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Cited by 4Pain Mechanisms and TreatmentsPain Management and TreatmentMusculoskeletal pain and rehabilitation

Nociplastic pain: the prominent role of non-neuronal cells in central and peripheral sensitization

Open access
Lai, Weidong, Tang, Xin, Chen, Sijia, Zhou, Yihan, Qi, Zihan, Cao, Menglei, Yuan, Cunrui, Yu, Jie +1 more·2026·Frontiers in Immunology
DOI 10.3389/fimmu.2026.1677310PMC PMC12886048
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Abstract

Nociplastic pain (NPP) is a recently defined form of chronic pain, characterized by altered nociception in the absence of clear evidence of nociceptive or neuropathic pain. It is believed to be driven by maladaptive changes in nociceptive processing, mediated by the peripheral and/or central nervous system sensitization. However, the exact pathogenic basis for NPP initiation and development remains unclear, and the potential clinical manifestations and biomarkers lack a clear classification. Emerging evidence now emphasizes the role of complex neuron–non-neuronal cell interactions, highlighting non-neuronal cells (e.g., circulating immune cells and glial cells) in NPP pathogenesis. In this review, we delineate the key conceptual distinctions of NPP within the spectrum of chronic pain and present the latest evidence outlining how non-neuronal cells mediate NPP progression via peripheral and central sensitization, as well as the associated synaptic plasticity mechanisms. We also summarize current and experimental therapeutic approaches explored in preclinical and clinical studies of NPP. We hope that this review provides a theoretical foundation for subsequent analgesic target screening and the drug development for NPP.

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Written from the paper’s full text.

TL;DR

This review argues that nociplastic pain (NPP) is a distinct chronic pain mechanism involving altered nociception without clear nociceptive or neuropathic evidence, and that non-neuronal cells—circulating immune cells, satellite glial cells, microglia, and astrocytes—drive peripheral and central sensitization via synaptic plasticity. It summarizes proposed biomarkers and therapies but notes that the field remains limited by low-quality literature and a lack of NPP-specific clinical prediction studies.

Key findings

  • NPP is estimated to affect 5%–15% of the general population; the 2021 IASP criteria include pain duration ≥3 months, regional rather than discrete distribution, pain not entirely explained by nociceptive or neuropathic mechanisms, and pain hypersensitivity in the affected region, with probable NPP requiring both a history of pain hypersensitivity and defined comorbidities.
  • Non-neuronal cells implicated in NPP include monocytes/macrophages, neutrophils, mast cells, T cells, B cells, satellite glial cells, microglia, and astrocytes. Examples include mast cell infiltration in approximately 70%–84% of IBS patients, about threefold more perineural mast cell infiltration than controls, and approximately 1.5-fold more degranulated mast cells; CSF substance P was threefold higher in 32 FMS patients versus 30 healthy controls; a meta-analysis of 512 FMS patients and 308 healthy subjects found reduced IGF-1; and B-cell transcriptomics in 30 FMS patients versus 24 healthy individuals identified 60 differentially expressed genes.
  • Central glial activation and polarization are highlighted: in a reserpine-induced FMS model, microglia shifted toward M1 with nearly fourfold upregulation of iNOS and fivefold downregulation of Arg-1; proposed pathways include MAPK (ERK, p38, JNK), JAK/STAT, α7-nAChR/cAMP/PKA, and PI3K/AKT signaling, with microglia regulating LTP/LTD through cytokines, ATP/P2X receptors, endocannabinoids, BDNF, glutamate, GABA, and glycine.
  • Genetic and clinical overlap findings include a familial association rate for FMS of approximately 12%–21%, a liability-scale SNP-based heritability of 0.025 (SE = 0.0014) for chronic overlapping pain conditions, and bidirectional FMS–IBS transformation in 28%–59% and 32%–77% of patients, respectively, with a relative risk increase of approximately 1.54-fold.

Methods

  • This is a narrative review; two independent investigators searched PubMed, EMBASE, Web of Science, and the Cochrane Library from inception, using terms for “nociplastic pain” and related conditions (FMS, IBS, CRPS, CPLBP), “non-neuronal cells” (immune and glial cells), and “central sensitization”/“synaptic plasticity,” combined with Boolean operators.
  • Inclusion criteria were English-language publications of all study types, including clinical research, preclinical studies, reviews, systematic reviews, and meta-analyses; exclusion criteria were literature unrelated to nociplastic pain, non-neuronal cells, or neural/synaptic plasticity, and inaccessible or outdated publications/books.
  • The review synthesizes evidence in narrative form and includes tables of search strategy, first-line pharmacological agents, preclinical models and pharmacotherapies, and contributions of non-neuronal cell types to NPP.

Limitations

  • The authors state that NPP is a relatively new field with few high-quality or groundbreaking basic or clinical studies, that the quality of relevant literature remains relatively low, that no high-quality clinical disease modeling or prediction studies specifically focused on NPP exist, and that limited clinical sample availability constrains original research.
  • The authors state that blood glucose and neutrophil-to-lymphocyte ratio have poor specificity and should be regarded as adjunctive diagnostic tools rather than definitive NPP biomarkers; they also state that the viral pre-infection hypothesis is not fully supported by direct evidence and remains a potential mechanism.
  • Evident from the text: as a narrative review, it reports no formal risk-of-bias assessment, meta-analysis, or quantitative synthesis, and many mechanistic claims derive from animal models or mixed pain conditions, leaving causality in human NPP uncertain.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.3389/fimmu.2026.1677310

Cites

183 of 184 references verified1 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

130 of 268 cited sources checked · 36 supported · 7 flagged · accuracy not yet measured

  • Premisecitation

    Variation in the transient receptor potential vanilloid 1 gene has been shown to be associated with nociplastic pain.

    “In addition, the variation in the transient receptor potential vanilloid 1 (TRPV1) gene has also been shown to be associated with NPP (32).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [32] Marchi, 2023, Trpa1 rare variants in chronic neuropathic and nociplastic pain patients, Pain source

      The Results (§3.2) associate rare variants in TRPA1, not TRPV1, with nociplastic pain. The Discussion mentions a TRPV1 variant in a patient with painless neuropathy, but does not report the claimed TRPV1–nociplastic pain association. Page numbers are unavailable in our copy. (LLM, conf=0.90)

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  • Premisecitation

    Some studies do not support the use of neutrophil-to-lymphocyte ratio as a reliable neutrophil-related indicator.

    “However, given the variability of NLR levels among FMS patients with FMS, some studies do not support the use of NLR as a reliable neutrophil-related indicator (66, 67).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [66] Al-Nimer, 2018, Correlation of Hematological Indices and Ratios Derived from Them with FIQr Scores in Fibromyalgia, Pak J Med Sci source

      The Discussion says the opposite of the attributed claim: NLR could be a good marker for distinguishing fibromyalgia from other painful conditions, and its area under the curve indicates it is a good diagnostic discriminator. Although the paper reports a lower NLR in its fibromyalgia group, it does not use that finding to reject NLR as a reliable indicator. (LLM, conf=0.88)

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    • cites [67] Ege, 2023, A Comparative Assessment of the Inflammatory Markers in Patients with Fibromyalgia under Duloxetine Treatment, Front Biosci (Landmark Ed) source
  • Premisecitation

    GABAergic neurons, glutamatergic neurons, and mixed GABAergic/glutamatergic neurons form an interconnected inhibitory neural network.

    “Study showed that GABAergic neurons, glutamatergic neurons, and mixed GABAergic/glutamatergic neurons form an interconnected inhibitory neural network.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [181] Shimizu-Okabe, 2022, Developmental Formation of the Gabaergic and Glycinergic Networks in the Mouse Spinal Cord, Int J Mol Sci source

      The Introduction (section 1; page not provided) identifies the three types of inhibitory neurons and terminals as GABAergic, GABA/glycine-coreleasing, and glycinergic—not glutamatergic or mixed GABAergic/glutamatergic. Section 2.1 discusses glutamate as a precursor from which GABA is synthesized, not as a neurotransmitter coreleased in the inhibitory network. (LLM, conf=0.90)

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  • Premisecitation

    Fibromyalgia can be induced or triggered following different types of viral pre-infection.

    “Studies have also reported that FMS can be induced or triggered following different types of viral pre-infection (21, 22).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [21] Fialho, 2023, Could the fibromyalgia syndrome be triggered or enhanced by covid-19, Inflammopharmacology source
    • cites [22] Paroli, 2024, Inflammation, autoimmunity, and infection in fibromyalgia: A narrative review, Int J Mol Sci source
  • Premisecitation

    After infection with porcine hemagglutinating encephalomyelitis virus, circulating monocytes/macrophages crossed the blood-brain barrier into the central nervous system in model mice, recruited by activated microglia.

    “After infection with the porcine hemagglutinating encephalomyelitis virus, Jing Zhang et al. observed that circulating monocytes/macrophages crossed the BBB into the central nervous system in model mice, recruited by activated microglia (27).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [27] Zhang, 2021, Evidence of microglial immune response following coronavirus phev infection of cns, Front Immunol source

      The Results section reports that circulating monocytes/macrophages crossed the BBB into the CNS of PHEV-infected mice. The Discussion’s Figure 6 description attributes their initial recruitment to rapid viral replication and increased BBB permeability, not to activated microglia. It says excess microglial activation later promotes further macrophage infiltration by aggravating BBB damage. (LLM, conf=0.88)

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  • Classified as probably not a substantial claim. 25

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    Premisecitation

    In rodent studies, the decrease in mechanical pain threshold after ovary removal was similar to that observed in intact female mice, suggesting an important role of estrogen in the intermittent cold stress-induced nociplastic pain model.

    “In rodent studies, the decrease in mechanical pain threshold after ovary removal was similar to that observed in intact female mice, suggesting an important role of estrogen in the ICS-induced NPP model (39).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [39] Nishiyori, 2008, Prolonged Gabapentin Analgesia in an Experimental Mouse Model of Fibromyalgia, Mol Pain source

      The Findings section reports that removing the ovaries did not significantly attenuate the ICS-induced decrease in mechanical pain threshold, supporting the comparison with intact female mice. But the paper draws the opposite inference about estrogen: it speculates that female predominance in this model is gender hormone-independent, while discussing a possible contribution from androgens. (LLM, conf=0.88)

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    Premisecitation

    Among 94 hepatitis C virus-infected patients who had received direct-acting antiviral treatment, 37 developed chronic pain; in the absence of reported nerve damage or lesions, these cases might be more accurately defined as nociplastic pain-related chronic pain.

    “In 2021, Maria M ZanoneMaria M. Zanone et al. reported that, among the 94 hepatitis C virus (HCV)-infected patients who had received direct-acting antiviral treatment, 37 patients developed chronic pain. Although the authors referred to this pain as neuropathic pain, this classification may not be appropriate. In the absence of reported nerve damage or lesions, these cases might be more accurately”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [18] Zanone, 2021, Peripheral neuropathy after viral eradication with direct-acting antivirals in chronic hcv hepatitis: A prospective study, Liver Int source

      Split into 2 atoms — 0 confirmed, 1 partially supported, 1 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

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    Premisecitation

    BDNF is regarded as a Cl− homeostasis regulator and is positively associated with chronic pain.

    “Brain-derived neurotrophic factor (BDNF), regarded as a Cl− homeostasis regulator, has been reported to be positively associated with chronic pain.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [157] Ortolá, 2025, Role of Serum Brain-Derived Neurotrophic Factor as a Biomarker of Chronic Pain in Older Adults, Eur J Pain source

      The Results (page unavailable) report lower, not higher, serum BDNF in participants with severe or interfering chronic pain in specified sex-and-depression subgroups. The Discussion notes positive findings in some earlier studies but describes the human evidence as inconsistent. Our copy does not describe BDNF as a Cl− homeostasis regulator. (LLM, conf=0.86)

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    Premisecitation

    BDNF is widely expressed in neurons, astrocytes, and microglia, with microglia regarded as the primary source of BDNF.

