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.

Recent translational work has shown that fibromyalgia might be an autoimmune condition with pathogenic mechanisms mediated by a peripheral, pain-inducing action of immunoglobulin G (IgG) antibodies binding to satellite glia cells (SGC) in the dorsal root ganglia. A first clinical assessment of the postulated autoimmunity showed that fibromyalgia subjects (FMS) had elevated levels of antibodies against SGC (termed anti-SGC IgG) compared to healthy controls and that anti-SGC IgG were associated with a more severe disease status. The overarching aim of the current study was to determine whether the role of anti-SGC IgG in driving pain is exclusively through peripheral mechanisms, as indirectly shown so far, or could be attributed also to central mechanisms. To this end, we wanted to first confirm, in a larger cohort of FMS, the relation between anti-SGC IgG and pain-related clinical measures. Secondly, we explored the associations of these autoantibodies with brain metabolite concentrations (assessed via magnetic resonance spectroscopy, MRS) and pressure-evoked cerebral pain processing (assessed via functional magnetic resonance imaging, fMRI) in FMS. Proton MRS was performed in the thalamus and rostral anterior cingulate cortex (rACC) of FMS and concentrations of a wide spectrum of metabolites were assessed. During fMRI, FMS received individually calibrated painful pressure stimuli corresponding to low and high pain intensities. Our results confirmed a positive correlation between anti-SGC IgG and clinical measures assessing condition severity. Additionally, FMS with high anti-SGC IgG levels had higher pain intensity and a worse disease status than FMS with low anti-SGC IgG levels. Further, anti-SGC IgG levels negatively correlated with metabolites such as scyllo-inositol in thalamus and rACC as well as with total choline and macromolecule 12 in thalamus, thus linking anti-SGC IgG levels to the concentration of metabolites in the brain of FMS. However, anti-SGC IgG levels in FMS were not associated with the sensitivity to pressure pain or the cerebral processing of evoked pressure pain. Taken together, our results suggest that anti-SGC IgG might be clinically relevant for spontaneous, non-evoked pain. Our current and previous translational and clinical findings could provide a rationale to try new antibody-related treatments in FMS.

Dysfunctional Activation of the Dorsolateral Prefrontal Cortex During Pain Anticipation Is Associated With Altered Subsequent Pain Experience in Fibromyalgia Patients.

The ability to accurately predict pain is an adaptive feature in healthy individuals. However, in chronic pain, this mechanism may be selectively impaired and can lead to increased anxiety and excessive avoidance behavior. Recently, we reported the first data demonstrating brain activation in fibromyalgia (FM) patients during conditioned pain responses, in which FM patients revealed a tendency to form new pain-related associations rather than extinguishing irrelevant ones. The aim of the present study was to extend our previous analysis, to elucidate potential neural divergences between subjects with FM (n = 65) and healthy controls (HCs) (n = 33) during anticipatory information (ie, prior to painful stimulus onset). Using functional magnetic resonance imaging (fMRI), the current analyses include 1) a congruently cued paradigm of low and high pain predictive cues, followed by 2) an incongruently cued paradigm where low and high pain predictive cues were followed by an identical mid-intensity painful pressure. During incongruently cued high-pain associations, FM exhibited reduced left dorsolateral prefrontal cortex (dlPFC) activation compared to HCs, which was followed by an altered subsequent pain experience in FM, as patients continued to rate the following painful stimuli as high, even though the pressure had been lowered. During congruently cued low pain anticipation, FM exhibited decreased right dlPFC activation compared to HCs, as well as decreased brain connectivity between brain regions implicated in cognitive modulation of pain (dlPFC) and nociceptive processing (primary somatosensory cortex/postcentral gyrus [S1] and supplementary motor area [SMA]/midcingulate cortex [MCC]). These results may reflect an important feature of validating low pain expectations in HCs and help elucidate behavioral reports of impaired safety processing in FM patients. PERSPECTIVE: FM exhibited a stronger conditioned pain response for high-pain associations, which was associated with reduced dlPFC activation during the incongruent trial. During (congruent and incongruent) low pain associations, FM dlPFC brain activation remained indifferent. Imbalances in threat and safety pain perception may be an important target for psychotherapeutic interventions.

Neurophysiological and psychosocial mechanisms of fibromyalgia: A comprehensive review and call for an integrative model.

