{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T00:00:31Z","timestamp":1792800031978,"version":"4.5.0"},"reference-count":131,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2025,2,17]],"date-time":"2025-02-17T00:00:00Z","timestamp":1739750400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brain Sciences"],"abstract":"<jats:p>Fibromyalgia is a common, high-impact condition of chronic widespread pain and sensory dysfunction associated with altered central and peripheral sensory processing. A growing body of evidence supports the role of neuroinflammation and immune changes in fibromyalgia, and a narrative review of this literature was undertaken. Published data suggest that the interactions between the neural pain networks and the immune system in fibromyalgia appear to be bidirectional and operate both centrally and peripherally. There is a growing focus on processes occurring in the dorsal root ganglia and the role of maladaptive microglial cell activation. Ongoing insight into neuroinflammatory mechanisms in fibromyalgia opens potential avenues for the development of mechanism-based therapies in what is, at present, a challenging-to-manage condition.<\/jats:p>","DOI":"10.3390\/brainsci15020206","type":"journal-article","created":{"date-parts":[[2025,2,17]],"date-time":"2025-02-17T04:40:25Z","timestamp":1739767225000},"page":"206","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":56,"title":["Neuroinflammatory and Immunological Aspects of Fibromyalgia"],"prefix":"10.3390","volume":"15","author":[{"given":"Kate","family":"Findeisen","sequence":"first","affiliation":[{"name":"Department of Rheumatology, Monash Health, Melbourne, VIC 3168, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6712-1331","authenticated-orcid":false,"given":"Emma","family":"Guymer","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Monash Health, Melbourne, VIC 3168, Australia"},{"name":"Department of Medicine, Monash University, Melbourne, VIC 3800, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7896-055X","authenticated-orcid":false,"given":"Geoffrey","family":"Littlejohn","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Monash Health, Melbourne, VIC 3168, Australia"},{"name":"Department of Medicine, Monash University, Melbourne, VIC 3800, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1016\/j.rbr.2016.10.004","article-title":"Prevalence of fibromyalgia: Literature review update","volume":"57","author":"Marques","year":"2017","journal-title":"Rev. Bras. Reumatol. Engl. Ed."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1547","DOI":"10.1001\/jama.2014.3266","article-title":"Fibromyalgia: A clinical review","volume":"311","author":"Clauw","year":"2014","journal-title":"JAMA"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1111\/j.1742-1241.2007.01638.x","article-title":"The health status burden of people with fibromyalgia: A review of studies that assessed health status with the SF-36 or the SF-12","volume":"62","author":"Hoffman","year":"2008","journal-title":"Int. J. Clin. Pract."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"152060","DOI":"10.1016\/j.semarthrit.2022.152060","article-title":"The economic burden of fibromyalgia: A systematic literature review","volume":"56","author":"Ciaffi","year":"2022","journal-title":"Semin. Arthritis Rheum."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1382","DOI":"10.1097\/j.pain.0000000000000507","article-title":"Do we need a third mechanistic descriptor for chronic pain states?","volume":"157","author":"Kosek","year":"2016","journal-title":"Pain"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"S2","DOI":"10.1016\/j.pain.2010.09.030","article-title":"Central sensitization: Implications for the diagnosis and treatment of pain","volume":"152","author":"Woolf","year":"2011","journal-title":"Pain"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1007\/s00281-018-0672-2","article-title":"Neurogenic inflammation in fibromyalgia","volume":"40","author":"Littlejohn","year":"2018","journal-title":"Semin. Immunopathol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1017\/S0033291720004547","article-title":"The role of lifetime stressors in adult fibromyalgia: Systematic review and meta-analysis of case-control studies","volume":"51","author":"Kaleycheva","year":"2021","journal-title":"Psychol. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1453","DOI":"10.1093\/rheumatology\/key075.533","article-title":"Concomitant fibromyalgia complicating chronic inflammatory arthritis: A systematic review and meta-analysis","volume":"57","author":"Duffield","year":"2018","journal-title":"Rheumatology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1007\/s10067-006-0304-4","article-title":"The frequency of hypermobility and its relationship with clinical findings of fibromyalgia patients","volume":"26","author":"Sendur","year":"2007","journal-title":"Clin. Rheumatol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1132","DOI":"10.1002\/art.1780301007","article-title":"The \u201cchronic, active Epstein-Barr virus infection\u201d syndrome and primary fibromyalgia","volume":"30","author":"Buchwald","year":"1987","journal-title":"Arthritis Rheum."