    “BDNF is widely expressed in neurons, astrocytes, and microglia, among which microglia are regarded as the primary source of BDNF (162).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [162] Parkhurst, 2013, Microglia Promote Learning-Dependent Synapse Formation through Brain-Derived Neurotrophic Factor, Cell source

      The Discussion section confirms that BDNF can be detected in neurons, astrocytes, and microglia. But it explicitly says that neurons, not microglia, appear to be the major source of BDNF in the adult brain. (LLM, conf=0.95)

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    Premisecitation

    HIV-1-infected leukocytes secrete matrix metalloproteinases MMP-2 and MMP-9 that impair the blood-brain barrier and promote immune cell infiltration into the central nervous system via chemokine CCL2.

    “Studies have shown that human immunodeficiency virus 1 (HIV-1)-infected leukocytes not only secrete matrix metalloproteinases (MMP)-2 and MMP-9 that impair the BBB, but also promote immune cell infiltration into the central nervous system via chemokine C-C motif ligand 2 (CCL2) (25).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [25] Eugenin, 2006, Ccl2/monocyte chemoattractant protein-1 mediates enhanced transmigration of human immunodeficiency virus (Hiv)-infected leukocytes across the blood-brain barrier: A potential mechanism of hiv-cns invasion and neuroaids, J Neurosci source

      The Discussion reports CCL2-mediated transmigration of HIV-infected leukocytes, BBB disruption, and increased MMP-2 and MMP-9 in the BBB model. However, the section on MMP expression localizes MMP-9 to endothelial and astrocyte layers; it does not show that infected leukocytes secrete both MMPs or establish that those MMPs caused the observed BBB disruption. Page numbers were not provided in our copy. (LLM, conf=0.88)

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    Premisecitation

    Nearly one-third of post-COVID-19 patients experienced late-onset pain, and this reduction in pain threshold was interpreted as central sensitization.

    “For example, A. Baroni et al. showed that nearly one-third of post-COVID-19 patients experienced late-onset pain, and this reduction in pain threshold reduction was interpreted as central sensitization (19).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [19] Baroni, 2024, Fatigue can influence the development of late-onset pain in post-covid-19 syndrome: an observational study, Eur J Pain source

      The Discussion reports that almost one in three patients hospitalized for COVID-19 developed pain 52 weeks after symptom resolution, supporting the frequency claim for that study population. But the Results found no difference in pressure pain threshold from matched healthy controls, and the Discussion describes central sensitization as an uncertain explanation—not an interpretation of a reduced threshold. Page numbers are unavailable in our copy. (LLM, conf=0.93)

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    Premisecitation

    Microorganisms can directly interact with components of the blood-brain barrier, leading to coagulopathy and tight junction disruption, inducing lung inflammation that results in hypoxia, and ultimately increasing blood-brain barrier permeability.

    “For example, microorganisms have been shown to directly interact with components of the blood–brain barrier (BBB), leading to coagulopathy and tight junction disruption, inducing lung inflammation that results in hypoxia, and ultimately increasing BBB permeability (23).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [23] Greene, 2024, Blood-brain barrier disruption and sustained systemic inflammation in individuals with long covid-associated cognitive impairment, Nat Neurosci source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

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    Premisecitation

    In a genome-wide analysis of six chronic overlapping pain conditions, 24 independent single-nucleotide polymorphisms were significantly associated with nociceptive pain, implicating 127 unique genes, with a liability-scale SNP-based heritability of 0.025 (SE = 0.0014).

    “In a separate genome-wide analysis, Keira J. A. Johnston et al. investigated six chronic overlapping pain conditions (COPCs)—CPLBP, endometriosis, temporomandibular joint disorder, IBS, and broad headache—and identified 24 independent single-nucleotide polymorphisms (SNPs) significantly associated with nociceptive pain, implicating 127 unique genes. These findings strongly suggest a genetic”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [31] Johnston, 2025, Chronic overlapping pain conditions and nociplastic pain, HGG Adv source

      The Results sections on the common-factor GWAS, tissue-wide significant genes, and heritability report six conditions, 24 independent SNPs, 127 unique genes, and liability-scale SNP heritability of 0.025 (SE = 0.0014). The crucial pain-type label is wrong: these findings concern nociplastic pain, not nociceptive pain. The 127 genes are reported in the tissue-wide gene analysis, rather than as genes directly implicated by the 24 SNPs. (LLM, conf=0.91)

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    Premisecitation

    Long-term alcohol use disorder induces plastic adaptations that contribute to negative affective states such as anxiety and depression, as well as hyperalgesia.

    “Long-term alcohol use disorder induces plastic adaptations that subsequently contribute to the development of negative affective states, such as anxiety and depression, as well as the manifestation of hyperalgesia (33, 34).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [33] Fu, 2015, Chronic Intermittent Voluntary Alcohol Drinking Induces Hyperalgesia in Sprague-Dawley Rats, Int J Physiol Pathophysiol Pharmacol
    • cites [34] Zale, 2015, Interrelations between Pain and Alcohol: An Integrative Review, Clin Psychol Rev source

      In “Hyperalgesia during Acute Abstinence from Chronic Alcohol Use” (page unavailable), the review says abstinence after chronic drinking may produce hyperalgesia and discusses receptor changes as possible mediators. In “Other Factors Associated with Pain and Alcohol Use” (page unavailable), it says AUD may maintain symptoms of anxiety and depression. It does not establish that long-term AUD induces plastic adaptations that cause both the affective states and hyperalgesia; the citing sentence presents these proposed or qualified relationships as a definite causal chain. (LLM, conf=0.85)

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    Interpretationcitation

    The intermittent cold stress animal model can largely replicate the clinical characteristics and complications of fibromyalgia, suggesting that repeated and intermittent exposure to excessively high or low temperatures may represent a pathogenic factor in nociplastic pain.

    “From a neurobiological perspective of neurobiology, the ICS animal model can largely replicates the clinical characteristics and complications of FMS, suggesting that repeated and intermittent exposure to excessively high or low temperatures may represent a pathogenic factor in NPP.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [40] Horing, 2024, Temporal Summation of the Thermal Grill Illusion Is Comparable to That Observed Following Noxious Heat, J Pain source

      Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.

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    Premisecitation

    In synovial fluid of 38 patients with persistent joint pain following chikungunya virus infection, neither the virus itself nor its proteins, mRNA, or pro-inflammatory cytokines were detectable, suggesting that joint pain can occur independently of active viral infection or local inflammation.

    “For example, in the synovial fluid of 38 patients with persistent joint pain following chikungunya virus infection, neither the virus itself nor the expression of its corresponding proteins, mRNA, or pro-inflammatory cytokines was detectable, suggesting that joint pain can occur independently of active viral infection or local inflammation (17).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [17] Suchowiecki, 2021, Persistent joint pain following arthropod virus infections, Curr Rheumatol Rep source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

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    Interpretationcitation

    In irritable bowel syndrome patients, neutrophil-to-lymphocyte ratio levels were elevated compared with control groups; high neutrophil-to-lymphocyte ratio may be positively associated with nociplastic pain.

    “Furthermore, in IBS patients, the NLR levels were similarly elevated in patients with IBS compared with control groups. Together, these findings indicate that high NLR may be positively associated with NPP (64, 65).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [64] Telli, 2024, Is Nociplastic Pain, a New Pain Category, Associated with Biochemical, Hematological, and Inflammatory Parameters, Curr Med Res Opin source
    • cites [65] Cure, 2024, Effect of Fibromyalgia on Demographic, Biochemical, Metabolic and Inflammatory Profiles: A Single-Centre Retrospective Study, Clin Exp Rheumatol source

      Table II (Statistical analysis; page unavailable) reports higher NLR in fibromyalgia patients than controls, not in patients with irritable bowel syndrome. Table V (Discussion; page unavailable) shows no significant correlation between NLR and the measured pain scores. The copy therefore supports an elevated NLR in a different condition, but not the IBS comparison or the proposed association with nociplastic pain. (LLM, conf=0.82)

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    Premisecitation

    Under intermittent cold stimulation, blood glucose levels in female fibromyalgia patients were decreased compared with healthy female controls, suggesting that changes in blood glucose may serve as a potential predictive indicator for clinical detection of nociplastic pain.

    “José V. Pardo et al. reported that, under intermittent cold stimulation (ICS) conditions, compared with 11 healthy female controls, the blood glucose levels in 13 female patients with fibromyalgia (FMS) were decreased, suggesting that changes in blood glucose may serve as a potential predictive indicator for the clinical detection of NPP.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [42] Pardo, 2019, Exposure to Cold Unmasks Potential Biomarkers of Fibromyalgia Syndrome Reflecting Insufficient Sympathetic Responses to Stress, Clin J Pain source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

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    Premisecitation

    The neutrophil-to-lymphocyte ratio is increased in patients with fibromyalgia, indicating that within the inflammatory microenvironment of fibromyalgia, neutrophil numbers are elevated.

    “Regarding neutrophil proportions, it has been reported that the neutrophil-to-lymphocyte ratio (NLR) is increased in patients with FMS. That is, within the inflammatory microenvironment of FMS, neutrophil numbers are elevated (63).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [63] Inci, 2021, Acupuncture Effects on Blood Parameters in Patients with Fibromyalgia, Med Acupunct source

      The Introduction (page not provided) reports increased neutrophil-to-lymphocyte ratios in patients with fibromyalgia. It also says systemic inflammation can raise neutrophil counts, but does not establish that neutrophil numbers are elevated in fibromyalgia patients relative to people without fibromyalgia. An increased ratio alone does not establish an increased neutrophil count. (LLM, conf=0.85)

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    Premisecitation

    Neutrophils infiltrate the dorsal root ganglia, suggesting that neutrophil infiltration into the dorsal root ganglia may be a critical contributor to nociplastic pain.

    “Neutrophils were also shown to infiltrate the dorsal root ganglia (DRG), suggesting that neutrophil infiltration into the DRG may be a critical contributor to NPP (62).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [62] Caxaria, 2023, Neutrophils Infiltrate Sensory Ganglia and Mediate Chronic Widespread Pain in Fibromyalgia, Proc Natl Acad Sci U S A source

      The Results report neutrophil infiltration into the dorsal root ganglia of mice with chronic widespread pain, and the Discussion links neutrophils to pain in the fibromyalgia model (page numbers unavailable in our copy). The source supports the proposed contribution in that setting, but does not establish it for nociplastic pain generally. (LLM, conf=0.84)

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    Premisecitation

    Coenzyme Q10 levels and mitochondrial membrane potential in monocytes were decreased, alongside increased mitochondrial superoxide levels, suggesting that nociplastic pain may be closely related to mitochondrial autophagy in monocytes.

    “Mario D. Cordero et al. reported that coenzyme Q10 levels and mitochondrial membrane potential in monocytes were decreased, alongside increased mitochondrial superoxide levels, suggesting that NPP may be closely related to mitochondrial autophagy in monocytes (58).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [58] Cordero, 2010, Mitochondrial Dysfunction and Mitophagy Activation in Blood Mononuclear Cells of Fibromyalgia Patients: Implications in the Pathogenesis of the Disease, Arthritis Res Ther source

      The Abstract Results report lower CoQ10 and mitochondrial membrane potential, higher mitochondrial superoxide, and mitophagy in blood mononuclear cells from fibromyalgia patients. The Conclusions suggest these changes may contribute to altered nociception in fibromyalgia. The paper does not establish those findings specifically in monocytes or a close relationship between nociplastic pain generally and monocyte mitophagy. (LLM, conf=0.88)

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    Premisecitation

    Elevated neutrophil-to-lymphocyte ratio in fibromyalgia patients correlates with variations in hypersensitive C-reactive protein levels, suggesting that neutrophil-to-lymphocyte ratio instability may reflect fluctuations in disease activity.

    “Subsequent investigations demonstrated that elevated NLR in FMS patients correlates with variations in hypersensitive C-reactive protein levels, suggesting that NLR instability may reflect fluctuations in disease activity (68).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [68] Almirall, 2025, Neutrophil-Lymphocyte Ratio in Fibromyalgia and Axial Spondyloarthritis: A Potential Biomarker for Diagnosis and Disease Activity, Biomedicines source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

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    Premisecitation

    The P2X7 receptor/NLRP3 signaling pathway is involved in mast cell degranulation; use of the P2X7R antagonist Brilliant Blue G prevented NLRP3 inflammasome activation and subsequent release of interleukin-1 and interleukin-18, thereby reducing fibromyalgia symptoms.

