, Scarone S, Pizzigallo E, Giamberardino MA, Sacerdote P (2002) Peripheral blood mononuclear cell beta-endorphin concentration is decreased in chronic fatigue syndrome and fibromyalgia but not in depression: preliminary report. Clin J Pain 18:270–273

    Article  PubMed  Google Scholar 

  11. Laske C, Stransky E, Eschweiler GW, Klein R, Wittorf A, Leyhe T, Richartz E, Köhler N, Bartels M, Buchkremer G, Schott K (2007) Increased BDNF serum concentration in fibromyalgia with or without depression or antidepressants. J Psychiatry Res 41:600–605

    Article  Google Scholar 

  12. Schmidt-Wilcke T, Clauw DJ (2011) Fibromyalgia: from pathophysiology to therapy. Nat Rev Rheumatol 7:518

    Article  PubMed  Google Scholar 

  13. Sumpton JE, Moulin DE (2008) Fibromyalgia: presentation and management with a focus on pharmacological treatment. Pain Res Manag 13:477–483

    Article  PubMed  PubMed Central  Google Scholar 

  14. Häuser W, Ablin J, Fitzcharles MA, Littlejohn G, Luciano JV, Usui C, Walitt B (2015) Fibromyalgia. Nat Rev Dis Primers 1:15022

    Article  PubMed  Google Scholar 

  15. Wolfe F, Clauw DJ, FitzCharles M, Goldenerberg D, Häuser W, Katz RS, Russell IJ, Mease PJ, Russell A, Walitt B (2016) Revisions to the 2010/2011 fibromyalgia diagnostic criteria [abstract]. Semin Arthritis Rheum 46:319–329

    Article  PubMed  Google Scholar 

  16. Heymann RE, Paiva ES, Martinez JE, Helfenstein M Jr, Rezende MC, Provenza JR, Ranzolin A, Assis MR, Feldman DP, Ribeiro LS, Souza EJR (2017) New guidelines for the diagnosis of fibromyalgia. Rev Bras Reumatol Engl Ed 57:467–476

    Article  PubMed  Google Scholar 

  17. Bair MJ, Robinson RL, Katon W, Kroenke K (2003) Depression and pain comorbidity: a literature review. Arch Intern Med 163:2433–2445

    Article  Google Scholar 

  18. Kia S, Choy E (2017) Update on treatment guideline in fibromyalgia syndrome with focus on pharmacology. Biomedicines 5:20

    Article  CAS  PubMed Central  Google Scholar 

  19. Häuser W, Bernardy K, Uçeyler N, Sommer C (2009) Treatment of fibromyalgia syndrome with gabapentin and pregabalin: a meta-analysis of randomized controlled trials. Pain 145:69–81

    Article  CAS  PubMed  Google Scholar 

  20. Rheker J, Rief W, Doering BK, Winkler A (2018) Assessment of adverse events in clinical drug trials: identifying amitriptyline’s placebo- and baseline-controlled side effects. Exp Clin Psychopharmacol 26:320–326

    Article  PubMed  Google Scholar 

  21. Kulshreshtha P, Gupta R, Yadav RK, Bijlani RL, Deepak KK (2012) Effect of low-dose amitriptyline on autonomic functions and peripheral blood flow in fibromyalgia: a pilot study. Pain Med 13:131–136

    Article  PubMed  Google Scholar 

  22. Cunha FQ, Lorenzetti BB, Poole S, Ferreira SH (1991) Interleukin-8 as a mediator of sympathetic pain. Br J Pharmacol 104:765–767

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 8:737–745

    Article  CAS  PubMed  Google Scholar 

  24. Wallace DJ, Linker-Israeli M, Hallegua D, Silverman S, Silver D, Weisman MH (2001) Cytokines play an aetiopathogenetic role in fibromyalgia: a hypothesis and pilot study. Rheumatology 40:743–749

    Article  CAS  PubMed  Google Scholar 

  25. Torpy DJ, Papanicolaou DA, Lotsikas AJ, Wilder RL, Chrousos GP, Pillemer SR (2000) Responses of the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis to interleukin-6: a pilot study in fibromyalgia. Arthritis Rheum 43:872–880

    Article  CAS  PubMed  Google Scholar 

  26. Russell IJ, Michalek JE, Vipraio GA, Fletcher EM, Wall K (1989) Serum amino acids in fibrositis/fibromyalgia syndrome. J Rheumatol Suppl 19:158–163

    CAS  PubMed  Google Scholar 

  27. Stratz T, Samborski W, Hrycaj P, Pap T, Mackiewicz S, Mennet P, Müller W (1993) Serotonin concentration in serum of patients with generalized tendomyopathy (fibromyalgia) and chronic polyarthritis. Med Klin 88:458–462

    CAS  Google Scholar 

  28. Arnold LM, Lu Y, Crofford LJ, Wohlreich M, Detke MJ, Iyengar S, Goldstein DJ (2004) A double-blind, multicenter trial comparing duloxetine with placebo in the treatment of fibromyalgia patients with or without major depressive disorder. Arthritis Rheum 50:2974–2984

    Article  CAS  PubMed  Google Scholar 

  29. Mease PJ, Clauw DJ, Gendreau RM, Rao SG, Kranzler J, Chen W, Palmer RH (2009) The efficacy and safety of milnacipran for treatment of fibromyalgia. a randomized, double-blind, placebo-controlled trial. J Rheumatol 36:398–409

    Article  CAS  PubMed  Google Scholar 

  30. Gürsoy S, Erdal E, Sezgin M, Barlas IO, Aydeniz A, Alaşehirli B, Sahin G (2008) Which genotype of the MAO gene that the patients have are likely to be most susceptible to the symptoms of fibromyalgia? Rheumatol Int 28:307–311

    Article  CAS  PubMed  Google Scholar 

  31. Tort S, Urrútia G, Nishishinya MB, Walitt B (2012) Monoamine oxidase inhibitors (MAOIs) for fibromyalgia syndrome. Cochrane Database Syst Rev CD009807

  32. Kolhekar R, Murphy S, Gebhart GF (1997) Thalamic NMDA receptors modulate inflammation-produced hyperalgesia in the rat. Pain 71:31–40

    Article  CAS  PubMed  Google Scholar 

  33. Neugebauer V (2002) Metabotropic glutamate receptors–important modulators of nociception and pain behavior. Pain 98:1–8

    Article  CAS  PubMed  Google Scholar 

  34. Ogino S, Nagakura Y, Tsukamoto M, Watabiki T, Ozawa T, Oe T, Shimizu Y, Ito H (2013) Systemic administration of 5-HT(2C) receptor agonists attenuates muscular hyperalgesia in reserpine-induced myalgia model. Pharmacol Biochem Behav 108:8–15