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"281","DOI":"10.7326\/0003-4819-117-4-281","article-title":"Lyme disease associated with fibromyalgia","volume":"117","author":"Dinerman","year":"1992","journal-title":"Ann. Intern. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1136\/ard-2023-224848","article-title":"Long COVID: A new word for naming fibromyalgia?","volume":"83","author":"Mariette","year":"2024","journal-title":"Ann. Rheum. Dis."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"944","DOI":"10.1002\/art.20042","article-title":"Family study of fibromyalgia","volume":"50","author":"Arnold","year":"2004","journal-title":"Arthritis Rheum."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1038\/s41584-020-00506-w","article-title":"Fibromyalgia: An update on clinical characteristics, aetiopathogenesis and treatment","volume":"16","author":"Giorgi","year":"2020","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1333","DOI":"10.1002\/art.10225","article-title":"Functional magnetic resonance imaging evidence of augmented pain processing in fibromyalgia","volume":"46","author":"Gracely","year":"2002","journal-title":"Arthritis Rheum."},{"key":"ref_17","first-page":"364","article-title":"Functional imaging of pain in patients with primary fibromyalgia","volume":"31","author":"Cook","year":"2004","journal-title":"J. Rheumatol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3146","DOI":"10.1002\/art.24849","article-title":"Elevated insular glutamate in fibromyalgia is associated with experimental pain","volume":"60","author":"Harris","year":"2009","journal-title":"Arthritis Rheum."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1002\/art.33339","article-title":"Reduced insular \u03b3-aminobutyric acid in fibromyalgia","volume":"64","author":"Foerster","year":"2012","journal-title":"Arthritis Rheum."},{"key":"ref_20","first-page":"2737","article-title":"Large-scale momentary brain co-activation patterns are associated with hyperalgesia and mediate focal neurochemistry and cross-network functional connectivity in fibromyalgia","volume":"164","author":"Mawla","year":"2023","journal-title":"Pain"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.bbi.2018.09.018","article-title":"Brain glial activation in fibromyalgia\u2014A multi-site positron emission tomography investigation","volume":"75","author":"Albrecht","year":"2019","journal-title":"Brain Behav. Immun."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2285","DOI":"10.1097\/j.pain.0000000000002927","article-title":"Evidence of neuroinflammation in fibromyalgia syndrome: A [18 F]DPA-714 positron emission tomography study","volume":"164","author":"Mueller","year":"2023","journal-title":"Pain"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Seo, S., Jung, Y.-H., Lee, D., Lee, W.J., Jang, J.H., Lee, J.-Y., Choi, S.-H., Moon, J.Y., Cheon, G.J., and Kang, D.-H. (2021). Abnormal neuroinflammation in fibromyalgia and CRPS using [11C]-(R)-PK11195 PET. PLoS ONE, 16.","DOI":"10.1371\/journal.pone.0246152"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.jneuroim.2011.10.013","article-title":"Evidence of central inflammation in fibromyalgia-increased cerebrospinal fluid interleukin-8 levels","volume":"242","author":"Kadetoff","year":"2012","journal-title":"J. Neuroimmunol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.bbi.2014.05.001","article-title":"Inflammation-induced hyperalgesia: Effects of timing, dosage, and negative affect on somatic pain sensitivity in human experimental endotoxemia","volume":"41","author":"Wegner","year":"2014","journal-title":"Brain Behav. Immun."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.bbi.2013.03.002","article-title":"Low-dose endotoxin potentiates capsaicin-induced pain in man: Evidence for a pain neuroimmune connection","volume":"30","author":"Hutchinson","year":"2013","journal-title":"Brain Behav. Immun."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"12468","DOI":"10.1073\/pnas.1511003112","article-title":"Imaging robust microglial activation after lipopolysaccharide administration in humans with PET","volume":"112","author":"Sandiego","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"100624","DOI":"10.1016\/j.bbih.2023.100624","article-title":"Abnormal immune system response in the brain of women with Fibromyalgia after experimental endotoxin challenge","volume":"30","author":"Mueller","year":"2023","journal-title":"Brain Behav. Immun.