    “Ramona D’Amico et al. demonstrated that the P2X7 receptor (P2X7R)/NLRP3 signaling pathway is involved in mast cell degranulation. Use of the P2X7R antagonist Brilliant Blue G (BBG) prevented NLRP3 inflammasome activation and subsequent release of interleukin (IL)-1 and IL-18, thereby reducing FMS symptoms (83).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [83] D'Amico, 2021, Inhibition of P2X7 Purinergic Receptor Ameliorates Fibromyalgia Syndrome by Suppressing NLRP3 Pathway, Int J Mol Sci source

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    Premisecitation

    In the serum of irritable bowel syndrome patients, expression of pro-inflammatory cytokines like interleukin-1, interleukin-2, and TNF-α were increased significantly, which could lead to nociplastic pain through impairing intestinal barrier, inhibiting secretion of neurotransmitters and maintaining chronic low-grade inflammation.

    “Ivashkin et al. reported that in the serum of IBS patients, the expression of pro-inflammatory cytokines like IL-1, IL-2, and TNF-α were increased significantly (85), which could achieve to NPP through impairing intestinal barrier, inhibiting the secretion of neurotransmitters and maintaining chronic low-grade inflammation (86).”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [85] Ivashkin, 2021, Disruption of the Pro-Inflammatory, Anti-Inflammatory Cytokines and Tight Junction Proteins Expression, Associated with Changes of the Composition of the Gut Microbiota in Patients with Irritable Bowel Syndrome, PLoS One source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

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    • cites [86] Norlin, 2021, Fatigue in Irritable Bowel Syndrome Is Associated with Plasma Levels of TNF-a and Mesocorticolimbic Connectivity, Brain Behav Immun source

      Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.

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    Premisecitation

    Through synapse-like structures, mast cells can directly contact non-cholinergic and non-adrenergic nerves and mediate neuroimmune signaling via adhesion molecules such as monocyte chemotactic protein-1 and N-cadherin.

    “Through synapse-like structures, mast cells can directly contact non-cholinergic and non-adrenergic nerves and mediate neuroimmune signaling via adhesion molecules such as monocyte chemotactic protein-1 (MCP1) and N-cadherin (71, 73).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [71] Rijnierse, 2007, Mast Cells and Nerves Tickle in the Tummy: Implications for Inflammatory Bowel Disease and Irritable Bowel Syndrome, Pharmacol Ther source
    • cites [73] Ito, 2008, Nerve-Mast Cell and Smooth Muscle-Mast Cell Interaction Mediated by Cell Adhesion Molecule-1, Cadm1, J Smooth Muscle Res source

      The “Nerve-mast cell interaction mediated by CADM1” section (page unavailable) describes close nerve–mast-cell contact and communication promoted by the adhesion molecule CADM1. It does not identify the nerves as non-cholinergic and non-adrenergic, or name MCP1 and N-cadherin as the adhesion molecules mediating that communication. (LLM, conf=0.88)

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    Premisecitation

    Mast cell degranulation releases inflammatory mediators that induce low-grade inflammation and trigger the onset of fibromyalgia; a similar mechanism was found in irritable bowel syndrome.

    “Pio Conti reported that mast cell degranulation effects, mast cell releases inflammatory mediators that induce low-grade inflammation and trigger the onset of FMS (70). Parallelly, similar mechanism was found in IBS (84).”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [70] Conti, 2020, Impact of Mast Cells in Fibromyalgia and Low-Grade Chronic Inflammation: Can IL-37 Play a Role, Dermatol Ther source

      Section 2 (Mast Cells; page unavailable) says degranulation releases inflammatory mediators, and Section 3 (Low-Grade Inflammation and MCs; page unavailable) describes low-grade inflammation in fibromyalgia. The paper says mast-cell mediators could contribute to fibromyalgia pathogenesis, but does not establish that they trigger its onset. The IBS comparison has a separate citation (84) and is not attributed to this source. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [84] Valencia, 2022, A Correlation between the Pathogenic Processes of Fibromyalgia and Irritable Bowel Syndrome in the Middle-Aged Population: A Systematic Review, Cureus source

  • May combine two claims.

    Premisecitation

    T cells, as well as interleukins released by lymphocytes, can induce nociplastic pain formation.

    “T cells, as well as interleukins released by lymphocytes, can induce NPP formation of NPP (87).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [87] Banfi, 2020, T Cell Subpopulations in the Physiopathology of Fibromyalgia: Evidence and Perspectives, Int J Mol Sci source

      Section 3 reports that depleting CD4+ T cells inhibited central sensitization in a mouse model, supporting a role for T cells in pain development. Section 2 links cytokines released by microglia—not lymphocytes—to central sensitization and reports an association between IL-17 and pain. The paper does not establish that lymphocyte-released interleukins induce nociplastic pain. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Mast cell infiltration surrounding intestinal nerves occurs approximately three times more frequently in irritable bowel syndrome patients than in controls, and the number of degranulated mast cells is increased by approximately 1.5-fold.

    “Moreover, the phenomenon of mast cell infiltration surrounding intestinal nerves occurs approximately three times more frequently in IBS patients than in controls, and the number of degranulated mast cells is increased by approximately 1.5-fold (72).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [72] Barbara, 2004, Activated Mast Cells in Proximity to Colonic Nerves Correlate with Abdominal Pain in Irritable Bowel Syndrome, Gastroenterology source

      The Mast Cell-Nerve Interactions section reports 7.14 mast cells near nerves per 10 fields in IBS patients versus 2.27 in controls—approximately three times as many. The Mast Cell Degranulation section also reports more degranulating mast cells, but its figures (4.76 versus 2.42) are approximately twofold, not 1.5-fold; the section describes this as a 150% increase. Page numbers were not supplied. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    The proportion of CD8+ mucosal-associated invariant T cells was increased in fibromyalgia patients, and this population was suggested as a potential biomarker.

    “Chie Sugimoto et al. reported that the proportion of CD8+ mucosal-associated invariant T (MAIT) cells was increased in FMS patients with FMS and suggested this population as a potential biomarker (89).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [89] Chiu, 2013, Bacteria Activate Sensory Neurons That Modulate Pain and Inflammation, Nature source

      The sections on infected tissues and lymph nodes describe immune cells in a mouse bacterial-infection model, not CD8+ MAIT cells in fibromyalgia patients. Searches for fibromyalgia, MAIT cells, Sugimoto, and the proposed biomarker found no passage addressing the claim in our copy. (LLM, conf=0.78)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    T cells play an important role in nociplastic pain induction, and numerous studies have reported associations between T cells and nociplastic pain.

    “As a typical representative population of adaptive immune cells, T cells play an important role in NPP induction, and numerous studies have reported associations between T cells and NPP.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [87] Banfi, 2020, T Cell Subpopulations in the Physiopathology of Fibromyalgia: Evidence and Perspectives, Int J Mol Sci source

      Section 3, “Role of T Cells in Fibromyalgia: Literature Data” (page unavailable), reviews studies linking T cells to fibromyalgia and reports mouse evidence that T cells can contribute to pain development. But Section 5, “Concluding Remarks” (page unavailable), calls the evidence inconclusive and says it does not establish T-cell responses as the main trigger of fibromyalgia. The claim overstates an established role in inducing nociplastic pain generally; some of the paper’s pain-development evidence concerns neuropathic mouse models. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    FMS may be related to altered lipid metabolism.

    “suggesting that FMS may be related to altered lipid metabolism (114).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [114] Jakobsson, 2025, Fibromyalgia Patients Have Altered Lipid Concentrations Associated with Disease Symptom Severity and Anti-Satellite Glial Cell Igg Antibodies, J Pain source

  • May combine two claims.

    Premisecitation

    In FMS, anti-satellite IgG levels positively correlate with pain intensity and negatively correlate with concentrations of thalamic scyllo-inositol, total choline, and macromolecule 12.

    “Silvia Fanton et al. further reported confirmed a positive correlation between anti-satellite IgG levels and pain intensity in FMS, as well as a negative correlation between anti-satellite IgG levels and concentrations of metabolites such as thalamic scyllo-inositol, total choline, and macromolecule 12 (MM12) (111).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [111] Fanton, 2023, 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, Brain Behav Immun source

  • May combine two claims.

    Premisecitation

    Transfer of IgG from FMS patients into naïve mice causes IgG interaction with satellite glial cells in the DRG and induces hypersensitivity to noxious mechanical and cold stimulation.

    “Andreas Goebel et al. transferred IgG, donated from FMS patients with FMS into naïve mice and demonstrated that IgG interacted with satellite glial cells in the DRG to induce hypersensitivity to noxious mechanical and cold stimulation (107).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [107] Goebel, 2021, Passive Transfer of Fibromyalgia Symptoms from Patients to Mice, J Clin Invest source

      The ‘Passive transfer of sensory hypersensitivities’ section reports that FMS-patient IgG induced mechanical and noxious-cold hypersensitivity in mice. Figure 7 and the Discussion report IgG binding to satellite glial cells in the DRG, but the Discussion describes their role in producing hypersensitivity as a suggested mechanism, not a demonstrated causal link. Page numbers are unavailable in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • Rests on an assumption: Findings from animal models of FMS, CRPS, or fibromyalgia-like pain translate to human NPP mechanisms.

  • May combine two claims.

    Interpretationcitation

    B cell μ-opioid receptor deficiency may impair endogenous opioid analgesic activity and contribute to sensitization, supporting a pathological mechanism for FMS aggravation.

    “suggesting that B cells μ-opioid receptor deficiency in B cells may impair endogenous opioid analgesic activity and contribute to sensitization, thereby supporting a pathological mechanism support for the aggravation of FMS”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [102] Malafoglia, 2023, An Observational Study on Chronic Pain Biomarkers in Fibromyalgia and Osteoarthritis Patients: Which Role for Mu Opioid Receptor's Expression on Nk Cells, Biomedicines source

      The Introduction proposes that reduced μ-opioid receptor expression on B cells alters endogenous opioid analgesic activity and contributes to pain development. The Discussion also links lower expression to greater pain intensity in FM and OA patients. Neither passage establishes sensitization or aggravation of FMS as the proposed mechanism; the paper presents the receptor-reserve explanation as a hypothesis. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    In female chronic widespread pain model mice, MHC class II-positive B cells and activated plasma cells are increased in peripheral blood, and memory B cells are elevated in bone marrow.

    “Melissa E. Lenert et al. found increased numbers of MHC class II–positive B cells and activated plasma cells increased in peripheral blood, as well as elevated proportions of memory B cells was elevated in the bone marrow of female chronic widespread pain (CWP) model mice (101).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [101] Lenert, 2024, B-Cell and Plasma Cell Activation in a Mouse Model of Chronic Muscle Pain, Neurobiol Pain source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    FMS symptom severity is positively associated with lysophosphatidylcholines (LPCs).

    “Jenny E. Jakobsson et al. reported that FMS symptom severity was positively associated with lysophosphatidylcholines (LPCs)”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [114] Jakobsson, 2025, Fibromyalgia Patients Have Altered Lipid Concentrations Associated with Disease Symptom Severity and Anti-Satellite Glial Cell Igg Antibodies, J Pain source

  • May combine two claims.

    Interpretationcitation

    Microglia can regulate synaptic plasticity and participate in central sensitization.

    “These findings indicate that microglia can regulate synaptic plasticity and participate in central sensitization.”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [128] Yuan, 2020, Inhibition of Microglial Activation in the Amygdala Reverses Stress-Induced Abdominal Pain in the Male Rat, Cell Mol Gastroenterol Hepatol source
    • cites [129] Zhou, 2019, Microglia Are Indispensable for Synaptic Plasticity in the Spinal Dorsal Horn and Chronic Pain, Cell Rep source
    • cites [130] Zhong, 2010, The Direction of Synaptic Plasticity Mediated by C-Fibers in Spinal Dorsal Horn Is Decided by Src-Family Kinases in Microglia: The Role of Tumor Necrosis Factor-Alpha, Brain Behav Immun source

  • May combine two claims.

    Premisecitation

    In a CRPS model, the spinal cord shows increased populations of reactive astrocytes and microglia, elevated expression of M1 marker CD86, and reduced Arg-1 expression.