Research into the neurobiological and psychosocial mechanisms involved in fibromyalgia has progressed remarkably in recent years. Despite this, current accounts of fibromyalgia fail to capture the complex, dynamic, and mutual crosstalk between neurophysiological and psychosocial domains. We conducted a comprehensive review of the existing literature in order to: a) synthesize current knowledge on fibromyalgia; b) explore and highlight multi-level links and pathways between different systems; and c) build bridges connecting disparate perspectives. An extensive panel of international experts in neurophysiological and psychosocial aspects of fibromyalgia discussed the collected evidence and progressively refined and conceptualized its interpretation. This work constitutes an essential step towards the development of a model capable of integrating the main factors implicated in fibromyalgia into a single, unified construct which appears indispensable to foster the understanding, assessment, and intervention for fibromyalgia.

Fibromyalgia patients with elevated levels of anti-satellite glia cell immunoglobulin G antibodies present with more severe symptoms.

ABSTRACT: Transferring fibromyalgia patient immunoglobulin G (IgG) to mice induces pain-like behaviour, and fibromyalgia IgG binds mouse and human satellite glia cells (SGCs). These findings suggest that autoantibodies could be part of fibromyalgia pathology. However, it is unknown how frequently fibromyalgia patients have anti-SGC antibodies and how anti-SGC antibodies associate with disease severity. Here, we quantified serum or plasma anti-SGC IgG levels in 2 fibromyalgia cohorts from Sweden and Canada using an indirect immunofluorescence murine cell culture assay. Fibromyalgia serum IgG binding to human SGCs in human dorsal root ganglia tissue sections was also assessed by immunofluorescence. In the cell culture assay, anti-SGC IgG levels were increased in both fibromyalgia cohorts compared with control group. Elevated anti-SGC IgG was associated with higher levels of self-reported pain in both cohorts, and higher fibromyalgia impact questionnaire scores and increased pressure sensitivity in the Swedish cohort. Anti-SGC IgG levels were not associated with fibromyalgia duration. Swedish fibromyalgia (FM) patients were clustered into FM-severe and FM-mild groups, and the FM-severe group had elevated anti-SGC IgG compared with the FM-mild group and control group. Anti-SGC IgG levels detected in culture positively correlated with increased binding to human SGCs. Moreover, the FM-severe group had elevated IgG binding to human SGCs compared with the FM-mild and control groups. These results demonstrate that a subset of fibromyalgia patients have elevated levels of anti-SGC antibodies, and the antibodies are associated with more severe fibromyalgia symptoms. Screening fibromyalgia patients for anti-SGC antibodies could provide a path to personalized treatment options that target autoantibodies and autoantibody production.

The effects of a 15-week physical exercise intervention on pain modulation in fibromyalgia: Increased pain-related processing within the cortico-striatal- occipital networks, but no improvement of exercise-induced hypoalgesia.

Dysfunctional top-down pain modulation is a hallmark of fibromyalgia (FM) and physical exercise is a cornerstone in FM treatment. The aim of this study was to explore the effects of a 15-week intervention of strengthening exercises, twice per week, supervised by a physiotherapist, on exercise-induced hypoalgesia (EIH) and cerebral pain processing in FM patients and healthy controls (HC). FM patients (n = 59) and HC (n = 39) who completed the exercise intervention as part of a multicenter study were examined at baseline and following the intervention. Following the exercise intervention, FM patients reported a reduction of pain intensity, fibromyalgia severity and depression. Reduced EIH was seen in FM patients compared to HC at baseline and no improvement of EIH was seen following the 15-week resistance exercise intervention in either group. Furthermore, a subsample (Stockholm site: FM n = 18; HC n = 19) was also examined with functional magnetic resonance imaging (fMRI) during subjectively calibrated thumbnail pressure pain stimulations at baseline and following intervention. A significant main effect of exercise (post > pre) was observed both in FM patients and HC, in pain-related brain activation within left dorsolateral prefrontal cortex and caudate, as well as increased functional connectivity between caudate and occipital lobe bordering cerebellum (driven by the FM patients). In conclusion, the results indicate that 15-week resistance exercise affect pain-related processing within the cortico-striatal-occipital networks (involved in motor control and cognition), rather than directly influencing top-down descending pain inhibition. In alignment with this, exercise-induced hypoalgesia remained unaltered.