-Health"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"686","DOI":"10.1038\/306686a0","article-title":"Evidence for a central component of post-injury pain hypersensitivity","volume":"306","author":"Woolf","year":"1983","journal-title":"Nature"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1016\/j.jpain.2005.01.357","article-title":"Effects of the N-methyl-D-aspartate receptor antagonist dextromethorphan on temporal summation of pain are similar in fibromyalgia patients and normal control subjects","volume":"6","author":"Staud","year":"2005","journal-title":"J. Pain"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"15022","DOI":"10.1038\/nrdp.2015.22","article-title":"Fibromyalgia","volume":"1","author":"Ablin","year":"2015","journal-title":"Nat. Rev. Dis. Primer"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1908","DOI":"10.1097\/j.pain.0000000000001306","article-title":"Targeting toll-like receptor-4 (TLR4)-an emerging therapeutic target for persistent pain states","volume":"159","author":"Bruno","year":"2018","journal-title":"Pain"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"S99","DOI":"10.1097\/j.pain.0000000000002740","article-title":"Central sensitization: Clinical utility of a physiological concept for the International Statistical Classification of Diseases and Related Health Problems and for nociplastic pain","volume":"163","author":"Treede","year":"2022","journal-title":"Pain"},{"key":"ref_34","first-page":"1","article-title":"Fibromyalgia: A satellite gliopathy?","volume":"43","author":"Mercado","year":"2024","journal-title":"Clin. Exp. Rheumatol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1007\/s10067-020-05528-z","article-title":"Dorsal root ganglia: Fibromyalgia pain factory?","volume":"40","year":"2021","journal-title":"Clin. Rheumatol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1038\/s41583-020-0333-z","article-title":"Emerging importance of satellite glia in nervous system function and dysfunction","volume":"21","author":"Hanani","year":"2020","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1097\/j.pain.0000000000002330","article-title":"Beta 2-adrenergic receptor mediates noradrenergic action to induce cyclic adenosine monophosphate response element-binding protein phosphorylation in satellite glial cells of dorsal root ganglia to regulate visceral hypersensitivity","volume":"163","author":"Shen","year":"2022","journal-title":"Pain"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1828","DOI":"10.1097\/j.pain.0000000000002881","article-title":"Fibromyalgia patients with elevated levels of anti-satellite glia cell immunoglobulin G antibodies present with more severe symptoms","volume":"164","author":"Krock","year":"2023","journal-title":"Pain"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e144201","DOI":"10.1172\/JCI144201","article-title":"Passive transfer of fibromyalgia symptoms from patients to mice","volume":"131","author":"Goebel","year":"2021","journal-title":"J. Clin. Investig."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"U\u00e7eyler, N., H\u00e4user, W., and Sommer, C. (2011). Systematic review with meta-analysis: Cytokines in fibromyalgia syndrome. BMC Musculoskelet. Disord., 12.","DOI":"10.1186\/1471-2474-12-245"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1038\/nrrheum.2015.100","article-title":"Neurogenic neuroinflammation in fibromyalgia and complex regional pain syndrome","volume":"11","author":"Littlejohn","year":"2015","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1038\/nrn3617","article-title":"Neurogenic neuroinflammation: Inflammatory CNS reactions in response to neuronal activity","volume":"15","author":"Xanthos","year":"2014","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_43","first-page":"1154","article-title":"MCP-1 and IL-8 as pain biomarkers in fibromyalgia: A pilot study","volume":"12","author":"Ang","year":"2011","journal-title":"Pain. Med. Malden Mass"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1111\/j.1476-5381.1991.tb12502.x","article-title":"Interleukin-8 as a mediator of sympathetic pain","volume":"104","author":"Cunha","year":"1991","journal-title":"Br. J. Pharmacol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.jneuroim.2015.02.002","article-title":"Evidence of different mediators of central inflammation in dysfunctional and inflammatory pain\u2014Interleukin-8 in fibromyalgia and interleukin-1 \u03b2 in rheumatoid arthritis","volume":"280","author":"Kosek","year":"2015","journal-title":"J. Neuroimmunol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/0304-3959(88)90019-X","article-title":"Elevated CSF levels of substance P and high incidence of Raynaud phenomenon in patients with fibromyalgia: New features for diagnosis","volume":"32","author":"Helle","year":"1988","journal-title":"Pain"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1593","DOI":"10.1002\/art.1780371106","article-title":"Elevated cerebrospinal fluid levels of substance P in patients with the fibromyalgia syndrome","volume":"37","author":"Russell","year":"1994","journal-title":"Arthritis Rheum."