    Article  CAS  PubMed  Google Scholar 

  35. Moldofsky H, Scarisbrick P, England R, Smythe H (1975) Musculosketal symptoms and non-REM sleep disturbance in patients with “fibrositis syndrome” and healthy subjects. Psychosom Med 37:341–351

    Article  CAS  PubMed  Google Scholar 

  36. Klein R, Bänsch M, Berg PA (1992) Clinical relevance of antibodies against serotonin and gangliosides in patients with primary fibromyalgia syndrome. Psychoneuroendocrinology 17:593–598

    Article  CAS  PubMed  Google Scholar 

  37. Klein R, Berg PA (1995) High incidence of antibodies to 5-hydroxytryptamine, gangliosides and phospholipids in patients with chronic fatigue and fibromyalgia syndrome and their relatives: evidence for a clinical entity of both disorders. Eur J Med Res 1:21–26

    CAS  PubMed  Google Scholar 

  38. Samborski W, Sluzewska A, Lacki JK, Sobieska M, Klein R, Mackiewicz S (1998) Antibodies against serotonin and gangliosides in patients with fibromyalgia and major depression. Hum Psychopharmacol 13:137–138

    Article  Google Scholar 

  39. Olin R, Klein R, Berg PA (1998) A randomised double-blind 16-week study of ritanserin in fibromyalgia syndrome: clinical outcome and analysis of auto-antibodies to serotonin, gangliosides and phospholipids. Clin Rheumatol 17:89–94

    Article  CAS  PubMed  Google Scholar 

  40. Park DJ, Takahashi Y, Kang JH, Yim YR, Kim JE, Lee JW, Lee KE, Lee JK, Lee SS (2017) Anti-N-methyl-D-aspartate receptor antibodies are associated with fibromyalgia in patients with systemic lupus erythematosus: a case–control study. Clin Exp Rheumatol 35:54–60

    PubMed  Google Scholar 

  41. Legangneux E, Mora JJ, Spreux-Varoquaux O, Thorin I, Herrou M, Alvado G, Gomeni C (2001) Cerebrospinal fluid biogenic amine metabolites, plasma-rich platelet serotonin and [3H] imipramine reuptake in the primary fibromyalgia syndrome. Rheumatology 40:290–296

    Article  CAS  PubMed  Google Scholar 

  42. Riva R, Mork PJ, Westgaard RH, Okkenhaug Johansen T, Lundberg U (2012) Catecholamines and heart rate in female fibromyalgia patients. J Psychosom Res 72:51–57

    Article  PubMed  Google Scholar 

  43. Ledermann K, Jenewein J, Sprott H, Hasler G, Schnyder U, Warnock G, Johayem A, Kollias S, Buck A, Martin-Soelch C (2016) Relation of dopamine receptor 2 binding to pain perception in female fibromyalgia patients with and without depression: A [11C] raclopride PET-study. Eur Neuropsychopharmacol 26:320–330

    Article  CAS  PubMed  Google Scholar 

  44. Malt EA, Olafsson S, Aakvaag A, Lund A, Ursin H (2003) Altered dopamine D2 receptor function in fibromyalgia patients: a neuroendocrine study with buspirone in women with fibromyalgia compared to female population based controls. J Affect Disord 75:77–82

    Article  CAS  PubMed  Google Scholar 

  45. Wood PB, Glabus MF, Simpson R, Patterson JC (2009) Changes in gray matter density in fibromyalgia: correlation with dopamine metabolism. J Pain 10:609–618

    Article  CAS  PubMed  Google Scholar 

  46. Holman AJ (2003) Ropinirole, open preliminary observations of a dopamine agonist for refractory fibromyalgia. J Clin Rheumatol 9:277–279

    Article  PubMed  Google Scholar 

  47. Holman AJ, Myers RR (2005) A randomized, double-blind, placebo-controlled trial of pramipexole, a dopamine agonist, in patients with fibromyalgia receiving concomitant medications. Arthritis Rheum 52:2495–2505

    Article  CAS  PubMed  Google Scholar 

  48. Mattson MP, Maudsley S, Martin B (2004) BDNF and 5-HT: a dynamic duo in age-related neuronal plasticity and neurodegenerative disorders. Trends Neurosci 27:589–594

    Article  CAS  PubMed  Google Scholar 

  49. Nijs J, Meeus M, Versijpt J, Moens M, Bos I, Knaepen K, Meeusen R (2015) Brain-derived neurotrophic factor as a driving force behind neuroplasticity in neuropathic and central sensitization pain: a new therapeutic target? Expert Opin Ther Targets 19:565–576

    Article  CAS  PubMed  Google Scholar 

  50. Nugraha B, Korallus C, Gutenbrunner C (2013) Serum level of brain-derived neurotrophic factor in fibromyalgia syndrome correlates with depression but not anxiety. Neurochem Int 62:281–286

    Article  CAS  PubMed  Google Scholar 

  51. 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

    Article  CAS  PubMed  Google Scholar 

  52. Duman RS, Malberg J, Nakagawa S, D’Sa C (2000) Neuronal plasticity and survival in mood disorders. Biol Psychiatry 48:732–739

    Article  CAS  PubMed  Google Scholar 

  53. Karege F, Perret G, Bondolfi G, Schwald M, Bertschy G, Aubry JM (2002) Decreased serum brain-derived neurotrophic factor levels in major depressed patients. Psychiatry Res 109:143–148

    Article  CAS  Google Scholar 

  54. Hoheisel U, Unger T, Mense S (2007) Sensitization of rat dorsal horn neurons by NGF-induced sub threshold potentials and low-frequency activation. A study employing intracellular recordings in vivo. Brain Res 1169:34–43

    Article  CAS  PubMed  Google Scholar 

  55. Merighi A, Salio C, Ghirri A, Lossi L, Ferrini F, Betelli C, Bardoni R (2008) BDNF as a pain modulator. Prog Neurobiol 85:297–317

    Article  CAS  PubMed  Google Scholar 

  56. Harris RE, Napadow V, Huggins JP, Pauer L, Kim J, Hampson J, Sundgren PC, Foerster B, Petrou M, Schmidt-Wilcke T, Clauw DJ (2013) Pregabalin rectifies aberrant brain chemistry, connectivity, and functional response in chronic pain patients. Anesthesiology 119:1453–1464

    Article  CAS  PubMed  Google Scholar 

  57. Pyke TL, Osmotherly PG, Baines S (2017) Measuring glutamate levels in the brains of fibromyalgia patients and a potential role for glutamate in the pathophysiology of fibromyalgia symptoms: a systematic review. Clin J Pain 33:944–954