The Vastus Lateralis Muscle Interstitium Proteome Changes after an Acute Nociception in Patients with Fibromyalgia Compared to Healthy Subjects-A Microdialysis Study.

Fibromyalgia (FM) is a complex disorder and a clinical challenge to diagnose and treat. Microdialysis is a valuable tool that has been used to investigate the interstitial proteins and metabolites of muscle in patients with fibromyalgia. The implantation of the catheter in the muscle causes acute tissue trauma and nociception. The aim of this study was to investigate acute proteome changes in the vastus lateralis muscle in women fibromyalgia patients (FM) and healthy subjects (CON). A further aim was to study if a 15-week resistance exercise program in FM had any influence on how chronic painful muscle responds to acute nociception. Twenty-six women patients with FM and twenty-eight CON were included in this study. A microdialysis catheter (100 kilo Dalton cut off, membrane 30 mm) was inserted in the vastus lateralis muscle, and samples were collected every 20 min. Subjects rated pain before catheter insertion, directly after, and every 20 min of sample collection. Dialysate samples from time points 0-120 were pooled and considered trauma samples due to the catheter insertion. The samples were analyzed with nano-liquid chromatography-tandem mass spectrometry (nLC-MS/MS). Advanced multivariate data analysis was used to investigate protein profile changes between the groups. Multivariate data analysis showed significant (CV-ANOVA p = 0.036) discrimination between FM and CON based on changes in 26 proteins. After the 15-week exercise intervention, the expression levels of the 15 proteins involved in muscle contraction, response to stimulus, stress, and immune system were increased to the same expression levels as in CON. In conclusion, this study shows that microdialysis, in combination with proteomics, can provide new insights into the interstitial proteome in the muscle of FM. In response to acute nociception, exercise may alter the innate reactivity in FM. Exercise may also modulate peripheral muscle proteins related to muscle contraction, stress, and immune response in patients with FM.

Emotion regulation and the salience network: a hypothetical integrative model of fibromyalgia.

Fibromyalgia is characterized by widespread pain, fatigue, sleep disturbances and other symptoms, and has a substantial socioeconomic impact. Current biomedical and psychosocial treatments are unsatisfactory for many patients, and treatment progress has been hindered by the lack of a clear understanding of the pathogenesis of fibromyalgia. We present here a model of fibromyalgia that integrates current psychosocial and neurophysiological observations. We propose that an imbalance in emotion regulation, reflected by an overactive 'threat' system and underactive 'soothing' system, might keep the 'salience network' (also known as the midcingulo-insular network) in continuous alert mode, and this hyperactivation, in conjunction with other mechanisms, contributes to fibromyalgia. This proposed integrative model, which we term the Fibromyalgia: Imbalance of Threat and Soothing Systems (FITSS) model, should be viewed as a working hypothesis with limited supporting evidence available. We hope, however, that this model will shed new light on existing psychosocial and biological observations, and inspire future research to address the many gaps in our knowledge about fibromyalgia, ultimately stimulating the development of novel therapeutic interventions.

The OPRM1 gene and interactions with the 5-HT1a gene regulate conditioned pain modulation in fibromyalgia patients and healthy controls.

Fibromyalgia (FM) patients have dysfunctional endogenous pain modulation, where opioid and serotonergic signaling is implicated. The aim of this study was to investigate whether genetic variants in the genes coding for major structures in the opioid and serotonergic systems can affect pain modulation in FM patients and healthy controls (HC). Conditioned pain modulation (CPM), evaluating the effects of ischemic pain on pressure pain sensitivity, was performed in 82 FM patients and 43 HC. All subjects were genotyped for relevant functional polymorphisms in the genes coding for the µ-opioid receptor (OPRM1, rs1799971), the serotonin transporter (5-HTT, 5-HTTLPR/rs25531) and the serotonin 1a receptor (5-HT1a, rs6295). Results showed the OPRM1 G-allele was associated with decreased CPM. A significant gene-to-gene interaction was found between the OPRM1 and the 5-HT1a gene. Reduced CPM scores were seen particularly in individuals with the OPRM1 G*/5-HT1a CC genotype, indicating that the 5-HT1a CC genotype seems to have an inhibiting effect on CPM if an individual has the OPRM1 G-genotype. Thus, regardless of pain phenotype, the OPRM1 G-allele independently as well as with an interaction with the 5-HT1a gene influenced pain modulation. FM patients had lower CPM than HC but no group differences were found regarding the genetic effects on CPM, indicating that the results reflect more general mechanisms influencing pain modulatory processes rather than underlying the dysfunction of CPM in FM. In conclusion, a genetic variant known to alter the expression of, and binding to, the my-opioid receptor reduced a subject's ability to activate descending pain inhibition. Also, the results suggest a genetically inferred gene-to-gene interaction between the main opioid receptor and a serotonergic structure essential for 5-HT transmission to modulate pain inhibition. The results in this study highlight the importance of studying joint synergistic and antagonistic effects of neurotransmittor systems in regard to pain modulation.