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1124\/jpet.115.230060","article-title":"Neuropeptides CRH, SP, HK-1, and Inflammatory Cytokines IL-6 and TNF Are Increased in Serum of Patients with Fibromyalgia Syndrome, Implicating Mast Cells","volume":"356","author":"Tsilioni","year":"2016","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1171","DOI":"10.3181\/0712-RM-328","article-title":"High plasma levels of MCP-1 and eotaxin provide evidence for an immunological basis of fibromyalgia","volume":"233","author":"Zhang","year":"2008","journal-title":"Exp. Biol. Med. Maywood NJ"},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Behnoush, A.H., Khalaji, A., Khanmohammadi, S., Alehossein, P., Saeedian, B., Shobeiri, P., Teixeira, A.L., and Rezaei, N. (2023). Brain-derived neurotrophic factor in fibromyalgia: A systematic review and meta-analysis of its role as a potential biomarker. PLoS ONE, 18.","DOI":"10.1371\/journal.pone.0296103"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"463","DOI":"10.46497\/ArchRheumatol.2020.7783","article-title":"Serum Calcitonin Gene-Related Peptide and Receptor Protein Levels in Patients With Fibromyalgia Syndrome: A Cross-Sectional Study","volume":"35","author":"Korucu","year":"2020","journal-title":"Arch. Rheumatol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"768","DOI":"10.1159\/000363041","article-title":"Activation of microglia by histamine and substance P","volume":"34","author":"Zhu","year":"2014","journal-title":"Cell Physiol. Biochem. Int. J. Exp. Cell Physiol. Biochem. Pharmacol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1016\/j.bbi.2023.09.003","article-title":"Anti-satellite glia cell IgG antibodies in fibromyalgia patients are related to symptom severity and to metabolite concentrations in thalamus and rostral anterior cingulate cortex","volume":"114","author":"Fanton","year":"2023","journal-title":"Brain Behav. Immun."},{"key":"ref_54","unstructured":"Berwick, R., Sensi, S., Scheibenbogen, C., and Goebel, A. (2022). Patients with Painful Long-COVID Syndrome Produce Immunoglobulin G Autoantibodies Which Stain Dorsal Root Ganglion Satellite Glial Cells Similarly to Patients with Fibromyalgia Syndrome (Abstract). Toronto, Research Gate. Available online: https:\/\/www.researchgate.net\/publication\/363660932_Patients_with_Painful_Long-COVID_Syndrome_Produce_Immunoglobulin_G_Autoantibodies_which_Stain_Dorsal_Root_Ganglion_Satellite_Glial_Cells_Similarly_to_Patients_with_Fibromyalgia_Syndrome."},{"key":"ref_55","unstructured":"Mercado, F., Segura-Chama, P., Almanza, A., Martinez-Martinez, L.A., and Martinez-Lavin, M. (2024, January 14\u201319). Acute Activation of the Rat Dorsal Root Ganglion Nociceptive Cells by the Serum of Patients Suffering from Fibromyalgia [Abstract]. Proceedings of the ACR Convergence 2024, Washington, DC, USA."},{"key":"ref_56","first-page":"10","article-title":"Autoantibodies in patients with fibromyalgia syndrome","volume":"13","author":"Seefried","year":"2025","journal-title":"Pain"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"2855","DOI":"10.1097\/j.pain.0000000000001662","article-title":"Autoantibodies produce pain in complex regional pain syndrome by sensitizing nociceptors","volume":"160","author":"Cuhadar","year":"2019","journal-title":"Pain"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"2377","DOI":"10.1016\/j.pain.2014.09.007","article-title":"Autoimmunity contributes to nociceptive sensitization in a mouse model of complex regional pain syndrome","volume":"155","author":"Li","year":"2014","journal-title":"Pain"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1186\/s12974-021-02309-6","article-title":"The semantics of microglia activation: Neuroinflammation, homeostasis, and stress","volume":"18","author":"Woodburn","year":"2021","journal-title":"J. Neuroinflamm."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Paroli, M., Gioia, C., Accapezzato, D., and Caccavale, R. (2024). Inflammation, Autoimmunity, and Infection in Fibromyalgia: A Narrative Review. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25115922"},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Theoharides, T.C., Tsilioni, I., and Bawazeer, M. (2019). Mast Cells, Neuroinflammation and Pain in Fibromyalgia Syndrome. Front. Cell Neurosci., 13.","DOI":"10.3389\/fncel.2019.00353"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1403","DOI":"10.1007\/s10067-010-1474-7","article-title":"Abnormal overexpression of mastocytes in skin biopsies of fibromyalgia patients","volume":"29","author":"Blanco","year":"2010","journal-title":"Clin. Rheumatol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1310","DOI":"10.1016\/j.bbi.2010.06.008","article-title":"Involvement of the peripheral sensory and sympathetic nervous system in the vascular endothelial expression of ICAM-1 and the recruitment of opioid-containing immune cells to inhibit inflammatory pain","volume":"24","author":"Mousa","year":"2010","journal-title":"Brain Behav. Immun."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Machelska, H., and Celik, M.