    “Consistently, in a CRPS model, the spinal cord showed increased populations of reactive astrocytes and microglia were observed in the spinal cord, along with elevated expression of the M1 marker CD86 and reduced Arg-1 expression”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [122] Han, 2022, Dicam in the Extracellular Vesicles from Astrocytes Attenuates Microglia Activation and Neuroinflammation, Cells source

      Results §3.1 reports increased Iba-1-positive microglia and GFAP-positive astrocytes in the spinal cord dorsal horn of DICAM-knockout mice in a CRPS model, compared with wild-type mice. Results §3.2 reports increased CD86 and decreased Arg-1 in cultured mixed glial cells, not in the spinal cord of the CRPS-model mice. The claim conflates those two settings. (LLM, conf=0.91)

      Experimental — accuracy not yet measured
    • Rests on an assumption: Findings from animal models of FMS, CRPS, or fibromyalgia-like pain translate to human NPP mechanisms.

  • May combine two claims.

    Premisecitation

    Astrocytes and microglia are structurally connected to synapses via gap junctions and form a structural barrier surrounding synapses.

    “Astrocytes, together with microglia, are structurally connected to synapses via gap junctions and form a structural barrier surrounding synapses.”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [124] Herculano-Houzel, 2014, The Glia/Neuron Ratio: How It Varies Uniformly across Brain Structures and Species and What That Means for Brain Physiology and Evolution, Glia source
    • cites [125] Lu, 2023, Astrocytes in Chronic Pain: Cellular and Molecular Mechanisms, Neurosci Bull source

      The Introduction says astrocytes contact neuronal synapses, supporting that part of the claim. It describes gap junctions as connections between astrocytes, not between glia and synapses, and does not say that microglia share those connections or that the cells form a structural barrier around synapses. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Interpretationcitation

    Cortical plasticity occurs in the brains of FMS patients and is primarily mediated by microglial activation.

    “suggesting that cortical plasticity occurs in the brains of FMS patients with FMS and is primarily mediated by microglial activation (127).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [127] Albrecht, 2019, Brain Glial Activation in Fibromyalgia - a Multi-Site Positron Emission Tomography Investigation, Brain Behav Immun source

      The Discussion (page not provided) reports elevated cortical TSPO signal in fibromyalgia patients and says the findings may support microglial rather than astrocytic activation. It does not establish cortical plasticity or show that microglial activation primarily mediates it. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    This arrangement prevents glutamate leakage and facilitates exchange of ions, neurotransmitters, and other small molecules.

    “This arrangement not only prevents glutamate (Glu) leakage of Glu, but also facilitates the exchange function of ions, neurotransmitters, and other small molecules (124, 125).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [124] Herculano-Houzel, 2014, The Glia/Neuron Ratio: How It Varies Uniformly across Brain Structures and Species and What That Means for Brain Physiology and Evolution, Glia source
    • cites [125] Lu, 2023, Astrocytes in Chronic Pain: Cellular and Molecular Mechanisms, Neurosci Bull source

      The Introduction (page unavailable) says astrocyte gap junctions allow adjoining cells to exchange ions and small cytosolic components. It does not say this arrangement prevents glutamate leakage or that neurotransmitters pass through those junctions; the separate discussion of neurotransmitters as secreted mediators does not establish that connection. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Activated astrocytes show hypertrophy with elongated and thickened processes, and activated microglia show soma enlargement with shortened or retracted processes that may adopt an amoeboid morphology.

    “the specific transformations observed in activated states are characterized by astrocytic hypertrophy with elongated and thickened processes, alongside microglial soma enlargement with shortened or retracted processes that may adopt an amoeboid morphology.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [12] Ji, 2018, Neuroinflammation and central sensitization in chronic and widespread pain, Anesthesiology source

      The section “Glial activation, gliosis, and gliopathy after painful injuries” (page unavailable) describes hypertrophy and process retraction or extension as morphological changes in activated microglia and astrocytes. It does not specify elongated, thickened astrocytic processes, enlarged microglial somata, or amoeboid microglia, so the detailed cell-specific description goes beyond the source. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The MAPK pathway comprises three major branches: ERK, p38, and JNK.

    “This pathway comprises three major branches: extracellular signal-regulated kinase (ERK), p38, and c-Jun N-terminal kinase (JNK).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [131] Zhang, 2018, Sustained Stimulation of ?(2)- and ?(3)-Adrenergic Receptors Leads to Persistent Functional Pain and Neuroinflammation, Brain Behav Immun source

      Section 4.3 of the Discussion identifies p38 and ERK as MAPKs. It does not identify JNK or state that the MAPK pathway has three major branches, so those parts of the claim are unsupported by our copy. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [132] Liu, 2025, Acupressure Attenuates Fibromyalgia Central Sensitization Via Mapk Phosphorylation-Mediated Neuroinflammation Regulation, J Orthop Surg Res source

      The Introduction identifies p38 and JNK as MAPK subfamilies, supporting two branches in the claim. It does not identify ERK or state that the pathway has three major branches; a search for ERK found no supporting passage in our copy. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    The discrepancy in ERK phosphorylation may result from limited sampling in Western blot analyses.

    “We suggest that this discrepancy may result from limited sampling in Western blot analyses”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [122] Han, 2022, Dicam in the Extracellular Vesicles from Astrocytes Attenuates Microglia Activation and Neuroinflammation, Cells source

      The Results (§3.3; page unavailable) report no significant difference in ERK1/2 signaling, and Methods (§2.11; page unavailable) describe the Western blot analysis. Neither passage attributes an ERK phosphorylation discrepancy to limited sampling; searches for that explanation found no supporting passage in our copy. (LLM, conf=0.74)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Interpretationcitation

    Morphological alterations alone may not definitively indicate functional activation; they provide an anatomical substrate for subsequent alterations in synaptic plasticity.

    “However, the morphological alterations alone may not definitively indicate functional activation. Instead, these adaptations provide an anatomical substrate for subsequent alterations in synaptic plasticity changes.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [12] Ji, 2018, Neuroinflammation and central sensitization in chronic and widespread pain, Anesthesiology source

      In “Glial activation, gliosis, and gliopathy after painful injuries” (page not provided), the review distinguishes morphological glial reaction from other activation states and cautions that it may not directly cause pain. The “Sex dimorphism” section further reports similar morphological activation in male and female rodents despite different responses to microglial interventions. The review discusses glial regulation of synaptic plasticity, but does not say that the morphological changes provide an anatomical substrate for subsequent plasticity. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Activated astrocytes release ATP, generating synaptic LTD in NK1R+ neurons, leading to antinociception.

    “Activated astrocytes subsequently release ATP, generating synaptic long-term depression (LTD) in neurokinin-1 receptor–positive (NK1R+) neurons, leading to antinociception.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [151] Xu, 2021, Astrocytes Contribute to Pain Gating in the Spinal Cord, Sci Adv source

      The Introduction reports that Aβ-fiber stimulation activates astrocytes, induces LTD in NK1R+ neurons, and inhibits pain. The Results propose ATP release from activated astrocytes as a possible mechanism, but do not establish it as fact; they identify conversion of ATP to adenosine as the proposed step mediating neuronal inhibition. The citing sentence states that causal pathway more definitively than the paper does. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    15 of 20 studies support increased BDNF levels in FMS.

    “whereas Amir Hossein Behnoush et al. found that 15 of 20 studies supported increased level of BDNF levels in FMS (159).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [159] Behnoush, 2023, Brain-Derived Neurotrophic Factor in Fibromyalgia: A Systematic Review and Meta-Analysis of Its Role as a Potential Biomarker, PLoS One source

      The Abstract Results and §3.2 report that 20 studies were included in the review and that a meta-analysis of 15 studies found higher circulating BDNF in fibromyalgia overall. They do not say that all 15 studies individually supported an increase; the study-characteristics table (§3.1) includes studies reporting lower BDNF. The claim confuses the number pooled with the number supporting the finding. (LLM, conf=0.90)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Activated microglia upregulate CB2, promoting transformation toward an anti-inflammatory phenotype, restricting microglial activity to the ipsilateral dorsal horn, and inducing release of anti-inflammatory cytokines such as IL-10, thereby alleviating NPP.

    “Activated microglia upregulate CB2 expression of CB2, which promotes transformation toward an anti-inflammatory phenotype, restricts microglial activity to the ipsilateral dorsal horn, and induces release of anti-inflammatory cytokines such as IL-10, thereby alleviating NPP (156).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [156] van den Hoogen, 2021, Cannabinoids in Chronic Pain: Therapeutic Potential through Microglia Modulation, Front Neural Circuits source

      The “Microglial CB2R in Nociceptive Signaling” section reports that CB2R activation shifts microglia toward an anti-inflammatory state, increases IL-10 release, and restricts microglial activity to the ipsilateral dorsal horn in the cited animal models. It also reports increased CB2R expression in inflammatory and neuropathic pain states, but says that this increase *may* promote the phenotype shift; the claim presents that link as certain. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Interpretationreasoning

    Conflicting findings on BDNF may arise from multiple contributing factors and do not negate the clinical relevance of BDNF.

    “Notably, these conflicting findings may arise from multiple contributing factors and do not negate the clinical relevance of BDNF.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [158] Baumeister, 2019, No Evidence for Altered Plasma Ngf and Bdnf Levels in Fibromyalgia Patients, Sci Rep source

      The Discussion (Findings; page unavailable) attributes the conflicting BDNF results to fibromyalgia heterogeneity and the greater likelihood of chance findings in smaller studies. The paper calls for further investigation and says its plasma findings cannot establish whether central growth-factor levels are altered, but it does not affirm BDNF’s clinical relevance; it says the utility of neurotrophic biomarkers remains unclear. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [159] Behnoush, 2023, Brain-Derived Neurotrophic Factor in Fibromyalgia: A Systematic Review and Meta-Analysis of Its Role as a Potential Biomarker, PLoS One source

      The Discussion identifies several possible contributors to differing BDNF findings, including study populations, treatment regimens, comorbidities and measurement kits. The Conclusion says BDNF warrants further investigation as a potential diagnostic or prognostic biomarker in fibromyalgia, but does not establish its clinical relevance as the claim implies. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Some studies report no significant differences in BDNF or NGF levels between FMS patients and controls.

    “some studies reported no significant differences between FMS and control patients with FMS and controls (158)”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [158] Baumeister, 2019, No Evidence for Altered Plasma Ngf and Bdnf Levels in Fibromyalgia Patients, Sci Rep source

  • May combine two claims.

    Premisecitation

    Astrocytes express glutamine synthetase, which modulates central glutamine synthesis and participates in glutamatergic neurotransmission through the Glu-Gln cycle.

    “Astrocytes can express glutamine synthetase (GS), which modulates central glutamine (Gln) synthesis and participates in glutamatergic neurotransmission through the Glu–Gln cycle (171).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [171] Baek, 2024, The Role of Glutamine Homeostasis in Emotional and Cognitive Functions, Int J Mol Sci source

  • May combine two claims.

    Premisecitation

    BDNF promotes dephosphorylation of KCC2 and downregulates KCC2 expression via the TrkB pathway.

    “BDNF promotes dephosphorylation of KCC2 and downregulates KCC2 expression via the TrkB pathway (164).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [164] Rivera, 2002, Bdnf-Induced Trkb Activation Down-Regulates the K+-Cl- Cotransporter Kcc2 and Impairs Neuronal Cl- Extrusion, J Cell Biol source

      The Results and discussion (Fig. 1; page not specified in our copy) report that BDNF reduces KCC2 mRNA and protein expression in hippocampal cultures and that blocking TrkB-related signaling prevents this effect. The paper does not report that BDNF promotes dephosphorylation of KCC2. (LLM, conf=0.90)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Through Shc/FRS-2 and PLCγ/CREB signaling, BDNF inhibits intracellular Cl− efflux and regulates ionic plasticity.

    “Through activation of downstream Src homology 2 domain-containing transforming protein/FGF receptor substrate 2 (Shc/FRS-2) and phospholipase Cγ- (PLCγ)/cAMP response element-binding protein signaling pathway, BDNF inhibits intracellular Cl- efflux and regulates ionic plasticity (165).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [165] Rivera, 2004, Mechanism of Activity-Dependent Downregulation of the Neuron-Specific K-Cl Cotransporter Kcc2, J Neurosci source

  • May combine two claims.

    Premisecitation

    PGE2 selectively inhibits excitatory signals of glycinergic synapses on non-glycinergic neurons, suppressing glycinergic inhibition and promoting chronic pain.

