Role of ERK in gender difference of fibromyalgia pain.

This study investigated the ERK pathway of the peripheral nervous system and discovered a gender-specific pattern of ERK activation in the dorsal root ganglion of an acid-induced chronic widespread muscular pain model. We employed a twice acid-induced chronic musculoskeletal pain model in rats to evaluate mechanical pain behavior in both male and female groups. We further conducted protein analysis of dissected dorsal root ganglions from both genders. Both male and female rats exhibited a similar pain behavior trend, with females demonstrating a lower pain threshold. Protein analysis of the dorsal root ganglion (DRG) showed a significant increase in phosphorylated ERK after the second acid injection in all groups. However, phosphorylation of ERK was observed in the dorsal root ganglion, with higher levels in the male ipsilateral group compared to the female group. Moreover, there was a no difference between the left and right sides in males, whereas the significant difference was observed in females. In conclusions, the administration of acid injections induced painful behavior in rats, and concurrent with this, a significant upregulation of pERK was observed in the dorsal root ganglia, with a greater magnitude of increase in males than females, and in the contralateral side compared to the ipsilateral side. Our findings shed light on the peripheral mechanisms underlying chronic pain disorders and offer potential avenues for therapeutic intervention.

Repeated cold stress, an animal model for fibromyalgia, elicits proprioceptor-induced chronic pain with microglial activation in mice.

BACKGROUND: Fibromyalgia is characterized by chronic pain, fatigue, and other somatic symptoms. We have recently revealed that proprioceptor hyperactivation induces chronic pain in a rat model of myalgic encephalomyelitis. The present study explores whether similar proprioceptor-induced pain is elicited in a mouse model of fibromyalgia. METHODS: Repeated cold stress (RCS) was used as a fibromyalgia model. Pain behavior was examined using the von Frey test, and neuronal activation was examined immunohistochemically as activating transcription factor (ATF)3 expression. The Atf3:BAC transgenic mouse, in which mitochondria in hyperactivated neurons are specifically labeled by green fluorescent protein, was used to trace the activated neuronal circuit. PLX3397 (pexidartinib) was used for microglial suppression. RESULTS: RCS elicited long-lasting pain in mice. ATF3, a marker of cellular hyperactivity and injury, was expressed in the lumbar dorsal root ganglion (DRG) 2 days after RCS initiation; the majority of ATF3-expressing DRG neurons were tropomyosin receptor kinase C- and/or vesicular glutamate transporter 1-positive proprioceptors. Microglial activation and increased numbers of microglia were observed in the medial part of the nucleus proprius 5 days after RCS initiation, and in the dorsal region of the ventral horn 7 days after RCS. In the ventral horn, only a subset of motor neurons was positive for ATF3; these neurons were surrounded by activated microglia. A retrograde tracer study revealed that ATF3-positive motor neurons projected to the intrinsic muscles of the foot (IMF). Using Atf3:BAC transgenic mice, we traced hyperactivated neuronal circuits along the reflex arc. Green fluorescent protein labeling was observed in proprioceptive DRG neurons and their processes originating from the IMF, as well as in motor neurons projecting to the IMF. Microglial activation was observed along this reflex arc, and PLX3397-induced microglial ablation significantly suppressed pain behavior. CONCLUSION: Proprioceptor hyperactivation leads to local microglial activation along the reflex arc; this prolonged microglial activation may be responsible for chronic pain in the present model. Proprioceptor-induced microglial activation might be the common cause of chronic pain in both the fibromyalgia and myalgic encephalomyelitis models, although the experimental models are different.

Acupoint Catgut Embedding Diminishes Fibromyalgia Pain through TRPV1 in the Mouse Brain.

BACKGROUND: Chronic pain refers to pain that persists for over three months. Chronic pain may restrict activities of daily living, including work, learning, social life, and can lead to anxiety, depression, and sleep disturbance. Imaging data have demonstrated that central sensitization often occurs in the brain of patients with chronic pain, which arises from imbalanced neurotransmission in the central nervous system. Transient receptor potential vanilloid 1 (TRPV1) is an ion channel to serve as an inflammatory detector in the brain. We aim to determine the properties of acupoint catgut embedding (ACE) on cold stress-induced mice fibromyalgia (FM) and surveyed the character of TRPV1 and linked molecules in chronic FM pain. METHODS: Intermittent cold stress (ICS) was used to induce mice FM model. Mice were subgrouped into normal mice, ICS-induced FM group, FM mice with ACE, and FM in Trpv1-⁣/- group. ACE is a novel acupuncture technique that provides convenience and continuous nerve stimulation that has been reported effective on pain management. RESULTS: Our behavioral experiments showed similar levels of pain response among all groups before treatment. After ICS, prolonged mechanical and thermal pain was initiated (mechanical threshold: 1.96 ± 0.12 g; thermal latency: 4.86 ± 0.21 s) and were alleviated by ACE treatment and TRPV1 gene deletion. Inflammatory mediators were increased in the plasma of FM mice, while TRPV1 and related kinases were amplified in the hypothalamus and cerebellum. These changes were ameliorated in the ACE-treated and Trpv1-⁣/- groups. CONCLUSIONS: These novel findings suggest that chronic FM pain can be modulated by ACE or TRPV1 gene deletion. The analgesic effect of ACE through the TRPV1 pathway may reflect its potential as a therapeutic target for FM treatment.