\u00d6. (2020). Opioid Receptors in Immune and Glial Cells-Implications for Pain Control. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.00300"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"e2211631120","DOI":"10.1073\/pnas.2211631120","article-title":"Neutrophils infiltrate sensory ganglia and mediate chronic widespread pain in fibromyalgia","volume":"120","author":"Caxaria","year":"2023","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Tecchio, C., Micheletti, A., and Cassatella, M.A. (2014). Neutrophil-derived cytokines: Facts beyond expression. Front. Immunol., 5.","DOI":"10.3389\/fimmu.2014.00508"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"104580","DOI":"10.1016\/j.phrs.2019.104580","article-title":"The role of neutrophils in neuro-immune modulation","volume":"151","author":"Kanashiro","year":"2020","journal-title":"Pharmacol. Res."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1149","DOI":"10.1016\/j.intimp.2010.06.016","article-title":"Long-term intrathecal morphine and bupivacaine upregulate MOR gene expression in lymphocytes","volume":"10","author":"Campana","year":"2010","journal-title":"Int. Immunopharmacol."},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Brejchova, J., Holan, V., and Svoboda, P. (2020). Expression of Opioid Receptors in Cells of the Immune System. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22010315"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1016\/j.bbi.2019.10.011","article-title":"Morphine decreases the function of primary human natural killer cells by both TLR4 and opioid receptor signaling","volume":"83","author":"Maher","year":"2020","journal-title":"Brain Behav. Immun."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/j.intimp.2013.11.015","article-title":"Effects of opioid therapy on human natural killer cells","volume":"18","author":"Tabellini","year":"2014","journal-title":"Int. Immunopharmacol."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Malafoglia, V., Ilari, S., Gioia, C., Vitiello, L., Tenti, M., Iannuccelli, C., Cristiani, C.M., Garofalo, C., Passacatini, L.C., and Viglietto, G. (2023). An Observational Study on Chronic Pain Biomarkers in Fibromyalgia and Osteoarthritis Patients: Which Role for Mu Opioid Receptor\u2019s Expression on NK Cells?. Biomedicines, 11.","DOI":"10.3390\/biomedicines11030931"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"e821","DOI":"10.1097\/j.pain.0000000000002498","article-title":"Unbiased immune profiling reveals a natural killer cell-peripheral nerve axis in fibromyalgia","volume":"163","author":"Verma","year":"2022","journal-title":"Pain"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.jneuroim.2007.06.002","article-title":"Adhesion molecules and cytokine expression in fibromyalgia patients: Increased L-selectin on monocytes and neutrophils","volume":"188","author":"Macedo","year":"2007","journal-title":"J. Neuroimmunol."},{"key":"ref_75","first-page":"219","article-title":"Lymphocyte profiles in patients with chronic low back pain enrolled in a clinical trial","volume":"17","author":"Brennan","year":"1994","journal-title":"J. Manipulative Physiol. Ther."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1046\/j.1468-2982.1992.1204250.x","article-title":"Immunological alterations in cluster headache during remission and cluster period. Comparison with low back pain patients","volume":"12","author":"Bussone","year":"1992","journal-title":"Cephalalgia Int. J. Headache"},{"key":"ref_77","first-page":"104898","article-title":"Phenotypic Identification of Spinal Cord-Infiltrating CD4+ T Lymphocytes in a Murine Model of Neuropathic Pain","volume":"122","author":"Draleau","year":"2014","journal-title":"J. Pain. Relief."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"104898","DOI":"10.1016\/j.psyneuen.2020.104898","article-title":"Inducing a stressed phenotype in healthy recipient mice by adoptively transferring CD4+ lymphocytes from mice undergoing chronic psychosocial stress","volume":"122","author":"Amoroso","year":"2020","journal-title":"Psychoneuroendocrinology"},{"key":"ref_79","first-page":"81","article-title":"T helper 1 response is correlated with widespread pain, fatigue, sleeping disorders and the quality of life in patients with fibromyalgia and is modulated by hyperbaric oxygen therapy","volume":"37","author":"Guggino","year":"2019","journal-title":"Clin. Exp. Rheumatol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1111\/j.1365-2249.2008.03787.x","article-title":"May genetic factors in fibromyalgia help to identify patients with differentially altered frequencies of immune cells?","volume":"154","author":"Carvalho","year":"2008","journal-title":"Clin. Exp. Immunol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1159\/000115041","article-title":"Lymphocyte subsets and the role of TH1\/TH2 balance in stressed chronic pain patients","volume":"14","author":"Kaufmann","year":"2007","journal-title":"Neuroimmunomodulation"},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Fineschi, S., Klar, J., Gustafsson, K.A., Jonsson, K., Karlsson, B., and Dahl, N. (2022). Inflammation and Interferon Signatures in Peripheral B-Lymphocytes and Sera of Individuals With Fibromyalgia. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.874490"},{"key":"ref_83","unstructured":"Lewis, T. (1927). The Blood Vessels of the Human Skin and Their Responses, Shaw & Sons Ltd."},{"key":"ref_84","first-page":"1022","article-title":"Increased neurogenic inflammation in fibrositis syndrome","volume":"14","author":"Littlejohn","year":"1987","journal-title":"J. Rheumatol."},{"key":"ref_85","first-page":"1586","article-title":"Effects of selective slow wave sleep disruption on musculoskeletal pain and fatigue in middle aged women","volume":"26","author":"Lentz","year":"1999","journal-title":"J. Rheumatol."},{"key":"ref_86","first-page":"115","article-title":"Evaluation of vascular injury with proinflammatory cytokines, thrombomodulin and fibronectin in patients with primary fibromyalgia","volume":"63","author":"Pay","year":"2000","journal-title":"Nagoya J. Med. Sci."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.1038\/nn.3144","article-title":"Neurogenic inflammation and the peripheral nervous system in host defense and immunopathology","volume":"15","author":"Chiu","year":"2012","journal-title":"Nat. Neurosci."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1007\/s00281-018-0675-z","article-title":"Skin neurogenic inflammation","volume":"40","author":"Choi","year":"2018","journal-title":"Semin. Immunopathol"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1857","DOI":"10.1093\/brain\/awt053","article-title":"Small fibre pathology in patients with fibromyalgia syndrome","volume":"136","author":"Zeller","year":"2013","journal-title":"Brain J. Neurol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"e1220","DOI":"10.1097\/PR9.0000000000001220","article-title":"Small fiber pathology in fibromyalgia syndrome","volume":"10","author":"Sommer","year":"2025","journal-title":"Pain. Rep."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1016\/j.semarthrit.2018.08.003","article-title":"A systematic review and meta-analysis of the prevalence of small fiber pathology in fibromyalgia: Implications for a new paradigm in fibromyalgia etiopathogenesis","volume":"48","author":"Grayston","year":"2019","journal-title":"Semin. Arthritis Rheum."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"934","DOI":"10.1016\/S1474-4422(17)30329-0","article-title":"The diagnostic challenge of small fibre neuropathy: Clinical presentations, evaluations, and causes","volume":"16","author":"Terkelsen","year":"2017","journal-title":"Lancet Neurol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"2319","DOI":"10.1097\/j.pain.0000000000000285","article-title":"Reduced dermal nerve fiber diameter in skin biopsies of patients with fibromyalgia","volume":"156","author":"Doppler","year":"2015","journal-title":"Pain"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1002\/ana.24065","article-title":"Hyperexcitable C nociceptors in fibromyalgia","volume":"75","author":"Serra","year":"2014","journal-title":"Ann. Neurol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1002\/ejp.2049","article-title":"Small-fibre damage is associated with distinct sensory phenotypes in patients with fibromyalgia and small-fibre neuropathy","volume":"27","author":"Leone","year":"2023","journal-title":"Eur. J. Pain."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.psyneuen.2015.09.018","article-title":"Stress exacerbates pain in the everyday lives of women with fibromyalgia syndrome\u2014The role of cortisol and alpha-amylase","volume":"63","author":"Fischer","year":"2016","journal-title":"Psychoneuroendocrinology"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"R185","DOI":"10.1186\/ar3513","article-title":"Nocturnal heart rate variability parameters as potential fibromyalgia biomarker: Correlation with symptoms severity","volume":"13","author":"Lerma","year":"2011","journal-title":"Arthritis Res. Ther."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1016\/j.semarthrit.2013.03.004","article-title":"Heart rate variability in patients with fibromyalgia and patients with chronic fatigue syndrome: A systematic review","volume":"43","author":"Meeus","year":"2013","journal-title":"Semin. Arthritis Rheum."},{"key":"ref_99","doi-asserted-by":"crossref","unstructured":"Martinez-Lavin, M., Vidal, M., Barbosa, R.E., Pineda, C., Casanova, J.M., and Nava, A. (2002). Norepinephrine-evoked pain in fibromyalgia. A randomized pilot study [ISRCTN70707830]. BMC Musculoskelet Disord., 3.","DOI":"10.1186\/1471-2474-3-2"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1186\/1742-2094-8-151","article-title":"Origin and consequences of brain Toll-like receptor 4 pathway stimulation in an experimental model of depression","volume":"8","author":"Madrigal","year":"2011","journal-title":"J. Neuroinflamm."