    Article  PubMed  Google Scholar 

  58. Cohen SP, Verdolin MH, Chang AS, Kurihara C, Morlando BJ, Mao J (2006) The intravenous ketamine test predicts subsequent response to an oral dextromethorphan treatment regimen in fibromyalgia patients. J Pain 7:391–398

    Article  CAS  PubMed  Google Scholar 

  59. Sörensen J, Bengtsson A, Bäckman E, Henriksson KG, Bengtsson M (1995) Pain analysis in patients with fibromyalgia. Effects of intravenous morphine, lidocaine, and ketamine. Scand J Rheumatol 24:360–365

    Article  PubMed  Google Scholar 

  60. Rogalski SL, Appleyard SM, Pattillo A, Terman GW, Chavkin C (2000) TrkB activation by brain-derived neurotrophic factor inhibits the G protein-gated inward rectifier Kir3 by tyrosine phosphorylation of the channel. J Biol Chem 275:25082–25088

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Du J, Feng L, Zaitsev E, Je HS, Liu XW, Lu B (2003) Regulation of TrkB receptor tyrosine kinase and its internalization by neuronal activity and Ca2+ influx. J Cell Biol 163:385–395

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Guo W, Robbins MT, Wei F, Zou S, Dubner R, Ren K (2006) Supraspinal brain-derived neurotrophic factor signaling: a novel mechanism for descending pain facilitation. J Neurosci 26:126–137

    Article  CAS  PubMed  Google Scholar 

  63. Wong H, Kang I, Dong XD, Christidis N, Ernberg M, Svensson P, Cairns BE (2014) NGF-induced mechanical sensitization of the masseter muscle is mediated through peripheral NMDA receptors. Neuroscience 269:232–244

    Article  CAS  PubMed  Google Scholar 

  64. Bai G, Kusiak JW (1997) Nerve growth factor up-regulates the N-methyl-D-aspartate receptor subunit 1 promoter in PC12 cells. J BiolChem 272:5936–5942

    CAS  Google Scholar 

  65. Staud R, Vierck CJ, Robinson ME, Price DD (2005) Effects of the N-methyl-D-aspartate receptor antagonist dextromethorphan on temporal summation of pain are similar in fibromyalgia patients and normal control subjects. J Pain 6:323–332

    Article  CAS  PubMed  Google Scholar 

  66. Zhang JM, An J (2007) Cytokines, inflammation and pain. Int Anesthesiol Clin 45:27–37

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Watkins LR, Milligan ED, Maier SF (2003) Glial proinflammatory cytokines mediate exaggerated pain states: implications for clinical pain. Adv Exp Med Biol 521:1–21

    CAS  PubMed  Google Scholar 

  68. Maes M, Libbrecht I, Van Hunsel F, Lin AH, De Clerck L, Stevens W, Kenis G, de Jongh R, Bosmans E, Neels H (1999) The immune-inflammatory pathophysiology of fibromyalgia: increased serum soluble gp130, the common signal transducer protein of various neurotrophic cytokines. Psychoneuroendocrinology 24:371–383

    Article  CAS  PubMed  Google Scholar 

  69. Mendieta D, De la Cruz-Aguilera DL, Barrera-Villalpando MI, Becerril-Villanueva E, Arreola R, Hernández-Ferreira E, Pérez-Tapia SM, Pérez-Sánchez G, Garcés-Alvarez ME, Aguirre-Cruz L, Velasco-Velázquez MA, Pavón L (2016) IL-8 and IL-6 primarily mediate the inflammatory response in fibromyalgia patients. J Neuroimmunol 290:22–25

    Article  CAS  PubMed  Google Scholar 

  70. Salemi S, Rethage J, Wollina U, Michel BA, Gay RE, Gay S, Sprott H (2003) Detection of interleukin 1beta (IL-1beta), IL-6, and tumor necrosis factor-alpha in skin of patients with fibromyalgia. J Rheumatol 30:146–150

    CAS  PubMed  Google Scholar 

  71. Hader N, Rimon D, Kinarty A, Lahat N (1991) Altered interleukin-2 secretion in patients with primary fibromyalgia syndrome. Arthritis Rheum 34:866–872

    Article  CAS  PubMed  Google Scholar 

  72. Gür A, Karakoç M, Nas K, Remzi Cevik, Denli A, Saraç J (2002) Cytokines and depression in cases with fibromyalgia. J Rheumatol 29:358–361

    PubMed  Google Scholar 

  73. Bazzichi L, Rossi A, Massimetti G, Giannaccini G, Giuliano T, De Feo F, Ciapparelli A, Dell’Osso L, Bombardieri S (2007) Cytokine patterns in fibromyalgia and their correlation with clinical manifestations. Clin Exp Rheumatol 25:225–230

    CAS  PubMed  Google Scholar 

  74. Togo F, Natelson BH, Adler GK, Ottenweller JE, Goldenberg DL, Struzik ZR, Yamamoto Y (2009) Plasma cytokine fluctuations over time in healthy controls and patients with fibromyalgia. Exp Biol Med 234:232–240

    Article  CAS  Google Scholar 

  75. 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 242:33–38

    Article  CAS  PubMed  Google Scholar 

  76. Kashipaz MRA, Swinden D, Todd I, Powell RJ (2003) Normal production of inflammatory cytokines in chronic fatigue and fibromyalgia syndromes determined by intracellular cytokine staining in short-term cultured blood mononuclear cells. Clin Exp Immunol 132:360–365

    Article  Google Scholar 

  77. Kim YK, Na KS, Shin KH, Jung HY, Choi SH, Kim JB (2007) Cytokine imbalance in the pathophysiology of major depressive disorder. Prog Neuropsychopharmacol Biol Psychiatry 31:1044–1053

    Article  CAS  PubMed  Google Scholar 

  78. Yang P, Gao Z, Zhang H, Fang Z, Wu C, Xu H, Huang QJ (2015) Changes in proinflammatory cytokines and white matter in chronically stressed rats. Neuropsychiatr Dis Treat 11:597–607

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Shin HC, Oh S, Jung SC, Park J, Won CK (1997) Differential modulation of short and long latency sensory responses in the SI cortex by IL-6. NeuroReport 8:2841–2844

    Article  CAS  PubMed  Google Scholar 

  80. Yabuuchi K, Maruta E, Yamamoto J, Nishiyori A, Takami S, Minami M, Satoh M (1997) Intracerebroventricular injection of isoproterenol produces its analgesic effect through interleukin-1beta production. Eur J Pharmacol 334:133–140