    “while PGE2 selectively inhibits excitatory signals of glycinergic synapses on non-glycinergic neurons, thereby suppressing glycinergic inhibition and promoting chronic pain (185, 186).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [185] Chirila, 2014, Long-Term Potentiation of Glycinergic Synapses Triggered by Interleukin 1ß, Proc Natl Acad Sci U S A source

      The paper’s introductory discussion says that, during chronic inflammation, PGE2 selectively depresses glycinergic synaptic inputs onto nonglycinergic neurons. It describes glycinergic inputs as inhibitory, not excitatory signals. The same discussion links loss of glycinergic inhibition to pain hypersensitivity, but does not specifically establish that this PGE2 effect promotes chronic pain. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [186] Reinold, 2005, Spinal Inflammatory Hyperalgesia Is Mediated by Prostaglandin E Receptors of the Ep2 Subtype, J Clin Invest source

  • May combine two claims.

    Interpretationcitation

    Under disinhibition, non-noxious mechanical stimulation can activate pain pathways and induce hyperalgesia.

    “indicating that under disinhibition, non-noxious mechanical stimulation can activate the pain pathways and induce hyperalgesia.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [184] Torsney, 2006, Disinhibition Opens the Gate to Pathological Pain Signaling in Superficial Neurokinin 1 Receptor-Expressing Neurons in Rat Spinal Cord, J Neurosci source

      In “Disinhibition revealed input,” the paper suggests that low-threshold tactile stimuli could drive central nociceptive circuitry under disinhibition. It links that input to allodynia, however, and says that revealed high-threshold input may contribute to hyperalgesia. Thus the claim’s pain-pathway component is supported, but its attribution of hyperalgesia to non-noxious stimulation is not. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Microglia-derived IL-1β self-activates TLR4, reducing presynaptic GABA synthesis, and activates PKC in neurons to suppress postsynaptic GABA receptor activity.

    “Microglia-derived IL-1β can self-activate toll-like receptor 4 (TLR4), thereby reducing presynaptic GABA synthesis, and can activate protein kinase C (PKC) in neurons to suppress postsynaptic GABA receptor activity (180).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [180] Yan, 2015, Activation of Toll Like Receptor 4 Attenuates Gaba Synthesis and Postsynaptic Gaba Receptor Activities in the Spinal Dorsal Horn Via Releasing Interleukin-1 Beta, J Neuroinflammation source

      The Conclusions and Discussion report that TLR4 activation causes microglia to release IL-1β, which reduces presynaptic GABA synthesis and suppresses postsynaptic GABA receptor activity through neuronal PKC. The claim reverses the first step: our copy does not say that IL-1β self-activates TLR4. (LLM, conf=0.90)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    GABA is a major inhibitory neurotransmitter acting on GABA receptors on presynaptic or postsynaptic membranes to inhibit synaptic signal transmission and neuronal excitation.

    “γ-Aminobutyric acid (GABA) is a major inhibitory neurotransmitter acting on GABA receptors (GABA-AR, GABA_BR, and GABA_CR) on the presynaptic membrane or postsynaptic membranes to inhibit synaptic signal transmission and neuronal excitation (178).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [178] Kadota, 2010, Implicit Visuomotor Processing for Quick Online Reactions Is Robust against Aging, J Neurosci source

      The Results and Discussion passages concern aging, visual stimuli, and reaching reactions, not neurotransmission. Searches for GABA, GABA receptors, and presynaptic or postsynaptic inhibition found no passage in our copy addressing the claim. (LLM, conf=0.78)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Excessive glutamate uptake disrupts ionic balance, leading to astrocytic depolarization and influx of extracellular water, transforming astrocytes toward the A1 phenotype and promoting central sensitization and NP.

    “Excessive Glu uptake disrupts ionic balance, leading to astrocytic depolarization and influx of extracellular water, transforming the morphology of astrocytes toward the polarized A1 phenotype and promoting the central sensitization and NP (175).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [175] O'Connor, 1993, Role of Calcium in Astrocyte Volume Regulation and in the Release of Ions and Amino Acids, J Neurosci source

      The paper’s discussion of volume regulation (page not available in our copy) links astrocyte swelling with depolarization and notes that glutamate can be a cause of astrocytic edema. It does not establish that excessive glutamate uptake initiates the claimed sequence; its proposed volume-regulation mechanism has ions and water leaving swollen cells. The passages do not address A1 polarization, central sensitization, or neuropathic pain. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    NLR demonstrates adequate sensitivity but poor specificity and is influenced by disease activity in FMS.

    “Although NLR demonstrates adequate sensitivity, it also exhibits poor specificity and is influenced by the disease activity in FMS (68).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [68] Almirall, 2025, Neutrophil-Lymphocyte Ratio in Fibromyalgia and Axial Spondyloarthritis: A Potential Biomarker for Diagnosis and Disease Activity, Biomedicines source

      The Results report that NLR differed between severe and non-severe fibromyalgia cases, supporting an association with disease severity, though the Discussion describes the correlation with FIQR scores as weak. The claim of poor specificity needs qualification: specificity was 62.07% for predicting severe fibromyalgia, but 82.14% for fibromyalgia diagnosis (Results; Discussion). (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisereasoning

    Conditions related to central sensitization, including chronic widespread pain, fibromyalgia, irritable bowel syndrome, chronic primary low back pain, complex regional pain syndrome, chronic primary headaches and orofacial pain, chronic visceral pain syndromes, and chronic primary musculoskeletal pain, are generally classified under nociplastic pain.

    “Accordingly, several conditions related to central sensitization, such as chronic widespread pain, fibromyalgia (FMS), irritable bowel syndrome (IBS), chronic primary low back pain (CPLBP), complex regional pain syndrome (CRPS), chronic primary headaches and orofacial pain, chronic visceral pain syndromes, and chronic primary musculoskeletal pain, etc., are generally classified under NPP (Figure 1”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Pre-existing infection may act as an inducing factor, with pathological changes in the nervous system being more likely responsible for sustained pain.

    “These findings suggest that the pre-existing infection may act as an inducing factor, with pathological changes in the nervous system being more likely responsible for sustained pain.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In collagen-induced arthritis mouse models, CD4+ T cells crossed the blood-brain barrier and induced central nervous system inflammation through activating microglial activation, indicating that immune cell invasion may participate in nociplastic pain development following pre-infection.

    “In addition, in the collagen-induced arthritis (CIA) mouse models, CD4+ T cells were shown to cross the BBB and induce central nervous system inflammation through activating microglial activation, indicating that immune cell invasion may participate in NPP development following pre-infection (Figure 2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Nociplastic pain is present in four conditions-chronic primary low back pain, fibromyalgia, chronic temporomandibular disorders, and irritable bowel syndrome-and the female-to-male incidence ratio is approximately 2:1.

    “According to a review published in The Lancet in 2021, NPP is present in four conditions: CPLBP, FMS, chronic temporomandibular disorders (TMD), and IBS. The female-to-male incidence ratio is approximately 2:1”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [3] Fitzcharles, 2021, Nociplastic pain: towards an understanding of prevalent pain conditions, Lancet source

  • May combine two claims.

    Premisecitation

    In rodent models, a temperature of 4°C is sufficient to induce long-term abnormal pain, whereas at 6°C corresponding long-term pain cannot be successfully induced.

    “In rodent models, a temperature of 4°C is sufficient to induce long-term abnormal pain, whereas at 6°C, corresponding long-term pain cannot be successfully induced (38).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [38] Nasu, 2010, Persistent Deep Mechanical Hyperalgesia Induced by Repeated Cold Stress in Rats, Eur J Pain source

  • May combine two claims.

    Interpretationcitation

    After exogenous insulin injection, an exaggerated ACTH response was induced in patients; in chronic primary low back pain, ACTH levels were also significantly increased compared with controls, and HPA axis impairment and hyperresponsiveness of ACTH release may represent significant features of nociplastic pain.

    “After exogenous insulin injection, an exaggerated ACTH response of the ACTH in the patients was successfully induced in patients (48). In CPLBP, its ACTH levels were also significantly increased compared with those in control groups (49). HPA axis impairment and hyperresponsiveness of ACTH release may therefore represent significant features of NPP.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [48] Griep, 1993, Altered Reactivity of the Hypothalamic-Pituitary-Adrenal Axis in the Primary Fibromyalgia Syndrome, J Rheumatol
    • cites [49] Griep, 1998, Function of the Hypothalamic-Pituitary-Adrenal Axis in Patients with Fibromyalgia and Low Back Pain, J Rheumatol

  • May combine two claims.

    Interpretationcitation

    Sympathetic inactivation caused by frequent internal or external stimulation reduces adrenaline secretion, thereby inhibiting neuropeptide Y and suppressing adrenaline-mediated increases in blood glucose.

    “This phenomenon may be related to sympathetic inactivation caused by frequent internal or external stimulation, which reduces adrenaline secretion in the body, thereby inhibiting the secretion of neuropeptide Y (a marker of chronic sympathoadrenal activity) and suppressing the adrenaline-mediated increases in blood glucose (45).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [45] Crofford, 1994, Hypothalamic-Pituitary-Adrenal Axis Perturbations in Patients with Fibromyalgia, Arthritis Rheum source

  • May combine two claims.

    Premisecitation

    Compared with healthy controls, there were no significant differences in estradiol and progesterone levels in patients with fibromyalgia, suggesting that either estrone, estradiol, or other estrogen subtypes may mediate the onset of nociplastic pain.

    “Interestingly, research conducted by Włodzimierz Samborski et al. demonstrated that, compared with healthy controls, there were no significant differences in estradiol and progesterone levels in patients with FMS. This suggests that either estrone, estradiol, or other types of estrogen subtypes may mediate the onset of NPP (41).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [41] Samborski, 2005, Normal Profile of Sex Hormones in Women with Primary Fibromyalgia, Ann Acad Med Stetin

  • May combine two claims.

    Premisecitation

    Treatment with dried powdered ginger rhizome improved allodynia and hyperalgesia by decreasing inflammatory responses mediated by nitric oxide, prostaglandin E2, thromboxane B2, and interleukin-1β in lipopolysaccharide-stimulated macrophages in fibromyalgia model mice, indicating that macrophages may contribute to nociplastic pain through the release of pro-inflammatory mediators.

    “It was shown that treatment with dried powdered ginger rhizome improved both allodynia and hyperalgesia by decreasing the inflammatory responses mediated by nitric oxide (NO), prostaglandin E2 (PGE2), thromboxane B2 (TXB2), and interleukin-1β (IL-1β) in lipopolysaccharide (LPS)-stimulated macrophages in FMS model mice, indicating that macrophages may contribute to NPP through the release of pro”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [56] Montserrat-de la Paz, 2018, Ginger Rhizome Enhances the Anti-Inflammatory and Anti-Nociceptive Effects of Paracetamol in an Experimental Mouse Model of Fibromyalgia, Inflammopharmacology source

  • May combine two claims.

    Interpretationcitation

    In the cerebrospinal fluid of fibromyalgia patients, increased substance P expression was positively correlated with smoking, while substance P expression was independent of calcitonin gene-related peptide and beta-endorphin levels, suggesting that substance P may represent another potential biomarker.

    “Moreover, in the CSF of FMS patients, increased SP expression was positively correlated with smoking, while the SP expression was independent of both calcitonin gene-related peptide (CGRP) and beta-endorphin levels, suggesting that SP may represent another potential biomarker (52, 53).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [52] Vaerøy, 1989, Modulation of Pain in Fibromyalgia (Fibrositis Syndrome): Cerebrospinal Fluid (CSF) Investigation of Pain Related Neuropeptides with Special Reference to Calcitonin Gene Related Peptide (CGRP), J Rheumatol Suppl

      Not checked in the free run.

    • cites [53] Vaeroy, 1988, Cerebrospinal Fluid Levels of Beta-Endorphin in Patients with Fibromyalgia (Fibrositis Syndrome), J Rheumatol

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In patients with fibromyalgia, imbalance of the Th1/Th2 cell ratio and excessive secretion of interleukin-8 and heat shock proteins are prominent features.

    “In patients with FMS, imbalance of the Th1/Th2 cell ratio and excessive secretion of IL-8 and heat shock proteins are the prominent features.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [97] Nguyen, 2019, Altered Cytokine Networks in Fibromyalgia Patients, Immunol Lett source

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    No significant differences in T-cell subtype proportions were identified between fibromyalgia patients and healthy individuals, but upregulation of several cytokines secreted by CD4+ T cells, including IL-17A, IL-22, IL-9, TNF-α, and IFN-γ, was observed.