International, multidisciplinary Delphi consensus recommendations on non-pharmacological interventions for fibromyalgia.

OBJECTIVES: To develop evidence-based expert recommendations for non-pharmacological treatments for pain, fatigue, sleep problems, and depression in fibromyalgia. METHODS: An international, multidisciplinary Delphi exercise was conducted. Authors of EULAR and the Canadian Fibromyalgia Guidelines Group, members of the American Pain Society and clinicians with expertise in fibromyalgia were invited. Participants were asked to select non-pharmacological interventions that could be offered for specific fibromyalgia symptoms and to classify them as either core or adjunctive treatments. An evidence summary was provided to aid the decision making. Items receiving >70% votes were accepted, those receiving <30% votes were rejected and those obtaining 30-70% votes were recirculated for up to two additional rounds. RESULTS: Seventeen experts participated (Europe (n = 10), North America (n = 6), and Israel (n = 1)) in the Delphi exercise and completed all three rounds. Aerobic exercise, education, sleep hygiene and cognitive behavioural therapy were recommended as core treatments for all symptoms. Mind-body exercises were recommended as core interventions for pain, fatigue and sleep problems. Mindfulness was voted core treatment for depression, and adjunctive treatment for other symptoms. Other interventions, namely music, relaxation, hot bath, and local heat were voted as adjunctive treatments, varying between symptoms. CONCLUSIONS: This study provided evidence-based expert consensus recommendations on non-pharmacological treatments for fibromyalgia that may be used to individualise treatments in clinical practice targeting the diverse symptoms associated with fibromyalgia.

Uncovering a Genetic Polymorphism Located in Huntingtin Associated Protein 1 in Modulation of Central Pain Sensitization Signaling Pathways.

Fibromyalgia syndrome (FMS) is characterized by widespread pain and increased sensitivity to nociceptive stimulus or tenderness. While familial aggregation could suggest a potential hereditary component in FMS development, isolation of genetic determinants has proven difficult due to the multi-factorial nature and complexity of the syndrome. Central sensitization is thought to be one of the key mechanisms leading to FMS in a subset of patients. Enhanced central pain signaling can be measured using the Nociceptive Flexion Reflex (NFR) or RIII threshold. We performed a genome-wide association study (GWAS) using an array to genotype 258,756 human genetic polymorphisms in 225 FMS patients and 77 healthy volunteers and searched for genetic variants associated with a lowered NFR threshold. We have identified a potential association between a single nucleotide polymorphism resulting in a common non-synonymous coding mutation in the Huntingtin associated protein 1 (HAP1) gene (rs4796604, MAF = 0.5) and the NFR threshold (p = 4.78E-06). The Hap1 protein is involved in trafficking and is particularly enriched in neurons. Our results suggest a possible involvement of the neuronal trafficking protein HAP1 in modulating pain signaling pathways and thus participate in the establishment of the NFR threshold.

Proteomic Investigation in Plasma from Women with Fibromyalgia in Response to a 15-wk Resistance Exercise Intervention.

PURPOSE: Fibromyalgia (FM) is a complex pain condition, and exercise is considered the first option of treatment. Few studies have examined the effect of exercise on molecular mechanisms in FM. The aim of this study was to analyze the plasma proteome in women with FM and healthy controls (CON) before and after 15 wk of resistance exercise. This study further investigated whether clinical and exercises-related outcomes correlated with identified plasma proteins in FM. METHODS: Plasma samples from 40 FM/25 CON (baseline) and 21 FM/24 CON (postexercise) were analyzed using shotgun proteomics. Clinical/background data were retrieved through questionnaires. Exercise-related variables and pressure pain thresholds were assessed using standardized instruments. Multivariate statistics were applied to analyze the proteomic profile at baseline and postexercise, and correlation with clinical/exercise-related data. RESULTS: Fifteen weeks of resistance exercises improved clinical symptoms and muscle strength, and affected circulating proteins related to immunity, stress, mRNA stability, metabolic processes, and muscle structure development in FM. Pressure pain threshold was related to a specific protein profile, with proteins involved in metabolic and immune response. Subgroups of FM based on plasma proteins, FM duration, and improved muscle strength were identified. CONCLUSIONS: Exercise seems to affect circulating proteins, clinical characteristics, and muscle strength in FM. This study contributes to better understanding of systemic protein changes in FM compared with CON and how resistance exercise affects such changes.