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.ynstr.2016.03.001","article-title":"The microbiome: A key regulator of stress and neuroinflammation","volume":"4","author":"Rea","year":"2016","journal-title":"Neurobiol. Stress"},{"key":"ref_102","first-page":"741746","article-title":"Dysfunctional neurotransmitter systems in fibromyalgia, their role in central stress circuitry and pharmacological actions on these systems","volume":"2012","author":"Becker","year":"2012","journal-title":"Pain. Res. Treat."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"e1224","DOI":"10.1097\/PR9.0000000000001224","article-title":"Decoding the connection: Unraveling the role of gut microbiome in fibromyalgia","volume":"10","author":"Minerbi","year":"2024","journal-title":"Pain Rep."},{"key":"ref_104","doi-asserted-by":"crossref","unstructured":"Cai, W., Haddad, M., Haddad, R., Kesten, I., Hoffman, T., Laan, R., Wong, C., Brown, N., Tansley, S., and Lister, K.C. (2023). Gut microbiota promotes pain in fibromyalgia. bioRxiv.","DOI":"10.1101\/2023.10.24.563794"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"1136","DOI":"10.1016\/j.neubiorev.2021.10.021","article-title":"The role of the vagus nerve in fibromyalgia syndrome","volume":"131","author":"Martins","year":"2021","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"988","DOI":"10.1016\/S0025-6196(12)62272-1","article-title":"The central autonomic network: Functional organization, dysfunction, and perspective","volume":"68","author":"Benarroch","year":"1993","journal-title":"Mayo Clin. Proc"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/S0049-0172(00)80010-4","article-title":"Autonomic dysfunction in patients with fibromyalgia: Application of power spectral analysis of heart rate variability","volume":"29","author":"Cohen","year":"2000","journal-title":"Semin. Arthritis Rheum."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.autneu.2008.11.010","article-title":"Reduced heart rate variability and vagal tone in anxiety: Trait versus state, and the effects of autogenic training","volume":"145","author":"Miu","year":"2009","journal-title":"Auton. Neurosci. Basic. Clin."},{"key":"ref_109","doi-asserted-by":"crossref","unstructured":"Bonaz, B., Sinniger, V., and Pellissier, S. (2017). The Vagus Nerve in the Neuro-Immune Axis: Implications in the Pathology of the Gastrointestinal Tract. Front. Immunol., 8.","DOI":"10.3389\/fimmu.2017.01452"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1038\/nature01321","article-title":"The inflammatory reflex","volume":"420","author":"Tracey","year":"2002","journal-title":"Nature"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"1583","DOI":"10.1002\/art.1780371105","article-title":"Hypothalamic-pituitary-adrenal axis perturbations in patients with fibromyalgia","volume":"37","author":"Crofford","year":"1994","journal-title":"Arthritis Rheum."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"3660","DOI":"10.1002\/art.21372","article-title":"Momentary relationship between cortisol secretion and symptoms in patients with fibromyalgia","volume":"52","author":"McLean","year":"2005","journal-title":"Arthritis Rheum."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1111\/ijcp.12760","article-title":"A randomised, double-blinded study comparing giving etoricoxib vs. placebo to female patients with fibromyalgia","volume":"70","author":"Mahagna","year":"2016","journal-title":"Int. J. Clin. Pract."},{"key":"ref_114","first-page":"980","article-title":"A double blind crossover trial of prednisone versus placebo in the treatment of fibrositis","volume":"12","author":"Clark","year":"1985","journal-title":"J. Rheumatol."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"17","DOI":"10.2174\/138161206775193208","article-title":"Is there a role for cytokine based therapies in fibromyalgia","volume":"12","author":"Wallace","year":"2006","journal-title":"Curr. Pharm. Des"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"e001131","DOI":"10.1136\/rmdopen-2019-001131","article-title":"Comparative effectiveness of improvement in pain and physical function for baricitinib versus adalimumab, tocilizumab and tofacitinib monotherapies in rheumatoid arthritis patients who are na\u00efve to treatment with biologic or conventional synthetic disease-modifying antirheumatic drugs: A matching-adjusted indirect comparison","volume":"6","author":"Fautrel","year":"2020","journal-title":"RMD Open"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"2386","DOI":"10.1093\/rheumatology\/keac659","article-title":"Disproportionate articular pain is a frequent phenomenon in rheumatoid arthritis and responds to treatment with sarilumab","volume":"62","author":"Choy","year":"2023","journal-title":"Rheumatology"},{"key":"ref_118","doi-asserted-by":"crossref","unstructured":"Ku\u010di\u0107, N., Ra\u010dki, V., \u0160verko, R., Vidovi\u0107, T., Grahovac, I., and Mr\u0161i\u0107-Pel\u010di\u0107, J. (2021). Immunometabolic Modulatory Role of Naltrexone in BV-2 Microglia Cells. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22168429"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1016\/j.jad.2011.11.016","article-title":"Increased autoimmune activity against 5-HT: A key component of depression that is associated with inflammation and activation of cell-mediated immunity, and with severity and staging of depression","volume":"136","author":"Maes","year":"2012","journal-title":"J. Affect. Disord."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"1211","DOI":"10.1016\/j.jpain.2015.08.004","article-title":"Effect of Milnacipran Treatment on Ventricular Lactate in Fibromyalgia: A Randomized, Double-Blind, Placebo-Controlled Trial","volume":"16","author":"Natelson","year":"2015","journal-title":"J. Pain"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1002\/glia.22610","article-title":"Antidepressants reduce neuroinflammatory responses and astroglial alpha-synuclein accumulation in a transgenic mouse model of Multiple System Atrophy","volume":"62","author":"Valera","year":"2014","journal-title":"Glia"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1016\/j.neuroscience.2010.03.067","article-title":"Evidence that tricyclic small molecules may possess toll-like receptor and myeloid differentiation protein 2 activity","volume":"168","author":"Hutchinson","year":"2010","journal-title":"Neuroscience"},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.euroneuro.2019.12.106","article-title":"An investigation into the modulation of T cell phenotypes by amitriptyline and nortriptyline","volume":"31","author":"Royds","year":"2020","journal-title":"Eur. Neuropsychopharmacol. J. Eur. Coll. NeuropsychoPharmacol."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1159\/000525657","article-title":"Gabapentinoids Suppress Lipopolysaccharide-Induced Interleukin-6 Production in Primary Cell Cultures of the Rat Spinal Dorsal Horn","volume":"30","author":"Rummel","year":"2023","journal-title":"Neuroimmunomodulation"},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1016\/j.bbi.2012.10.013","article-title":"A comparison of mindfulness-based stress reduction and an active control in modulation of neurogenic inflammation","volume":"27","author":"Rosenkranz","year":"2013","journal-title":"Brain Behav. Immun."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.bbi.2019.02.030","article-title":"Immune-inflammatory pathways and clinical changes in fibromyalgia patients treated with Mindfulness-Based Stress Reduction (MBSR): A randomized, controlled clinical trial","volume":"80","author":"Maes","year":"2019","journal-title":"Brain Behav. Immun."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"152377","DOI":"10.1016\/j.semarthrit.2024.152377","article-title":"Effects of exercise-based interventions on inflammatory markers in patients with fibromyalgia: A systematic review and meta-analysis","volume":"65","author":"Calatayud","year":"2024","journal-title":"Semin. Arthritis Rheum."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1186\/s12974-014-0162-y","article-title":"Diet-induced obesity and low testosterone increase neuroinflammation and impair neural function","volume":"11","author":"Jayaraman","year":"2014","journal-title":"J. Neuroinflamm."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1007\/s11064-014-1266-6","article-title":"Chronic functional bowel syndrome enhances gut-brain axis dysfunction, neuroinflammation, cognitive impairment, and vulnerability to dementia","volume":"39","author":"Daulatzai","year":"2014","journal-title":"Neurochem. Res."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1007\/s40122-024-00598-2","article-title":"A Personalized Mediterranean Diet Improves Pain and Quality of Life in Patients with Fibromyalgia","volume":"13","author":"Casini","year":"2024","journal-title":"Pain Ther."},{"key":"ref_131","unstructured":"Health Research Authority [Internet] (2024, December 15). Efficacy and Safety Study of Rozanolixizumab to Treat. Severe Fibromyalgia Syndrome Patients. Available online: https:\/\/www.hra.nhs.uk\/planning-and-improving-research\/application-summaries\/research-summaries\/efficacy-and-safety-study-of-rozanolixizumab-to-treat-severe-fibromyalgia-syndrome-patients\/."}],"container-title":["Brain Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3425\/15\/2\/206\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T16:36:01Z","timestamp":1760027761000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3425\/15\/2\/206"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,17]]},"references-count":131,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2025,2]]}},"alternative-id":["brainsci15020206"],"URL":"https:\/\/doi.org\/10.3390\/brainsci15020206","relation":{},"ISSN":["2076-3425"],"issn-type":[{"value":"2076-3425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,17]]}}}