Metabolic, Apoptotic and Fibro-Inflammatory Profiles of the Heart Exposed to Environmental Electromagnetic Fields.

Environmental stress can disturb the integrative functioning of the cardiovascular system and trigger a number of adaptive and/or maladaptive cell responses. Concomitant with the expanding use of mobile communication systems, public exposure to electromagnetic fields (EMFs) raises the question of the impact of 900 MHz EMFs on cardiovascular health. Therefore, in this study, we experimentally investigated whether 915 MHz EMF exposure influenced cardiac metabolic, antioxidant, apoptotic, and fibro-inflammatory profiles in a mouse model. Healthy mice were sham-exposed or exposed to EMF for 14 days. Western blot analysis using whole cardiac tissue lysates demonstrated that there was no significant change in the expression of oxidative phosphorylation (OXPHOS) complexes between the control and EMF-exposed mice. In addition, the myocardial expression of fibro-inflammatory cytokines, antioxidant enzymes, and apoptosis-related markers remained unchanged in the EMF-challenged hearts. Finally, the structural integrity of the cardiac tissues was preserved among the groups. These findings suggest that the apoptotic, antioxidant, metabolic, and fibro-inflammatory profiles of the heart remained stable under conditions of EMF exposure in the analyzed mice.

Peripheral Beta-2 Adrenergic Receptors Mediate the Sympathetic Efferent Activation from Central Nervous System to Splenocytes in a Mouse Model of Fibromyalgia.

Abnormalities in the peripheral immune system are involved in the pathophysiology of fibromyalgia, although their contribution to the painful symptoms remains unknown. Our previous study reported the ability of splenocytes to develop pain-like behavior and an association between the central nervous system (CNS) and splenocytes. Since the spleen is directly innervated by sympathetic nerves, this study aimed to examine whether adrenergic receptors are necessary for pain development or maintenance using an acid saline-induced generalized pain (AcGP) model (an experimental model of fibromyalgia) and whether the activation of these receptors is also essential for pain reproduction by the adoptive transfer of AcGP splenocytes. The administration of selective ß2-blockers, including one with only peripheral action, prevented the development but did not reverse the maintenance of pain-like behavior in acid saline-treated C57BL/6J mice. Neither a selective α1-blocker nor an anticholinergic drug affects the development of pain-like behavior. Furthermore, ß2-blockade in donor AcGP mice eliminated pain reproduction in recipient mice injected with AcGP splenocytes. These results suggest that peripheral ß2-adrenergic receptors play an important role in the efferent pathway from the CNS to splenocytes in pain development.

Lysophosphatidic acid receptor type-1 mediates brain activation in micro-positron emission tomography analysis in a fibromyalgia-like mouse model.

The intermittent cold stress-induced generalized pain response mimics the pathophysiological and pharmacotherapeutic features reported for fibromyalgia patients, including the presence of chronic generalized pain and female dominance. In addition, the intermittent cold stress-induced generalized pain is abolished in lysophosphatidic acid receptor type-1 knockout mice, as reported in many cases of neuropathic pain models. This study aimed to identify the brain loci involved in the intermittent cold stress generalized pain response and test their dependence on the lysophosphatidic acid receptor type-1. Positron emission tomography analyses using 2-deoxy-2-[18 F]fluoro-d-glucose in the presence of a pain stimulus showed that intermittent cold stress causes a significant increase in uptake in the ipsilateral regions, including the salience networking-related anterior cingulate cortex and insular cortex and the cognition-related hippocampus. A significant decrease was observed in the default mode network-related posterior cingulate cortex. Almost these intermittent cold stress-induced changes were abolished in lysophosphatidic acid receptor type-1 knockout mice. There results suggest that the intermittent cold stress-induced generalized pain response is mediated by the lysophosphatidic acid receptor type-1 in specific brain loci related to salience networking and cognition, which may lead to further developments in the treatment of fibromyalgia.