    Article  CAS  PubMed  Google Scholar 

  81. Schwarz YA, Amin RS, Stark JM, Trapnell BC, Wilmott RW (1999) Interleukin-1 receptor antagonist inhibits interleukin-8 expression in A549 respiratory epithelial cells infected in vitro with a replication-deficient recombinant adenovirus vector. Am J Respir Cell Mol Biol 21:388–394

    Article  CAS  PubMed  Google Scholar 

  82. Harley JB, Gallagher G (1998) Lupus and interleukin 10. J Rheumatol 24:2273–2275

    Google Scholar 

  83. Cho KI, Lee JH, Kim SM, Lee HG, Kim TI (2011) Assessment of endothelial function in patients with fibromyalgia–cardiac ultrasound study. Clin Rheumatol 30:647–654

    Article  PubMed  Google Scholar 

  84. Topal G, Donmez A, Doğan BS, Kucur M, Cengiz DT, Berkoz FB, Erdogan N (2011) Asymmetric dimethylarginine (ADMA) levels are increased in patients with fibromyalgia: correlation with tumor necrosis factor-α (TNF-α) and 8-iso-prostaglandin F(2α) (8-iso-PGF(2α)). Clin Biochem 44:364–367

    Article  CAS  PubMed  Google Scholar 

  85. Pache M, Ochs J, Genth E, Mierau R, Kube T, Flammer J (2003) Increased plasma endothelin-1 levels in fibromyalgia syndrome. Rheumatology 42:493–494

    Article  CAS  PubMed  Google Scholar 

  86. Nah SS, Lee H, Hong Y, Im J, Won H, Chang SH, Kim HK, Kwon JT, Kim HJ (2017) Association between endothelin-1 and fibromyalgia syndrome. Mol Med Rep 16:6234–6239

    Article  CAS  PubMed  Google Scholar 

  87. Haynes WG, Strachan FE, Webb DJ (1995) Endothelin ETA and ETB receptors cause vasoconstriction of human resistance and capacitance vessels in vivo. Circulation 92:357–363

    Article  CAS  PubMed  Google Scholar 

  88. Boger RH (2006) Asymmetric dimethylarginine (ADMA): a novel risk marker in cardiovascular medicine and beyond. Ann Med 38:126–136

    Article  CAS  PubMed  Google Scholar 

  89. Surdacki A, Martens-Lobenhoffer J, Wloch A, Marewicz E, Rakowski T, WieczorekSurdacka E (2007) Elevated plasma asymmetric dimethyl-l-arginine levels are linked to endothelial progenitor cell depletion and carotid atherosclerosis in rheumatoid arthritis. Arthritis Rheum 56:809–819

    Article  CAS  PubMed  Google Scholar 

  90. Ito A, Tsao PS, Adimoolam S, Kimoto M, Ogawa T, Cooke JP (1999) Novel mechanism for endothelial dysfunction: dysregulation of dimethyl arginine dimethylaminohydrolase. Circulation 99:3092–3095

    Article  CAS  PubMed  Google Scholar 

  91. Hudson JI, Goldenberg DL, Pope HG Jr, Keck PE Jr, Schlesinger L (1992) Comorbidity of fibromyalgia with medical and psychiatric disorders. Am J Med 92:363–367

    Article  CAS  PubMed  Google Scholar 

  92. Vij B, Whipple MO, Tepper SJ, Mohabbat AB, Stillman M, Vincent A (2015) Frequency of migraine headaches in patients with fibromyalgia. Headache 55:860–865

    Article  PubMed  Google Scholar 

  93. Cho SJ, Sohn JH, Bae JS, Chu MK (2017) Fibromyalgia among patients with Chronic migraine and chronic tension-type headache: a multicenter prospective cross-sectional study. Headache 57:1583–1592

    Article  PubMed  Google Scholar 

  94. Munno I, Centonze V, Marinaro M, Bassi A, Lacedra G, Causarano V, Nardelli P, Cassiano MA, Albano O (1998) Cytokines and migraine: increase of IL-5 and IL-4 plasma levels. Headache 38:465–467

    Article  CAS  PubMed  Google Scholar 

  95. Perini F, D’Andrea G, Galloni E, Pignatelli F, Billo G, Alba S, Bussone G, Toso V (2005) Plasma cytokine levels in migraineurs and controls. Headache 45:926–931

    Article  PubMed  Google Scholar 

  96. Aydın M, Feyzi-Demir C, Arıkanoğlu A, Bulut S, İlhan N (2015) Plasma cytokine levels in migraineurs during and outside of attacks. Eur J Gen Med 12:307–312

    Google Scholar 

  97. Veldhuis JD, Sharma A, Roelfsema F (2013) Age-dependent and gender-dependent regulation of hypothalamic-adrenocorticotropic-adrenal axis. Endocrinol Metab Clin N Am 42:201–225

    Article  CAS  Google Scholar 

  98. Rivier C, Vale W (1983) Modulation of stress-induced ACTH release by corticotropin-releasing factor, catecholamines and vasopressin. Nature 305:325–327

    Article  CAS  PubMed  Google Scholar 

  99. Crofford LJ, Pillemer SR, Kalogeras KT, Cash JM, Michelson D, Kling MA, Sternberg EM, Gold PW, Chrousos GP, Wilder RL (1994) Hypothalamic-pituitary-adrenal axis perturbations in patients with fibromyalgia. Arthritis Rheum 37:1583–1592

    Article  CAS  PubMed  Google Scholar 

  100. Adler GK, Kinsley BT, Hurwitz S, Mossey CJ, Goldenberg DL (1999) Reduced hypothalamic-pituitary and sympathoadrenal responses to hypoglycemia in women with fibromyalgia syndrome. Am J Med 106:534–543

    Article  CAS  PubMed  Google Scholar 

  101. Griep EN, Boersma JW, de Kloet ER (1993) Altered reactivity of the hypothalamic-pituitary-adrenal axis in the primary fibromyalgia syndrome. J Rheumatol 20:469–474

    CAS  PubMed  Google Scholar 

  102. 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 356:664–672

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. McLean SA, Williams DA, Stein PK, Harris RE, Lyden AK, Whalen G, Park KM, Liberzon I, Sen A, Gracely RH, Baraniuk JN, Clauw DJ (2006) Cerebrospinal fluid corticotropin-releasing factor concentration is associated with pain but not fatigue symptoms in patients with fibromyalgia. Neuropsychopharmacology 31:2776–2782

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Wager TD, Rilling JK, Smith EE, Sokolik A, Casey KL, Davidson RJ, Kosslyn SM, Rose RM, Cohen JD (2004) Placebo-induced changes in FMRI in the anticipation and experience of pain. Science 303:1162–1167