    “However, Giuliana Guggino et al. did not identify significant differences in the proportion of T-cell subtype proportions between patients compared with FMS and healthy individuals. Interestingly, they observed upregulation of several cytokines secreted by CD4+ T cells, including IL-17A, IL-22, IL-9, TNF-α, and IFN-γ (91).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [91] Hauser, 2017, Fibromyalgia in Women: Immune System and T Cell Involvement, Clin Exp Rheumatol source

  • Classified as probably not a substantial claim.

    Premisenone given

    Mast cells release histamine and proteases during degranulation.

    “Mast cells release histamine and proteases during degranulation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Mast cell-derived serine protease tryptase levels were increased following mast cell degranulation, which subsequently activated proteinase-activated receptor-2 signaling pathways to modulate hypersensitivity.

    “Kayo Masuko et al. demonstrated that through the degranulation effect of mast cells, the levels of mast cell–derived serine protease tryptase levels were also increased following mast cell degranulation, which subsequently activated proteinase-activated receptor-2 (PAR-2) signaling pathways to modulate hypersensitivity (78).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [78] Masuko, 2007, Functional Somatic Syndrome: How It Could Be Relevant to Rheumatologists, Mod Rheumatol source

  • May combine two claims.

    Premisecitation

    In water avoidance stress model rats, treatment with cromolyn sodium or nerve growth factor-neutralizing agents significantly inhibited synaptic plasticity in the mesenteric region and alleviated stress-induced abdominal pain, suggesting that mast cell degranulation together with nerve growth factor induces synaptic plasticity changes leading to abdominal pain.

    “In water avoidance stress model rats, treatment with cromolyn sodium or the neutralizing agent of nerve growth factor–neutralizing agents significantly inhibited synaptic plasticity in the mesenteric region and alleviated stress-induced abdominal pain induced by stress, suggesting that mast cell degranulation effect of mast cells, together with nerve growth factor (NGF), induces synaptic”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [77] Zhang, 2018, Sustained Pain Hypersensitivity in the Stressed Colon: Role of Mast Cell-Derived Nerve Growth Factor-Mediated Enteric Synaptic Plasticity, Neurogastroenterol Motil source

  • May combine two claims.

    Premisecitation

    Allodynia was observed in recipient mice following adoptive transfer of purified CD4+ T cells derived from splenocytes of acid-treated male mice into naïve mice, indicating that CD4+ T cells participate in fibromyalgia pathogenesis.

    “Hiroshi Ueda et al. observed allodynia in recipient mice following adoptive transfer of purified CD4+ T cells, derived from splenocytes of acid-treated male mice, into naïve mice, indicating that CD4+ T cells participate in FMS pathogenesis (88).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [88] Deshmukh, 2017, Immune Dysfunction in Irritable Bowel Syndrome: A Role for T Cells, Clin Exp Immunol source

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Mast cell infiltration in fibromyalgia model mice is accompanied by mechanical and cold allodynia as well as muscle fatigue; depletion of mast cell activity with compound 48/80 or ketotifen reversed mechanical and cold allodynia, supporting a pathogenic role of mast cell degranulation in nociplastic pain.

    “Evelyne da Silva Brum et al. observed mast cell infiltration in FMS model mice, accompanied by mechanical and cold allodynia as well as muscle fatigue. Following administration of compound 48/80 or the mast cell membrane stabilizer ketotifen to deplete mast cell activity, mechanical and cold allodynia were successfully reversed, supporting a pathogenic role of mast cell degranulation in NPP (76).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [76] Brum, 2024, Involvement of Peripheral Mast Cells in a Fibromyalgia Model in Mice, Eur J Pharmacol source

  • May combine two claims.

    Premisecitation

    In fibromyalgia model mice, the proportion of regulatory T helper cells (CD4+FOXP3+) was reduced, accompanied by increased interleukin-5 secretion from Th2 cells; inhibition of interleukin-5 reversed mechanical hypersensitivity, suggesting that fibromyalgia is closely associated with T-cell dysregulation.

    “In FMS model mice, the proportion of regulatory T helper cells (CD4+FOXP3+) was reduced, accompanied by increased IL-5 secretion from Th2 cells. Inhibition of IL-5 could successfully reversed mechanical hypersensitivity, suggesting that FMS is closely associated with T-cell dysregulation (96).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [96] Torres, 2021, Peripheral Immune Alterations in Fibromyalgia: A Multicenter Study, Clin Rheumatol source

  • May combine two claims.

    Premisecitation

    Physical exercise training can reduce the proportion of Th1 cells, rebalance the Th1/Th2 ratio, and inhibit the expression of interleukin-8 and heat shock protein, thereby alleviating pain and cognitive impairment in patients with fibromyalgia.

    “Studies have shown that physical exercise training can reduce the proportion of Th1 cells, rebalance the Th1/Th2 ratio, and inhibit the expression of IL-8 and heat shock protein expression, thereby alleviating pain and cognitive impairment in patients with FMS (97).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [97] Nguyen, 2019, Altered Cytokine Networks in Fibromyalgia Patients, Immunol Lett source

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    In CRPS patients, the ratio of CD8+ lymphocytes and the percentage of IL-2-producing T-cell subpopulations are lower than in healthy donors, indicating a Th1/Th2 imbalance in NPP.

    “patients with CRPS, Ines Kaufmann et al. reported that the ratio of CD8+ lymphocytes and the percentage of IL-2–producing T-cell subpopulations were lower than those in healthy donors, indicating a Th1/Th2 imbalance in NPP (99).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [99] Kim, 2021, Role of Inflammation in the Pathophysiology of Fibromyalgia, Rheumatology (Oxford) source

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    B lymphocytes contribute to adaptive immunity by migrating to injured sites and differentiating into plasma cells that release autoantibodies.

    “As an essential component of the immune system, B lymphocytes contribute to adaptive immunity by migrating to the injured sites and differentiating into plasma cells that release autoantibodies.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [100] Lopez, 2020, Cytokine Profiles and Immune Dysregulation in Fibromyalgia Patients: A Clinical Study, Clin Immunol source

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Glial cells support basic metabolic requirements of neurons and exert multiple functions in chronic pain modulation, including phagocytosis of cellular debris and regulation of neuronal development.

    “These cells bear the burden of supporting the basic metabolic requirements of neurons. Highly plastic glial cells not only mediate central immune responses and regulate central infections but also exert multiple functions involved in chronic pain modulation, such as phagocytosis of cellular debris and regulation of neuronal development (126).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [126] Borst, 2021, Microglia: Immune and Non-Immune Functions, Immunity source

  • May combine two claims.

    Premisecitation

    Suppression of α7-nAChR/cAMP/PKA/CREB signaling promotes microglial M1 polarization and induces neuronal apoptosis, altering neural plasticity.

    “Specifically, suppression of the α7-nAChR/cAMP/PKA/CREB signaling pathway, reserpine promoted microglial polarization of microglia toward the M1 phenotype and induced neuronal apoptosis, thereby altering neural plasticity (120).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [120] Atta, 2023, Targeting ?7-Nachr by Galantamine Mitigates Reserpine-Induced Fibromyalgia-Like Symptoms in Rats: Involvement of Camp/Pka, Pi3k/Akt, and M1/M2 Microglia Polarization, Eur J Pharmacol source
    • Rests on an assumption: Findings from animal models of FMS, CRPS, or fibromyalgia-like pain translate to human NPP mechanisms.

  • May combine two claims.

    Premisecitation

    TNF binding to TNFRSF1B activates TRAF2/MAPK signaling, enhances TRPV1 and SCN10A expression, and thereby facilitates NPP development.

    “In addition, tumor necrosis factor (TNF) binding to TNFRSF1B activates TRAF2/MAPK signaling, enhances TRPV1 and SCN10A expression, and thereby facilitates NPP development in sequence (134).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [134] Pohóczky, 2022, Discovery of Novel Targets in a Complex Regional Pain Syndrome Mouse Model by Transcriptomics: Tnf and Jak-Stat Pathways, Pharmacol Res source

  • May combine two claims.

    Premisecitation

    PICs can directly bind to glutamate receptors on neurons, enhancing synaptic excitability and promoting central sensitization and NPP development.

    “Studies have shown that PICs can directly bind directly to glutamate receptors on neurons, thereby enhancing synaptic excitability, and promoting both central sensitization and NPP development (137).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [137] Beltran, 2021, Microglia-Derived Cytokines Contribute to Pain Sensitization in Fibromyalgia, Brain Behav Immun source

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Reserpine injection inhibits expression of PKA, phosphorylated AKT1, and phosphorylated CREB.

    “Additionally, reserpine injection inhibited the expression of PKA, phosphorylated AKT1, and phosphorylated CREB.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [120] Atta, 2023, Targeting ?7-Nachr by Galantamine Mitigates Reserpine-Induced Fibromyalgia-Like Symptoms in Rats: Involvement of Camp/Pka, Pi3k/Akt, and M1/M2 Microglia Polarization, Eur J Pharmacol source
    • Rests on an assumption: Findings from animal models of FMS, CRPS, or fibromyalgia-like pain translate to human NPP mechanisms.

  • May combine two claims.

    Premisecitation

    Soluble IL-6 initially decreases sEPSCs, followed by increased sEPSCs and CREB phosphorylation.

    “while soluble IL-6 initially decreased sEPSCs, followed by increased sEPSCs and cAMP response element-binding protein (CREB) phosphorylation (138).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [138] Sheng, 2020, Activation of Spinal Microglia Contributes to Mechanical Allodynia in a Rat Model of Fibromyalgia, Mol Pain source

  • May combine two claims.

    Premisereasoning

    PICs enhance neuronal excitability by activating glial cells and promoting A1 or M1 polarization, leading to further release of pro-inflammatory cytokines.

    “Beyond direct regulation of neuronal excitability via synaptic plasticity, PICs can also enhance neuronal excitability by activating glial cells and promoting A1 (astrocytic) or M1 (microglial) polarization, leading to further release of pro-inflammatory cytokines.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    IL-1β exposure enhances GABA-induced currents, and IL-6 exposure enhances glutamate-induced currents.

    “Meanwhile, IL-1β and IL-6 exposure enhanced both γ-aminobutyric acid (GABA)- and glutamate-induced currents, respectively.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [138] Sheng, 2020, Activation of Spinal Microglia Contributes to Mechanical Allodynia in a Rat Model of Fibromyalgia, Mol Pain source

  • May combine two claims.

    Premisecitation

    Activated glial cells secrete glutamate, which binds to NMDARs on presynaptic membranes, elevating neuronal excitability.

    “Activated glial cells can secrete the excitatory neurotransmitter glutamate, which binds to N-methyl-D-aspartate receptors (NMDARs) on presynaptic membranes, thereby elevating neuronal excitability (139, 140).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [139] Cao, 2022, Astrocyte-Microglia Crosstalk Mediates Neuroinflammation in Fibromyalgia Models, J Neuroinflammation source
    • cites [140] Kim, 2021, Microglia Activation in the Spinal Cord Contributes to Hyperalgesia in a Fibromyalgia Mouse Model, Pain source

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Plasma NO levels are elevated in patients with FMS and migraine and appear positively correlated with NMDAR activation.

    “Consistently, elevated plasma NO levels have been detected in patients with FMS and migraine and appear to be positively correlated with NMDAR activation of NMDA receptors (142, 143).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [142] Li, 2022, Targeting Microglia via P2x7 Receptors Attenuates Fibromyalgia-Like Pain in Rodent Models, J Neuroinflammation source
    • cites [143] Wang, 2023, Suppression of Microglial Activation Mitigates Pain and Anxiety in Fibromyalgia Mouse Models, Neuropharmacology source

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    The P2X receptor family (P2X1-P2X7) serves as ATP receptors and is widely and heterogeneously expressed in the CNS.

    “The P2X receptor (P2XR) family, including P2X1–P2X7, serves as the receptor of ATP receptors. P2XR subtypes are widely and heterogeneously expressed in the central nervous system (144).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [144] Park, 2021, Inhibition of Microglial Tlr4 Reduces Hyperalgesia in Fibromyalgia Rats, Brain Res Bull source

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Cortical astrocytes express mRNA for P2X1-P2X7, while microglia predominantly express P2X4 and P2X7.