Role of Etanercept and Infliximab on Nociceptive Changes Induced by the Experimental Model of Fibromyalgia.

BACKGROUND: Fibromyalgia is a clinical condition that affects 1% to 5% of the population. No proper therapy has been currently found. It has been described that inflammation plays a central role in the nerve sensitizations that characterize the pathology. METHODS: This paper aimed to evaluate the efficacy of etanercept and infliximab in the management of pain sensitization. Fibromyalgia was induced by three injections once a day of reserpine at the dose of 1 mg/kg. Etanercept (3 mg/kg) and infliximab (10 mg/kg) were administered the day after the last reserpine injection and then 5 days after that. Behavioral analyses were conducted once a week, and molecular investigations were performed at the end of the experiment. RESULTS: Our data confirmed the major effect of infliximab administration as compared to etanercept: infliximab administration strongly reduced pain sensitization in thermal hyperalgesia and mechanical allodynia. From the molecular point of view, infliximab reduced the activation of microglia and astrocytes and the expression of the purinergic P2X7 receptor ubiquitously expressed on glia and neurons. Downstream of the P2X7 receptor, infliximab also reduced p38-MAPK overexpression induced by the reserpine administration. CONCLUSION: Etanercept and infliximab treatment caused a significant reduction in pain. In particular, rats that received infliximab showed less pain sensitization. Moreover, infliximab reduced the activation of microglia and astrocytes, reducing the expression of the purinergic receptor P2X7 and p38-MAPK pathway.

Dysfunctional energy metabolisms in fibromyalgia compared with healthy subjects.

This study aimed to investigate the levels of creatine (Cr) metabolites in the anterior cingulate cortex (ACC), thalamus, and insula of patients with fibromyalgia (FM) using proton magnetic resonance spectroscopy (MRS). The levels of Cr and phosphocreatine (PCr) relative to total Cr (tCr), which includes Cr and PCr, in the ACC, thalamus, and insula were determined using MRS in 12 patients with FM and in 13 healthy controls. The FM group had lower levels of PCr/tCr in the ACC and right insula compared to healthy controls. There was a negative correlation between Cr/tCr in the ACC and total pain levels (McGill Pain Questionnaire-Total; r = -0.579, p = 0.049) and between Cr/tCr in the left insula and affective pain levels (McGill Pain Questionnaire-Affective; r = -0.638, p = 0.047) in patients with FM. In addition, there were negative correlations between stress levels (Stress Response Inventory) and Cr/tCr in the right (r = -0.780, p = 0.005) and left thalamus (r = -0.740, p = 0.006), as well as in the right insula (r = -0.631, p = 0.028) in patients with FM. There were negative correlations between symptom levels of post-traumatic stress disorder (PTSD; PTSD checklist) and Cr/tCr in the right (r = -0.783, p = 0.004) and left thalamus (r = -0.642, p = 0.024) of patients with FM. These findings are paramount to understanding the decisive pathologies related to brain energy metabolism in patients with FM.

Abnormal neurometabolites in fibromyalgia patients: Magnetic resonance spectroscopy study.

This study aimed to investigate distinct neurometabolites in the anterior cingulate cortex (ACC), right and left thalamus, and insula of patients with fibromyalgia (FM) compared with healthy controls using proton magnetic resonance spectroscopy (MRS). Levels of N-acetylaspartate (NAA), N-acetylaspartylglutamate (NAAG), total NAA (tNAA = NAA + NAAG), myo-inositol (ml), glutamine (Gln), glutamate (Glu), Glx (Glu + Gln), glycerophosphocholine (GPC), total choline (tCho = GPC + phosphocholine) and glutathione (GSH) levels relative to total creatine (tCr) levels including creatine (Cr) and phosphocreatine (PCr) and relative to Cr levels were determined in the ACC, right and left thalamus, and insula in 12 patients with FM and 13 healthy controls using MRS. In the ACC, NAA/tCr (P = 0.028) and tCho/tCr (P = 0.047) were higher in patients with FM. In the right and left insula, tNAA/tCr (P = 0.019, P = 0.007, respectively) was lower in patients with FM. Patients with FM showed lower levels of ml/Cr (P = 0.037) in the right insula than healthy controls. These findings are paramount to understand decisive pathophysiological mechanisms related to abnormal features in the brain and parasympathetic nervous systems in FM. We suggest that the results presented herein may be essential to understand hidden pathological mechanisms and also life system potential as protective and recovering metabolic strategies in patients with FM.

Targeted Treatment of Age-Related Fibromyalgia with Supplemental Coenzyme Q10.