    Article  CAS  PubMed  Google Scholar 

  105. Makino S, Shibasaki T, Yamauchi N, Nishioka T, Mimoto T, Wakabayashi I, Gold PW, Hashimoto K (1999) Psychological stress increased corticotropin-releasing hormone mRNA and content in the central nucleus of the amygdala but not in the hypothalamic paraventricular nucleus in the rat. Brain Res 850:136–143

    Article  CAS  PubMed  Google Scholar 

  106. Fatima G, Mahdi F (2017) Deciphering the role of oxidative and antioxidative parameters and toxic metal ion content in women with fibromyalgia syndrome. Free Radic Biol Med 112:23–24

    Article  Google Scholar 

  107. Cordero MD, Moreno-Fernández AM, deMiguel M, Bonal P, Campa F, Jiménez-Jiménez LM, Ruiz-Losada A, Sánchez-Domínguez B, Sánchez Alcázar JA, Salviati L, Navas P (2009) Coenzyme Q10 distribution in blood is altered in patients with fibromyalgia. Clin Biochem 42:732–735

    Article  CAS  PubMed  Google Scholar 

  108. Lister RE (2002) An open, pilot study to evaluate the potential benefits of coenzyme Q10 combined with Ginkgo biloba extract in fibromyalgia syndrome. J Int Med Res 30:195–199

    Article  CAS  PubMed  Google Scholar 

  109. Bagis S, Tamer L, Sahin G, Bilgin R, Guler H, Ercan B, Erdogan C (2005) Free radicals and antioxidants in primary fibromyalgia: an oxidative stress disorder? Rheumatol Int 25:188–190

    Article  CAS  PubMed  Google Scholar 

  110. Andreazza AC, Kauer-Sant’anna M, Frey BN, Bond DJ, Kapczinski F, Young LT, Yatham LN (2008) Oxidative stress markers in bipolar disorder: a meta-analysis. J Affect Disord 111:135–144

    Article  CAS  Google Scholar 

  111. Palta P, Samuel LJ, Miller ER 3rd, Szanton SL (2014) Depression and oxidative stress: results from a meta-analysis of observational studies. Psychosom Med 76:12–19

    Article  CAS  PubMed  Google Scholar 

  112. Curti C, Mingatto FE, Polizello AC, Galastri LO, Uyemura SA, Santos AC (1999) Fluoxetine interacts with the lipid bilayer of the inner membrane in isolated rat brain mitochondria, inhibiting electron transport and F1F0-ATPase activity. Mol Cell Biochem 199:103–109

    Article  CAS  PubMed  Google Scholar 

  113. Schmidt AJ, Heiser P, Hemmeter UM, Krieg JC, Vedder H (2008) Effects of antidepressants on mRNA levels of antioxidant enzymes in human monocytic U-937 cells. Prog Neuropsychopharmacol Biol Psychiatry 32:1567–1573

    Article  CAS  PubMed  Google Scholar 

  114. Koroschetz J, Rehm SE, Gockel U, Brosz M, Freynhagen R, Tölle TR, Baron R (2011) Fibromyalgia and neuropathic pain–differences and similarities. A comparison of 3057 patients with diabetic painful neuropathy and fibromyalgia. BMC Neurol 11:55

    Article  PubMed  PubMed Central  Google Scholar 

  115. Pathak NN, Balaganur V, Lingaraju MC, Kant V, Latief N, More AS, Kumar D, Kumar D, Tandan SK (2014) Atorvastatin attenuates neuropathic pain in rat neuropathy model by down-regulating oxidative damage at peripheral, spinal and supraspinal levels. Neurochem Int 68:1–9

    Article  CAS  PubMed  Google Scholar 

  116. Montuschi P, Barnes P, Roberts LJ II (2007) Insights into oxidative stress: the isoprostanes. Curr Med Chem 14:703–717

    Article  CAS  PubMed  Google Scholar 

  117. Chen C, Li L, Zhou HJ, Min W (2017) The role of NOX4 and TRX2 in angiogenesis and their potential cross-talk. Antioxidants 6:42

    Article  CAS  PubMed Central  Google Scholar 

  118. Geis C, Geuss E, Sommer C, Schmidt HH, Kleinschnitz C (2017) NOX4 is an early initiator of neuropathic pain. Exp Neurol 288:94–103

    Article  CAS  PubMed  Google Scholar 

  119. Naik AK, Tandan SK, Dudhgaonkar SP, Jadhav SH, Kataria M, Prakash VR, Kumar D (2006) Role of oxidative stress in pathophysiology of peripheral neuropathy and modulation by N-acetyl-l-cysteine in rats. Eur J Pain 10:573–579

    Article  CAS  PubMed  Google Scholar 

  120. Orshal JM, Khalil RA (2004) Gender, sex hormones, and vascular tone. Am J Physiol Regul Integr Comp Physiol 286:233–249

    Article  Google Scholar 

  121. Van der Meulen MCH, Hernandez MCJ (2013) Chapter 21: adaptation of skeletal structure to mechanical loading. Osteoporosis, 4th edn. Elsevier, Amsterdam, pp 477–495

    Google Scholar 

  122. Martínez-Jauand M, Sitges C, Femenia J, Cifre I, González S, Chialvo D, Montoya P (2013) Age-of-onset of menopause is associated with enhanced painful and non-painful sensitivity in fibromyalgia. Clin Rheumatol 32:975–981

    Article  PubMed  Google Scholar 

  123. Schertzinger M, Wesson-Sides K, Parkitny L, Younger J (2018) Daily fluctuations of progesterone and testosterone are associated with fibromyalgia pain severity. J Pain 19:410–417

    Article  CAS  PubMed  Google Scholar 

  124. White HD, Brown LA, Gyurik RJ, Manganiello PD, Robinson TD, Hallock LS, Lewis LD, Yeo KT (2015) Treatment of pain in fibromyalgia patients with testosterone gel: pharmacokinetics and clinical response. Int Immunopharmacol 27:249–256

    Article  CAS  PubMed  Google Scholar 

  125. Vincent K, Tracey I (2008) Hormones and their interaction with the pain experience. Rev Pain 2:20–24

    Article  PubMed  PubMed Central  Google Scholar 

  126. Epperson CN, Amin Z, Ruparel K, Gur R, Loughead J (2012) Interactive effects of estrogen and serotonin on brain activation during working memory and affective processing in menopausal women. Psychoneuroendocrinology 37:372–382

    Article  CAS  PubMed  Google Scholar 

  127. Jones GT, Atzeni F, Beasley M, Flüß E, Sarzi-Puttini P, Macfarlane GJ (2015) The prevalence of fibromyalgia in the general population: a comparison of the American College of Rheumatology 1990, 2010, and modified 2010 classification criteria. Arthritis Rheumatol 67:568–575