Distinct aberrations in cerebral pain processing differentiating patients with fibromyalgia from patients with rheumatoid arthritis.

ABSTRACT: The current study used functional magnetic resonance imaging to directly compare disease-relevant cerebral pain processing in well-characterized patient cohorts of fibromyalgia (FM, nociplastic pain) and rheumatoid arthritis (RA, nociceptive pain). Secondary aims were to identify pain-related cerebral alterations related to the severity of clinical symptoms such as pain intensity, depression, and anxiety. Twenty-six patients with FM (without RA-comorbidity) and 31 patients with RA (without FM-comorbidity) underwent functional magnetic resonance imaging while stimulated with subjectively calibrated painful pressures corresponding to a pain sensation of 50 mm on a 100-mm visual analogue scale. Stimulation sites were at the most inflamed proximal interphalangeal joint in the left hand in patients with RA and the left thumbnail in patients with FM, 2 sites that have previously been shown to yield the same brain activation in healthy controls. The current results revealed disease-distinct differences during pain modulation in RA and FM. Specifically, in response to painful stimulation, patients with FM compared to patients with RA exhibited increased brain activation in bilateral inferior parietal lobe (IPL), left inferior frontal gyrus (IFG)/ventrolateral prefrontal cortex (vlPFC) encapsulating left dorsolateral prefrontal cortex, and right IFG/vlPFC. However, patients with RA compared to patients with FM exhibited increased functional connectivity (during painful stimulation) between right and left IPL and sensorimotor network and between left IPL and frontoparietal network. Within the FM group only, anxiety scores positively correlated with pain-related brain activation in left dorsolateral prefrontal cortex and right IFG/vlPFC, which further highlights the complex interaction between affective (ie, anxiety scores) and sensory (ie, cerebral pain processing) dimensions in this patient group.

Research Recommendations Following the Discovery of Pain Sensitizing IgG Autoantibodies in Fibromyalgia Syndrome.

BACKGROUND: Fibromyalgia syndrome (FMS) is the most common chronic widespread pain condition in rheumatology. Until recently, no clear pathophysiological mechanism for fibromyalgia had been established, resulting in management challenges. Recent research has indicated that serum immunoglobulin Gs (IgGs) may play a role in FMS. We undertook a research prioritisation exercise to identify the most pertinent research approaches that may lead to clinically implementable outputs. METHODS: Research priority setting was conducted in five phases: situation analysis; design; expert group consultation; interim recommendations; consultation and revision. A dialogue model was used, and an international multi-stakeholder expert group was invited. Clinical, patient, industry, funder, and scientific expertise was represented throughout. Recommendation-consensus was determined via a voluntary closed eSurvey. Reporting guideline for priority setting of health research were employed to support implementation and maximise impact. RESULTS: Arising from the expert group consultation (n = 29 participants), 39 interim recommendations were defined. A response rate of 81.5% was achieved in the consensus survey. Six recommendations were identified as high priority- and 15 as medium level priority. The recommendations range from aspects of fibromyalgia features that should be considered in future autoantibody research, to specific immunological investigations, suggestions for trial design in FMS, and therapeutic interventions that should be assessed in trials. CONCLUSIONS: By applying the principles of strategic priority setting we directed research towards that which is implementable, thereby expediating the benefit to the FMS patient population. These recommendations are intended for patients, international professionals and grant-giving bodies concerned with research into causes and management of patients with fibromyalgia syndrome.

The translocator protein gene is associated with endogenous pain modulation and the balance between glutamate and γ-aminobutyric acid in fibromyalgia and healthy subjects: a multimodal neuroimaging study.