    “Cortical astrocytes express mRNA for P2X1–P2X7, while microglia predominantly express both P2X4 and P2X7.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [145] Lee, 2022, Chronic Stress-Induced Microglial Activation Promotes Fibromyalgia-Like Pain Behaviors, Front Pharmacol source

  • May combine two claims.

    Premisecitation

    Activation of P2X7 promotes astrocyte differentiation, and astrocytes secrete D-serine, a co-agonist at NMDARs, to enhance homo- and heterosynaptic LTP.

    “Activation of P2X7 promotes astrocyte differentiation, and astrocytes can secrete D-serine, a co-agonist at NMDARs, to enhance both homo- and heterosynaptic long-term potentiation (LTP (146)).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [146] Chen, 2023, Microglial Modulation via Cannabinoid Receptor 2 Alleviates Fibromyalgia-Related Pain, Neuroscience source

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    ATP released from primary afferent neurons activates glial cells via C-fiber stimulation, while activated glial cells, particularly microglia, can induce LTP.

    “In addition, ATP, a ligand of P2XRs, being released from primary afferent neurons can activate glial cells via C-fiber stimulation, while activated glial cells—particularly microglia—can induce LTP (148–150).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [148] Wu, 2022, Role of Microglia in Central Sensitization and Pain Maintenance in Fibromyalgia, Pain Med source

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [149] Liu, 2023, Microglial Activation Drives Fibromyalgia-Like Pain via Nf-Kb Signaling Pathway, J Neuroinflammation source
    • cites [150] Chen, 2024, Regulation of Microglial Polarization Alleviates Fibromyalgia-Like Pain in Experimental Models, Front Cell Neurosci source

  • May combine two claims.

    Premisecitation

    P2X2Rs combine with GABAARs intracellularly; activating P2X2Rs enhances mobility and degradation of GABA(A)Rs, a potential mechanism for synaptic plasticity changes via purinergic signaling.

    “Interestingly, P2X2Rs were observed to combine with GABAARs in intracellular directly, activating P2X2Rs could enhance the mobility and degradation of GABA(A)Rs, which might be another potential mechanism for synaptic plasticity changes via purinergic signaling (147).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [147] Tan, 2024, Microglial Tnf-? Contributes to Pain Hypersensitivity in a Mouse Model of Fibromyalgia, Brain Res source

  • May combine two claims.

    Premisecitation

    CB1 is predominantly distributed in nerve cells of the CNS and PNS and regulates sensory and affective components of pain; CB2 is expressed mainly on immune cells, including central glial cells and peripheral immune cells.

    “Cannabinoid receptor 1 (CB1) is predominantly distributed in the nerve cells of both the CNS and PNS and regulates both the sensory and affective components of pain, while cannabinoid receptor 2 (CB2) is expressed mainly on immune cells, including central glial cells and peripheral immune cells (152).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [152] Pertwee, 2001, Cannabinoid Receptors and Pain, Prog Neurobiol source

  • May combine two claims.

    Premisecitation

    AEA and 2-AG are produced via NAPE-PLD- and DAGL-dependent pathways, respectively, and can bind to CB1 and CB2.

    “endogenous cannabinoids can produce endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG) are produced via N-acyl-phosphatidylethanolamine-phospholipase D (NAPE-PLD)– and diacylglycerol lipase (DAGL)–dependent pathways, respectively. AEA and 2-AG can bind to cannabinoid receptors CB1 and CB2 (154).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [154] Zygmunt, 1999, Vanilloid Receptors on Sensory Nerves Mediate the Vasodilator Action of Anandamide, Nature source

  • May combine two claims.

    Interpretationcitation

    BDNF may reflect disease activity, and its fluctuation may be attributable to differences in population-level disease status.

    “This suggests that BDNF may reflect disease activity, and its fluctuation may be attributable to differences in population-level disease status (160).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [160] Sarchielli, 2007, Increased Levels of Neurotrophins Are Not Specific for Chronic Migraine: Evidence from Primary Fibromyalgia Syndrome, J Pain source

  • May combine two claims.

    Premisecitation

    Exercise alleviates FMS symptoms and cognitive decline by activating the hippocampal PGC-1α/FNDC5/BDNF axis.

    “Exercise has been shown to alleviate FMS symptoms and cognitive decline by activating specific signaling pathways, including the hippocampal PGC-1α/FNDC5/BDNF axis (161).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [161] Belviranli, 2024, Exercise Training Alleviates Symptoms and Cognitive Decline in a Reserpine-Induced Fibromyalgia Model by Activating Hippocampal Pgc-1a/Fndc5/Bdnf Pathway, Neuroscience source

  • May combine two claims.

    Premisecitation

    Activated microglia release BDNF via ATP-gated Ca2+ influx mediated by P2X4 receptors, inducing phosphorylation and activation of p38-MAPK.

    “Activated microglia could release BDNF via ATP-gated Ca2+ influx mediated by P2X4 receptors, inducing phosphorylation and activation of p38-MAPK (163).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [163] Beggs, 2013, The Known Knowns of Microglia-Neuronal Signalling in Neuropathic Pain, Neurosci Lett source

  • May combine two claims.

    Premisecitation

    In the short term, BDNF regulates synaptic plasticity by enhancing postsynaptic NMDAR activity; in the long term, it increases postsynaptic currents by elevating mEPSC frequency and intracellular Ca2+ concentration mediated by AMPARs.

    “In the short term, BDNF regulates synaptic plasticity by enhancing postsynaptic NMDAR activity; in the long term, it increases postsynaptic currents by elevating both mEPSC frequency of mEPSCs and intracellular Ca²+ concentration mediated by AMPARs (169).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [169] Garraway, 2003, Bdnf Sensitizes the Response of Lamina Ii Neurons to High Threshold Primary Afferent Inputs, Eur J Neurosci source

  • May combine two claims.

    Premisecitation

    BDNF is released by glutamatergic presynaptic terminals and acts as a retrograde messenger to inhibit excitation of inhibitory dorsal horn neurons from the postsynaptic membrane.

    “BDNF is not only released by glutamatergic presynaptic terminals and also acts as a retrograde messenger to inhibit the excitation of inhibitory dorsal horn neurons from the postsynaptic membrane (168).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [168] Panja, 2014, Bdnf Mechanisms in Late Ltp Formation: A Synthesis and Breakdown, Neuropharmacology source

  • May combine two claims.

    Premisecitation

    Under stress conditions, norepinephrine levels increase, enhancing synaptic excitability.

    “Under stress conditions, norepinephrine levels increase, enhancing synaptic excitability of synapses.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [172] Hansson, 1995, Astrocytes in Glutamate Neurotransmission, Faseb J source

  • May combine two claims.

    Premisecitation

    BDNF exerts bidirectional regulation of GABAergic transmission by inhibiting GABA signaling in mature GABAergic neurons while enhancing GABA transmission and facilitating LTD in immature GABAergic neurons via the pro-BDNF/p75NTR pathway.

    “BDNF exerts bidirectional regulation of GABAergic transmission by inhibiting GABA signaling in mature GABAergic neurons while enhancing GABA transmission and facilitating LTD in immature GABAergic neurons via the pro-BDNF/p75 neurotrophin receptor (p75(NTR)) pathway (166, 167).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [166] Rivera, 2005, Two Developmental Switches in Gabaergic Signalling: The K+-Cl- Cotransporter Kcc2 and Carbonic Anhydrase Cavii, J Physiol source
    • cites [167] Woo, 2005, Activation of P75ntr by Probdnf Facilitates Hippocampal Long-Term Depression, Nat Neurosci source

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Common pathogenic features of NPP include peripheral and central sensitization.

    “Common pathogenic features of NPP include peripheral and central sensitization”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    This process prevents excessive GABA accumulation, avoiding excessive synaptic inhibition and reducing chronic pain.

    “This process prevents the excessive GABA accumulation, avoiding excessive synaptic inhibition and reducing chronic pain.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [179] Struzynska, 2004, Relationships between Glutamine, Glutamate, and Gaba in Nerve Endings under Pb-Toxicity Conditions, J Inorg Biochem source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Ca2+ acts as a second messenger regulating the adenylate cyclase/cAMP system, with distinct mGluR subtypes exhibiting heterogeneity in this regulation.

    “Ca²+ acts as a second messenger regulating the adenylate cyclase/cAMP system, with distinct mGluR subtypes exhibiting heterogeneity in this regulation of this signaling pathway) (177).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [177] Tanabe, 1992, A Family of Metabotropic Glutamate Receptors, Neuron source

  • May combine two claims.

    Premisecitation

    In the CNS, glial cells regulate nutrient delivery, neurotransmitter interactions, and ionic homeostasis.

    “In the CNS, glial cells regulate nutrient delivery, neurotransmitter interactions, and ionic homeostasis.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [179] Struzynska, 2004, Relationships between Glutamine, Glutamate, and Gaba in Nerve Endings under Pb-Toxicity Conditions, J Inorg Biochem source

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    There is still a lack of in-depth investigation into the interactions between non-neuronal cells and neurons.

    “There is still a lack of in-depth investigation into the interactions between non-neuronal cells and neurons.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    The quality of relevant literature on NPP remains relatively low.

    “In the databases currently available to us, the quality of relevant literature remains relatively low”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    For iGluRs, Na+ influx and K+ efflux increase extracellular K+, promote presynaptic depolarization to increase glutamate secretion and release, and enhance postsynaptic depolarization.

    “Regarding ionotropic glutamate receptors (iGluRs), Na+ influx of Na+ and outflow of K+ efflux increase the extracellular K+ concentration, promote presynaptic depolarization of the presynaptic terminal to increase the secretion of Glu, and Glu release, and enhance postsynaptic depolarization.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [176] Fellin, 2009, Communication between Neurons and Astrocytes: Relevance to the Modulation of Synaptic and Network Activity, J Neurochem source

  • May combine two claims.

    Premisecitation

    Activated immune cells including central glial cells release pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α, which bind to glutamate receptors on neurons, enhancing synaptic excitability and promoting central sensitization and NP development.

    “Additionally, studies have shown that activated immune cells (including central glial cells) can release pro-inflammatory cytokines such as IL-1β, IL-6 and TNF-α. These cytokines can directly bind to glutamate receptors on neurons, enhancing synaptic excitability, and promoting central sensitization and NP development (137).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [137] Beltran, 2021, Microglia-Derived Cytokines Contribute to Pain Sensitization in Fibromyalgia, Brain Behav Immun source

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    No high-quality clinical disease modeling or prediction studies specifically focused on NPP exist to date.

    “To date, there have been no high-quality clinical disease modeling or prediction studies specifically focused on NPP.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Several drugs for managing NPP have received FDA approval or are recommended by clinical guidelines.

    “although several drugs for managing NPP have received FDA approval or are recommended by clinical guidelines”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    NPP is a relatively new field compared with NCP or NP.

    “Compared with NCP or NP, NPP is a relatively new field”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    There is a notable scarcity of therapeutics that directly target non-neuronal cells implicated in NPP mechanisms, with cannabinoid receptor agonists being one of the few exceptions.

    “Given the heterogeneity of conditions underlying NPP, there is remains a notable scarcity of therapeutics that directly target non-neuronal cells implicated in NPP mechanisms, with cannabinoid receptor agonists being one of the few exceptions.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Conditions underlying NPP are heterogeneous.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    To date there have been few high-quality studies or groundbreaking advances in either basic or clinical research on NPP.

    “to date there have been few high-quality studies or groundbreaking advances in either basic or clinical research.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The GABA-Glu-Gln cycle enables glial regulation of GABA homeostasis: extracellular GABA enters cells via Glu transporters, is converted to Glu by GABA aminotransferase, and is subsequently synthesized into Gln by GS.

    “The “GABA–Glu–Gln cycle enables glial regulation of GABA homeostasis: extracellular GABA enters cells via Glu transporters, where it is converted to Glu by γ-aminobutyric acid aminotransferase, and subsequently synthesized into Gln by GS (179).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [179] Struzynska, 2004, Relationships between Glutamine, Glutamate, and Gaba in Nerve Endings under Pb-Toxicity Conditions, J Inorg Biochem source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    These agents may exert analgesic effects through mechanisms such as inhibition of central sensitization or activation of opioid receptors.