    Article  PubMed  Google Scholar 

  128. Carr DJ, Serou M (1995) Exogenous and endogenous opioids as biological response modifiers. Immunopharmacology 31:59–71

    Article  CAS  PubMed  Google Scholar 

  129. Khedr EM, Omran EAH, Ismail NM, El-Hammady DH, Goma SH, Kotb H, Galal H, Osman AM, Farghaly HSM, Karim AA, Ahmed GA (2017) Effects of transcranial direct current stimulation on pain, mood and serum endorphin level in the treatment of fibromyalgia: a double blinded, randomized clinical trial. Brain Stimul 10:893–901

    Article  PubMed  Google Scholar 

  130. Ignelzi RJ, Atkinson JH (1980) Pain and its modulation. Part 2. Efferent mechanisms. Neurosurgery 6:584–590

    Article  CAS  PubMed  Google Scholar 

  131. Sun YG, Lundeberg T, Yu LC (2003) Involvement of endogenous beta-endorphin in antinociception in the arcuate nucleus of hypothalamus in rats with inflammation. Pain 104:55–63

    Article  CAS  PubMed  Google Scholar 

  132. Shahed AR, Shoskes DA (2001) Correlation of beta-endorphin and prostaglandin E2 levels in prostatic fluid of patients with chronic prostatitis with diagnosis and treatment response. J Urol 166:1738–1741

    Article  CAS  PubMed  Google Scholar 

  133. Baraniuk JN, Whalen G, Cunningham J, Clauw DJ (2004) Cerebrospinal fluid levels of opioid peptides in fibromyalgia and chronic low back pain. BMC Musculoskelet Disord 5:48

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Fiquerola MD, Loe WH, Barontini M (1997) Plasma met-enkephalin response to local treatment in patients with fibromyalgia. J Neurol Sci 150:S335

    Article  Google Scholar 

  135. Vaerøy H, Nyberg F, Terenius L (1991) No evidence for endorphin deficiency in fibromyalgia following investigation of cerebrospinal fluid (CSF) dynorphin A and Met-enkephalin-Arg6-Phe7. Pain 46:139–143

    Article  PubMed  Google Scholar 

  136. Younger J, Mackey S (2009) Fibromyalgia symptoms are reduced by low-dose naltrexone: a pilot study. Pain Med 10:663–672

    Article  PubMed  PubMed Central  Google Scholar 

  137. Vaeroy H, Helle R, Førre O, Kåss E, Terenius L (1988) Cerebrospinal fluid levels of beta-endorphin in patients with fibromyalgia (fibrositis syndrome). J Rheumatol 15:1804–1806

    CAS  PubMed  Google Scholar 

  138. Yunus MB, Denko CW, Masi AT (1986) Serum beta-endorphin in primary fibromyalgia syndrome: a controlled study. J Rheumatol 13:183–186

    CAS  PubMed  Google Scholar 

  139. Price DD, Staud R, Robinson ME, Mauderli AP, Cannon R, Vierck CJ (2002) Enhanced temporal summation of second pain and its central modulation in fibromyalgia patients. Pain 99:49–59

    Article  PubMed  Google Scholar 

  140. Younger JW, Zautra AJ, Cummins ET (2009) Effects of naltrexone on pain sensitivity and mood in fibromyalgia: no evidence for endogenous opioid pathophysiology. PLoS ONE 4:e5180

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Kozanoglu E, Canataroglu A, Abayli B, Colakoglu S, Goncu K (2003) Fibromyalgia syndrome in patients with hepatitis C infection. Rheumatol Int 23:248–251

    Article  PubMed  Google Scholar 

  142. Rivera J, De Diego A, Trinchet M, Garcia Monforte A (1997) Fibromyalgia-associated hepatitis C virus infection. Br J Rheumatol 36:981–985

    Article  CAS  PubMed  Google Scholar 

  143. Buskila D, Shnaider A, Neumann L, Lorber M, Zilberman D, Hilzenrat N, Kuperman OJ, Sikuler E (1998) Musculoskeletal manifestations and autoantibody profilein 90 hepatitis C virus infected israeli patients. Semin Athritis Rheum 28:107–113

    Article  CAS  Google Scholar 

  144. Cacoub P, Poynard T, Ghillani P, Charlotte F, Olivi M, Charles Piette J, Opolon P (1999) Extrahepatic manifestations of chronic hepatitis C. Arthritis Rheum 42:2204–2212

    Article  CAS  PubMed  Google Scholar 

  145. Koziel MJ, Dudley D, Wong JT, Dienstag J, Houghton M, Ralston R, Walker BD (1992) Intrahepatic cytotoxic T lymphocytes specific for hepatitis C virus in persons with chronic hepatitis. J Immunol 149:3339–3344

    CAS  PubMed  Google Scholar 

  146. Cacciarelli TV, Martinez OM, Gish RG, Villanueva JC, Krams SM (1996) Immunoregulatory cytokines in chronic hepatitis C virus infection: pre-and post treatment with interferon alfa. Hepatology 24:6–9

    Article  CAS  PubMed  Google Scholar 

  147. Sivri A, Cindaş A, Dincer F, Sivri B (1996) Bowel dysfunction and irritable bowel syndrome in fibromyalgia patients. Clin Rheumatol 15:283–286

    Article  CAS  PubMed  Google Scholar 

  148. Lubrano E, Iovino P, Tremolaterra F, Parsons WJ, Ciacci C, Mazzacca G (2001) Fibromyalgia in patients with irritable bowel syndrome. Int J Colorectal Dis 16:211–215

    Article  CAS  PubMed  Google Scholar 

  149. Chang L (1998) The association of functional gastrointestinal disorders and fibromyalgia. Eur J Sur Suppl 583:32–36

    Article  Google Scholar 

  150. Yang TY, Chen CS, Lin CL, Lin WM, Kuo CN, Kao CH (2017) Risk for irritable bowel syndrome in fibromyalgia patients: a national database study. Medicine 96:e6657

    Article  PubMed  PubMed Central  Google Scholar 

  151. Yu YB, Zuo XL, Zhao QJ, Chen FX, Yang J, Dong YY, Wang P, Li YQ (2012) Brain-derived neurotrophic factor contributes to abdominal pain in irritable bowel syndrome. Gut 61:685–694

    Article  CAS  PubMed  Google Scholar 

  152. Wang P, Du C, Chen FX, Li CQ, Yu YB, Han T, Akhtar S, Zuo XL, Tan XD, Li YQ (2016) BDNF contributes to IBS-like colonic hypersensitivity via activating the enteroglia-nerve unit. Sci Rep 6:20320