ABSTRACT: A cerebral upregulation of the translocator protein (TSPO), a biomarker of glial activation, has been reported in fibromyalgia subjects (FMS). The TSPO binding affinity is genetically regulated by the Ala147Thr polymorphism in the TSPO gene (rs6971) and allows for a subject classification into high affinity binders (HABs) and mixed/low affinity binders (MLABs). The aim of the present multimodal neuroimaging study was to examine the associations of the TSPO polymorphism with: (1) conditioned pain modulation, (2) expectancy-modulated pain processing assessed during functional magnetic resonance imaging, and (3) the concentration and balance of glutamate and γ-aminobutyric acid in the rostral anterior cingulate cortex and thalamus using proton magnetic resonance spectroscopy in FMS (n = 83) and healthy controls (n = 43). The influence of TSPO on endogenous pain modulation presented in the form of TSPO HABs, as opposed to MLABs, displaying less efficient descending pain inhibition and expectancy-induced reduction of pain. Translocator protein HABs in both groups (FM and healthy controls) were found to have higher thalamic glutamate concentrations and exhibit a pattern of positive correlations between glutamate and γ-aminobutyric acid in the rostral anterior cingulate cortex, not seen in MLABs. Altogether, our findings point to TSPO-related mechanisms being HAB-dependent, brain region-specific, and non-FM-specific, although in FMS the disadvantage of an aberrant pain regulation combined with an HAB genetic set-up might hamper pain modulation more strongly. Our results provide evidence for an important role of TSPO in pain regulation and brain metabolism, thereby supporting the ongoing drug development targeting TSPO-associated mechanisms for pain relief.

Comorbid Conditions in Temporomandibular Disorders Myalgia and Myofascial Pain Compared to Fibromyalgia.

The impact of comorbidities in fibromyalgia (FM) and temporomandibular disorders (TMD) have been well documented, but whether TMD sub-diagnoses myalgia (MYA) and myofascial pain with referral (MFP) differ regarding comorbidity is unclear. We aimed to elucidate this by studying the presence and associations of comorbidities in FM, MFP and MYA. An extended version of the Diagnostic Criteria for TMD axis II questionnaire was used to examine demographics, pain and comorbidities in 81 patients with FM, 80 with MYA, and 81 with MFP. Patients with MFP and FM reported a higher percentage of irritable bowel syndrome (IBS), depression, anxiety, somatic symptoms, perceived stress, and insomnia compared to MYA. Patients with FM had more IBS, depression, and somatic symptom disorder versus MFP. After adjusting for confounding variables, participants with anxiety, somatic symptoms disorder, pain catastrophizing, and perceived stress, as well as a greater number of comorbidities, were more likely to have MFP than MYA, whereas FM participants were more associated with IBS, somatic symptoms and insomnia compared to MFP. The number of comorbidities was significantly associated with widespread pain but not pain duration, body mass index or being on sick leave. In conclusion, patients with MFP were more similar to those with FM regarding comorbidity and should be differentiated from MYA in clinical settings and pain management.

Passive transfer of fibromyalgia symptoms from patients to mice.

Fibromyalgia syndrome (FMS) is characterized by widespread pain and tenderness, and patients typically experience fatigue and emotional distress. The etiology and pathophysiology of fibromyalgia are not fully explained and there are no effective drug treatments. Here we show that IgG from FMS patients produced sensory hypersensitivity by sensitizing nociceptive neurons. Mice treated with IgG from FMS patients displayed increased sensitivity to noxious mechanical and cold stimulation, and nociceptive fibers in skin-nerve preparations from mice treated with FMS IgG displayed an increased responsiveness to cold and mechanical stimulation. These mice also displayed reduced locomotor activity, reduced paw grip strength, and a loss of intraepidermal innervation. In contrast, transfer of IgG-depleted serum from FMS patients or IgG from healthy control subjects had no effect. Patient IgG did not activate naive sensory neurons directly. IgG from FMS patients labeled satellite glial cells and neurons in vivo and in vitro, as well as myelinated fiber tracts and a small number of macrophages and endothelial cells in mouse dorsal root ganglia (DRG), but no cells in the spinal cord. Furthermore, FMS IgG bound to human DRG. Our results demonstrate that IgG from FMS patients produces painful sensory hypersensitivities by sensitizing peripheral nociceptive afferents and suggest that therapies reducing patient IgG titers may be effective for fibromyalgia.