    “While these agents may exert analgesic effects—either directly or indirectly—through mechanisms such as inhibition of central sensitization or activation of opioid receptors”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisenone given

    NPP is not a single disease but a novel mechanistic concept that may contribute to various conditions such as FMS, CRPS, and IBS.

    “However, it should be noted that NPP is not a single disease but rather a novel mechanistic concept that may contribute to various conditions, such as FMS, CRPS, and IBS.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    Our work is constrained by limited clinical sample availability and low quality of published NPP literature, hampering original research.

    “Our work is also constrained by challenges such as limited clinical sample availability and the generally low quality of currently published NPP literature, which hampers the ability to conduct corresponding original research.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based).

    Interpretationreasoning

    The low quality of literature may be attributed to insufficient attention given to NPP by researchers.

    “which may be attributed to insufficient attention given to NPP by researchers.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Inhibition of glycinergic/GABAergic synapses disrupts descending inhibitory control, enhances hyperalgesia, and induces central sensitization.

    “Inhibition of glycinergic/GABAergic synapses disrupts descending inhibitory control, enhances hyperalgesia, and induces central sensitization (183).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [183] Sivilotti, 1994, The Contribution of Gabaa and Glycine Receptors to Central Sensitization: Disinhibition and Touch-Evoked Allodynia in the Spinal Cord, J Neurophysiol source

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationnone given

    Existing research acknowledges the involvement of non-neuronal cells, particularly microglia, but the underlying mechanisms remain inadequately elucidated.

    “However, while existing research acknowledges the involvement of non-neuronal cells, particularly microglia, the underlying mechanisms remain inadequately elucidated.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    NPP is a type of chronic pain distinct from nociceptive and neuropathic pain, encompassing intractable pain disorders such as FMS, CRPS, and IBD.

    “NPP, another type of chronic pain distinct from nociceptive pain and neuropathic pain, encompasses several intractable pain disorders such as FMS, CRPS, IBD, and others (Table 4).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Table 4

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationnone given

    The viral pre-infection hypothesis is not yet fully supported by direct evidence and remains primarily a potential mechanism underlying NPP-related chronic pain.

    “However, the viral pre-infection hypothesis is currently not yet fully supported by direct evidence and currently remains primarily a potential, albeit promising, mechanism underlying the pathogenesis of NPP-related chronic pain.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    28-59% of FMS patients develop IBS, and 32-77% of IBS patients develop FMS, with a relative risk increase of approximately 1.54-fold.

    “For example, 28–59% of patients with FMS that develop IBS, and 32–77% of patients diagnosed with the diagnosis of IBS develop FMS during the course of their illness, with a relative risk increase of approximately 1.54-fold.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [194] De Santis, 2017, Pharmacological Treatment of Fibromyalgia: Current Evidence and Future Directions, Expert Opin Pharmacother source

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationnone given

    NPP remains a relatively new concept that has not yet been comprehensively explored, resulting in a scarcity of directly relevant literature addressing the impact of non-neuronal cells on synaptic plasticity in NPP.

    “Finally, NPP remains a relatively new concept that has not yet been comprehensively explored, resulting in a scarcity of directly relevant literature directly addressing the impact of non-neuronal cells on synaptic plasticity in NPP.”
    Quote in the paperSubstantial claim
123 of 123

  • The paper relies on this without support.

    The exact pathogenic basis for nociplastic pain initiation and development remains unclear.

    “However, the exact pathogenic basis for NPP initiation and development remains unclear, and the potential clinical manifestations and biomarkers lack a clear classification.”

  • The paper relies on this without support.

    The role of non-neuronal cells in the development and maintenance of nociplastic pain remains uncertain.

    “However, the role of non-neuronal cells in the development and maintenance of NPP remains uncertain.”

  • The paper relies on this without support.

    It remains unclear how synaptic plasticity mediates central sensitization and subsequently induces nociplastic pain, as well as which pathological factors drive changes in synaptic plasticity.

    “However, it remains unclear how synaptic plasticity mediates central sensitization and subsequently induces NPP, as well as which pathological factors drive changes in synaptic plasticity.”

  • The paper relies on this without support.

    Whether non-neuronal cells can also influence nociplastic pain through the regulation of synaptic plasticity and central sensitization requires further clarification.

    “Similarly, whether non-neuronal cells can also influence NPP through the regulation of synaptic plasticity and central sensitization requires further clarification.”

  • The paper relies on this without support.

    Findings from animal models of FMS, CRPS, or fibromyalgia-like pain translate to human NPP mechanisms.

    “Concomitant activation of microglia and astrocytes observed in a reserpine-induced FMS rat model underscores the pivotal role of central glial cell activation in NPP (117).”
    “Depletion of microglia using PLX3397 (pexidartinib) alleviated RCS-induced hyperalgesia, indicating that glial cell activation and excessive proliferation represent a critical pathway in NPP development of NPP (133).”

  • The paper relies on this without support.

    Mechanisms established for neuropathic pain generalize to NPP.

    “Alterations in synaptic plasticity may represent a common potential pathological mechanism underlying both neuropathic pain and NPP.”

  • The paper relies on this without support.

    Conditions underlying NPP are heterogeneous.

    “Given the heterogeneity of conditions underlying NPP”

  • The paper relies on this without support.

    Blood glucose levels are associated with NPP.

    “blood glucose levels have been widely reported to be associated with NPP”
8 of 8

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Table 5 reverses the reported effect of IL-1β on GABA-induced currents

    Major

    The text reports that IL-1β enhanced GABA-induced currents, whereas Table 5 says IL-1β diminishes currents induced by GABA or glycine.

  • TRPV1 claim cites a TRPA1-variant paper

    Minor

    The claim identifies variation in TRPV1 and cites reference 32, whose title instead identifies TRPA1 variants.

  • Named investigator does not match reference 88

    Minor

    The text attributes the cited finding to Hiroshi Ueda et al., but reference 88 lists Deshmukh, Keita, and Linden as its authors.

  • Five conditions are listed as six

    Minor

    The genome-wide analysis is said to cover six chronic overlapping pain conditions, but the ensuing list names only five.

  • Stated search terms are absent from Search #1

    Minor

    The methods say CRPS and CPLBP represented nociplastic pain in the literature search, but neither appears among the condition terms shown for Search #1 in Table 1.

  • Cited source of transferred CRPS IgG differs from the stated source

    Minor

    The text says the transferred IgG was isolated from CRPS model mice, while the title of its cited study says the transfer used human autoantibodies.

6 of 6

Cited works that were retracted

Works this paper cites that were later retracted, from the retraction notices publishers deposit. Major when the notice came out before this paper was published.

  • Cites a retracted work: 10.3390/ijms23116139

    Major

    The cited work was retracted on 2022-05-30 (notice 10.3390/ijms27031519), before this paper was published (2026-01-27). Its authors could have known.

    Cited work 10.3390/ijms23116139 · retracted 2022-05-30 · notice 10.3390/ijms27031519 · this paper published 2026-01-27

1 of 1

Cites

1 retracted

Flagged first, then by citations

Research works printed but not linked: 18

  1. Dydyk, 2025, Central pain syndrome
  2. Hauser, 2017, Fibromyalgia in Women: Immune System and T Cell Involvement, Clin Exp Rheumatol, 35, 81-8, 10.55563/clinexprheumatol/ooo59o · DOI
  3. Caro, 2019, Pro-Inflammatory Cytokine Levels in Fibromyalgia Patients, Rheumatol Int, 39, 2029-35, 10.1007/s00296-019-04325-7 · DOI
  4. Smith, 2021, Immune Profiling in Chronic Pain Syndromes, Front Immunol, 12, 657890, 10.3389/fimmu.2021.657890 · DOI
  5. Andersson, 2020, Inflammatory Biomarkers and Pain Severity in Fibromyalgia, Scand J Rheumatol, 49, 110-8, 10.1080/03009742.2019.1642345 · DOI
  6. Torres, 2021, Peripheral Immune Alterations in Fibromyalgia: A Multicenter Study, Clin Rheumatol, 40, 345-55, 10.1007/s10067-020-05432-1 · DOI
  7. Huang, 2022, Immune and Inflammatory Responses in Fibromyalgia Syndrome, J Immunol Res, 2022, 112345, 10.1155/2022/112345 · DOI
  8. Sheng, 2020, Activation of Spinal Microglia Contributes to Mechanical Allodynia in a Rat Model of Fibromyalgia, Mol Pain, 16, 1744806920905573, 10.1177/1744806920905573 · DOI
  9. Cao, 2022, Astrocyte-Microglia Crosstalk Mediates Neuroinflammation in Fibromyalgia Models, J Neuroinflammation, 19, 123, 10.1186/s12974-022-02489-0 · DOI
  10. Liu, 2023, Microglial Nlrp3 Inflammasome Activation Is Critical for Central Sensitization in Fibromyalgia, Front Cell Neurosci, 17, 1156890, 10.3389/fncel.2023.1156890 · DOI
  11. Li, 2022, Targeting Microglia via P2x7 Receptors Attenuates Fibromyalgia-Like Pain in Rodent Models, J Neuroinflammation, 19, 215, 10.1186/s12974-022-02560-3 · DOI
  12. Lee, 2022, Chronic Stress-Induced Microglial Activation Promotes Fibromyalgia-Like Pain Behaviors, Front Pharmacol, 13, 949382, 10.3389/fphar.2022.949382 · DOI
  13. Tan, 2024, Microglial Tnf-? Contributes to Pain Hypersensitivity in a Mouse Model of Fibromyalgia, Brain Res, 1885, 148595, 10.1016/j.brainres.2024.148595 · DOI
  14. Liu, 2023, Microglial Activation Drives Fibromyalgia-Like Pain via Nf-Kb Signaling Pathway, J Neuroinflammation, 20, 112, 10.1186/s12974-023-02748-1 · DOI
  15. Chen, 2024, Regulation of Microglial Polarization Alleviates Fibromyalgia-Like Pain in Experimental Models, Front Cell Neurosci, 18, 1198427, 10.3389/fncel.2024.1198427 · DOI
  16. Glombiewski, 2013, Psychological Interventions for Chronic Pain in Fibromyalgia: A Meta-Analysis, Clin J Pain, 29, 102-12, 10.1097/AJP.0b013e318247c9e1 · DOI
  17. De Santis, 2017, Pharmacological Treatment of Fibromyalgia: Current Evidence and Future Directions, Expert Opin Pharmacother, 18, 789-802, 10.1080/14656566.2017.1296203 · DOI
  18. Lee, 2020, Role of Descending Pain Modulation in Fibromyalgia, J Pain Res, 13, 305-16, 10.2147/JPR.S234981 · DOI

Cited by

Sorted by citations

Authors
Lai, W., Tang, X., Chen, S., Zhou, Y., Qi, Z., Cao, M., Yuan, C., Yu, J., & Wen, C.
Affiliations
Zhejiang Chinese Medical University (CN)
Corresponding author
  • Yu, Jie
  • Wen, Chengping
ORCID
Venue
Frontiers in Immunology
Publisher
Frontiers Media SA
Published
2026-01-27
Volume
17
Pages
1677310-1677310
ISSN
1664-3224 (ISSN-L)
DOI
10.3389/fimmu.2026.1677310
PMC
PMC12886048
OpenAlex
W7125711041
Semantic Scholar
cf65049620f4214115090e441c71d5081381c90e
Cited by
4
References
175
Citations by year
2026: 4
FWCI
16.37
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Immunology (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (submittedVersion, cc-by)
  • PubMed Central (submittedVersion, cc-by)
Topics
  • Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
  • Health Sciences › Medicine › Anesthesiology and Pain Medicine › Pain Management and Treatment
  • Health Sciences › Medicine › Pharmacology › Musculoskeletal pain and rehabilitation
Keywords
nociplastic pain, chronic pain, central sensitization, peripheral sensitization, non-neuronal cells, glial cells, circulating immune cells, neuron-glia interactions, synaptic plasticity, pain pathogenesis, analgesic drug development, biomarkers
MeSH terms
Nociplastic Pain, Animals, Humans, Neuroglia, Neuronal Plasticity, Neurons, Nociception, Nociceptive Pain, Central Nervous System Sensitization, Chronic Pain

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-12.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-12.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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