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Malatji BG, Meyer H, Mason S, Engelke UF, Wevers RA, Van Reenen M, Reinecke CJ (2017) A diagnostic biomarker profile for fibromyalgia syndrome based on an NMR metabolomics study of selected patients and controls. BMC Neurol 17:88

    Article  PubMed  PubMed Central  Google Scholar 

  154. Roman P, Estévez AF, Miras A, Sánchez-Labraca N, Cañadas F, Vivas AB, Cardona D (2018) A pilot randomized controlled trial to explore cognitive and emotional effects of probiotics in fibromyalgia. Sci Rep 8:10965

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Meddings JB, Swain MG (2000) Environmental stress-induced gastrointestinal permeability is mediated by endogenous glucocorticoids in the rat. Gastroenterology 119:1019

    Article  CAS  PubMed  Google Scholar 

  156. Liu L, Zhu G (2018) Gut-brain axis and mood disorder. Front Psychiatry 9:223

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Cani PD, Osto M, Geurts L, Everard A (2012) Involvement of gut microbiota in the development of low-grade inflammation and type 2 diabetes associated with obesity. Gut Microbes 3:279–288

    Article  PubMed  PubMed Central  Google Scholar 

  158. Dantzer R, Konsman JP, Bluthé RM, Kelley KW (2000) Neural and humoral pathways of communication from the immune system to the brain: parallel or convergent? Auton Neurosci 85:60–65

    Article  CAS  PubMed  Google Scholar 

  159. Kelly JR, Borre Y, O’Brien C, Patterson E, El Aidy S, Deane J, Kennedy PJ, Beers S, Scott K, Moloney G, Hoban AE (2016) Transferring the blues: depression-associated gut microbiota induces neurobehavioural changes in the rat. J Psychiatry Res 82:109–118

    Article  Google Scholar 

  160. Aizawa E, Tsuji H, Asahara T, Takahashi T, Teraishi T, Yoshida S, Koga N, Hattori K, Ota M, Kunugi H (2018) Bifidobacterium and Lactobacillus counts in the gut microbiota of patients with bipolar disorder and healthy controls. Front Psychiatry 9:730

    Article  PubMed  Google Scholar 

  161. Anch AM, Lue FA, MacLean AW, Moldofsky H (1991) Sleep physiology and psychological aspects of the fibrositis (fibromyalgia) syndrome. Can J Psychol 45:179–184

    Article  CAS  PubMed  Google Scholar 

  162. Bennett RM, Jones J, Turk DC, Russell IJ, Matallana L (2007) An internet survey of 2,596 people with fibromyalgia. BMC Musculoskelet Disord 8:27

    Article  PubMed  PubMed Central  Google Scholar 

  163. Häuser W, Zimmer C, Felde E, Köllner V (2008) What are the key symptoms of fibromyalgia? Results of a survey of the German fibromyalgia association. Schmerz 22:176–183

    Article  PubMed  Google Scholar 

  164. Affleck G, Urrows S, Tennen H, Higgins P, Abeles M (1996) Sequential daily relations of sleep, pain intensity, and attention to pain among women with fibromyalgia. Pain 68:363–368

    Article  CAS  PubMed  Google Scholar 

  165. Ağargün MY, Tekeoğlu I, Güneş A, Adak B, Kara H, Ercan M (1999) Sleep quality and pain threshold in patients with fibromyalgia. Compr Psychiatry 40:226–228

    Article  PubMed  Google Scholar 

  166. Gupta A, Silman AJ, Ray D, Morriss R, Dickens C, MacFarlane GJ, Chiu YH, Nicholl B, McBeth J (2007) The role of psychosocial factors in predicting the onset of chronic widespread pain: results from a prospective population-based study. Rheumatology 46:666–671

    Article  CAS  PubMed  Google Scholar 

  167. Bigatti SM, Hernandez AM, Cronan TA, Rand KL (2008) Sleep disturbances in fibromyalgia syndrome: relationship to pain and depression. Arthritis Rheum 59:961–967

    Article  PubMed  PubMed Central  Google Scholar 

  168. Consoli G, Marazziti D, Ciapparelli A, Bazzichi L, Massimetti G, Giacomelli C, Rossi A, Bombardieri S, Dell’Osso L (2012) The impact of mood, anxiety, and sleep disorders on fibromyalgia. Compr Psychiatry 53:962–967

    Article  PubMed  Google Scholar 

  169. Keskindag B, Karaaziz M (2017) The association between pain and sleep in fibromyalgia. Saudi Med J 38:5

    Article  Google Scholar 

  170. Lieb K, Ahlvers K, Dancker K, Strohbusch S, Reincke M, Feige B, Berger M, Riemann D, Voderholzer U (2002) Effects of the neuropeptide substance P on sleep, mood, and neuroendocrine measures in healthy young men. Neuropsychopharmacology 27:1041–1049

    Article  CAS  PubMed  Google Scholar 

  171. Andersen ML, Nascimento DC, Machado RB, Roizenblatt S, Moldofsky H, Tufik S (2006) Sleep disturbance induced by substance P in mice. Behav Brain Res 167:212–218

    Article  CAS  PubMed  Google Scholar 

  172. Sideri A, Bakirtzi K, Shih DQ, Koon HW, Fleshner P, Arsenescu R, Arsenescu V, Turner JR, Karagiannides I, Pothoulakis C (2015) Substance-P mediates pro-inflammatory cytokine release form mesenteric adipocytes in inflammatory bowel disease patients. Cell Mol Gastroenterol Hepatol 1:420–432

    Article  PubMed  PubMed Central  Google Scholar 

  173. Bennett RM (2002) Adult growth hormone deficiency in patients with fibromyalgia. Curr Rheumatol Rep 4:306–312

    Article  PubMed  Google Scholar 

  174. Cuatrecasas G, Gonzalez MJ, Alegre C, Sesmilo G, Fernandez-Solà J, Casanueva FF, Garcia-Fructuoso F, Poca-Dias V, Izquierdo JP, Puig-Domingo M (2010) High prevalence of growth hormone deficiency in severe fibromyalgia syndromes. J Clin Endocrinol Metab 95:4331–4337

    Article  CAS  PubMed  Google Scholar 

  175. Paiva ES, Deodhar A, Jones KD, Bennett R (2002) Impaired growth hormone secretion in fibromyalgia patients: evidence for augmented hypothalamic somatostatin tone. Arthritis Rheum 46:1344–1350

    Article  CAS  PubMed  Google Scholar 

  176. Beranek L, Hajdu I, Gardi J, Taishi P, Obál F Jr, Krueger JM (1999) Central administration of the somatostatin analog octreotide induces captopril-insensitive sleep responses. Am J Physiol Regul Integr Comp Physiol 277:1297–1304

    Article  Google Scholar 

  177. Ziegenbein M, Held K, Kuenzel HE, Murck H, Antonijevic IA, Steiger A (2004) The somatostatin analogue octreotide impairs sleep and decreases EEG sigma power in young male subjects. Neuropsychopharmacology 29:146

    Article  CAS  PubMed  Google Scholar 

  178. Bennett RM, Jones J, Turk DC, Russell IJ, Matallana L (2007) An internet survey of 2,596 people with fibromyalgia. BMC Musculoskel Disord 8:27

    Article  Google Scholar 

  179. Bou Khalil R, Khoury E, Richa S (2016) Do fibromyalgia flares have a neurobiological substrate? Pain Med 17:469–475

    PubMed  Google Scholar 

  180. Ablin JN, Zohar AH, Zaraya-Blum R, Buskila D (2016) Distinctive personality profiles of fibromyalgia and chronic fatigue syndrome patients. Peer J 4:2421

    Article  Google Scholar 

  181. Heisler LK, Pronchuk N, Nonogaki K, Zhou L, Raber J, Tung L, Yeo GS, O’Rahilly S, Colmers WF, Elmquist JK, Tecott LH (2007) Serotonin activates the hypothalamic–pituitary–adrenal axis via serotonin 2C receptor stimulation. J Neurosci 27:6956–6964

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Opp MR, Smith EM, Hughes TK Jr (1995) Interleukin-10 (cytokine synthesis inhibitory factor) acts in the central nervous system of rats to reduce sleep. J Neuroimmunol 60:165–168

    Article  CAS  PubMed  Google Scholar 

  183. Kushikata T, Fang J, Krueger JM (1999) Interleukin-10 inhibits spontaneous sleep in rabbits. J Interferon Cytokine Res 19:1025–1030

    Article  CAS  PubMed  Google Scholar 

  184. Denoyer M, Sallanon M, Kitahama K, Aubert C, Jouvet M (1989) Reversibility of para-chlorophenylalanine-induced insomnia by intrahypothalamic microinjection of L-5-hydroxytryptophan. Neuroscience 28:83–94

    Article  CAS  PubMed  Google Scholar 

  185. Borbély AA, Neuhaus HU, Tobler I (1981) Effect of p-chlorophenylalanine and tryptophan on sleep, EEG and motor activity in the rat. Behav Brain Res 2:1–22

    Article  PubMed  Google Scholar 

  186. Toth LA, Opp MR (2001) Cytokine- and microbially induced sleep responses of interleukin-10 deficient mice. Am J Physiol Regul Integr Comp Physiol 280:1806–1814

    Article  Google Scholar 

  187. Olsen OE, Neckelmann D, Ursin R (1994) Diurnal differences in l-tryptophan sleep and temperature effects in the rat. Behav Brain Res 65:195–203

    Article  CAS  PubMed  Google Scholar 

  188. Sarchielli P, Alberti A, Baldi A, Coppola F, Rossi C, Pierguidi L, Floridi A, Calabresi P (2006) Proinflammatory cytokines, adhesion molecules, and lymphocyte integrin expression in the internal jugular blood of migraine patients without aura assessed ictally. Headache 46:200–207

    Article  PubMed  Google Scholar 

  189. Bradley LA, Weigent DA, Sotolongo A, Alorcon GS, Arnold RE, Cianfrini LR (2000) Blood serum levels of nitric oxide are elevated in women with fibromyalgia:possible contributions to central and peripheral sensitization. Arthritis Rheum 43:173

    Google Scholar 

  190. Lafon-Cazal M, Culcasi M, Gaven F, Pietri S, Bockaert J (1993) Nitric oxide, superoxide and peroxynitrite: putative mediators of NMDA-induced cell death in cerebellar granule cells. Neuropharmacology 32:1259–1266

    Article  CAS  PubMed  Google Scholar 

  191. Brenman JE, Bredt DS (1997) Synaptic signaling by nitric oxide. Curr Opin Neurobiol 7:374–378

    Article  CAS  PubMed  Google Scholar 

  192. Callsen-Cencic P, Hoheisel U, Kaske A, Mense S, Tenschert S (1999) The controversy about spinal neuronal nitric oxide synthase: under which conditions is it up- or downregulated? Cell Tissue Res 295:183–194

    Article  CAS  PubMed  Google Scholar 

  193. Li P, Tong C, Eisenach JC, Figueroa JP (1994) NMDA causes release of nitric oxide from rat spinal cord in vitro. Brain Res 637:287–291

    Article  CAS  PubMed  Google Scholar 

  194. Mukherjee P, Cinelli MA, Kang S, Silverman RB (2011) Development of nitric oxide synthase inhibitors for neurodegeneration and neuropathic pain. Chem Soc Rev 43:6814–6838

    Article  Google Scholar 

  195. Benarroch EE (2011) Nitric oxide a pleiotropic signal in the nervous system. Neurology 77:1568–1576

    Article  CAS  PubMed  Google Scholar 

  196. Sandor NT, Brassai A, Pliskas A, Lendvai B (1995) Role of nitric oxide in modulating neurotransmitter release from rat striatum. Brain Res Bull 36:483–486

    Article  CAS  PubMed  Google Scholar 

  197. Theoharides TC, Donelan JM, Papadopoulou N, Cao J, Kempuraj D, Conti P (2004) Mast cells as targets of corticotropin-releasing factor and related peptides. Trends Pharmacol Sci 25:563–568

    Article  CAS  PubMed  Google Scholar 

  198. Cao J, Papadopoulou N, Kempuraj D, Boucher WS, Sugimoto K, Cetrulo CL, Theoharides TC (2005) Human mast cells express corticotropin-releasing hormone (CRH) receptors and CRH leads to selective secretion of vascular endothelial growth factor. J Immunol 174:7665–7675

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

RB is thankful to Department of Science and Technology (DST-SERB), Govt. of India for extra mural research funding (EMR/2016/005878). AK is thankful to the University Grants Commission (UGC), New Delhi for support under Maulana Azad National Fellowship (MANF) scheme.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Rajbir Bhatti.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Singh, L., Kaur, A., Bhatti, M.S. et al. Possible Molecular Mediators Involved and Mechanistic Insight into Fibromyalgia and Associated Co-morbidities. Neurochem Res 44, 1517–1532 (2019). https://doi.org/10.1007/s11064-019-02805-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-019-02805-5

Keywords

Navigation