Fibromyalgia is a common chronic pain condition of unknown aetiology, although mitochondrial dysfunction, oxidative stress, and inflammation have been implicated in the pathophysiology of this disorder. Treatment generally involves physiotherapy, anticonvulsants, and antidepressant therapy; however, the symptomatic relief conferred by these treatments can be very variable, and there is a need for additional therapeutic strategies. One such treatment which is gaining a lot of interest is the use of coenzyme Q10 (CoQ10) supplementation. The therapeutic efficacy associated with CoQ10 supplementation is thought to arise from the ability of supplementation to restore an underlying deficit in CoQ10 status which has been associated with fibromyalgia together with the ability of CoQ10 to improve mitochondrial activity, restore cellular antioxidant capacity, and ameliorate inflammation. This chapter outlines the evidence supporting the therapeutic utility of CoQ10 in the treatment of fibromyalgia.

Evaluation of sympathetic adrenergic branch of cutaneous neural control throughout thermography and its relationship to nitric oxide levels in patients with fibromyalgia.

BACKGROUND: Fibromyalgia syndrome is defined as a complex disease, characterized by chronic widespread musculoskeletal pain and other symptoms. The factors underlying physiopathology of fibromyalgia are not well understood, complicating its diagnosis and management. OBJECTIVES: To evaluate the peripheral vascular blood flow of the skin of the hands and the core body temperature as indirect measures of sympathetic adrenergic activity of the nervous system and its relationship to nitric oxide levels (NO) in women with fibromyalgia compared with healthy controls. METHODS: Forty-two women with fibromyalgia and 52 healthy women were enrolled in this observational pilot study. We used infrared thermography of the hands and an infrared dermal thermometer to evaluate the peripheral vascular blood flow and tympanic and axillary core body temperature, respectively. We measured NO levels using the ozone chemiluminescence-based method. RESULTS: Two-way analysis of covariance (ANCOVA) showed that the tympanic (P=0.002) and hand temperatures were significantly higher in the patients with fibromyalgia than in the controls (P≤0.001). Significant associations were also found between serum NO levels and minimum temperatures at the dorsal center of the dominant hand (ß=-3.501; 95% confidence interval [CI] -6.805, ­0.198; P= 0.038), maximum temperature (ß=-5.594; 95% CI ­10.106, ­1.081; P=0.016), minimum temperature (ß=-4.090; 95% CI ­7.905, ­0.275; P=0.036), and mean temperature (ß=-5.519; 95% CI ­9.933, ­1.106; P=0.015) of the center of the palm of the non-dominant hand, maximum temperature at the thenar eminence of the dominant hand (ß=-5.800; 95% CI ­10.508, ­1.092; P=0.017), and tympanic temperature (ß=-9.321; 95% CI ­17.974, ­0.669; P=0.035) in the controls. CONCLUSIONS: Our findings indicate that the women with fibromyalgia showed higher tympanic core body and hand temperature than the healthy controls. Moreover, there were negative associations between hand peripheral vasodilation and NO in the healthy women but not in those with fibromyalgia, suggesting a dysfunction of sympathetic cutaneous neural control.

Inhibition of P2X7 Purinergic Receptor Ameliorates Fibromyalgia Syndrome by Suppressing NLRP3 Pathway.

Fibromyalgia is a chronic condition characterized by persistent widespread pain that significantly reduces quality of life in patients. The purinergic P2X7 receptor (P2X7R) seems to be involved in different pain states and neuroinflammation. The purpose of this study is to investigate the positive effects of P2X7R inhibition by the antagonist Brilliant Blue G (BBG) in a rat model of reserpine-induced fibromyalgia. Sprague-Dawley male rats were injected with 1 mg/kg of reserpine for three consecutive days. Later, animals were administered BBG (50 mg/kg) intraperitoneally for seven days. Reserpine injections induced a significant increase in pain pro-inflammatory mediators as well as a significant increase in neuroinflammation. Chronic pain, in turn, led to depressive-like symptoms and reduced neurogenesis. Blockage of P2X7R by BBG administrations is able to attenuate the behavioral deficits, pain mediators and microglial activation induced by reserpine injection. Additionally, BBG prevents NLRP3 inflammasome activation and consequently the release of active interleukin (IL)-1 and IL-18, involved in the activation of nociceptors. In conclusion, these results suggest that inhibition of P2X7R should be further investigated to develop a potential approach for the management of fibromyalgia.

NR2A-NMDA Receptor Blockade Reverses the Lack of Morphine Analgesia Without Affecting Chronic Pain Status in a Fibromyalgia-Like Mouse Model.

We have developed an experimental fibromyalgia-like mouse model using intermittent cold stress (ICS), where chronic pain is generalized, female predominant, and abolished in type 1 lysophosphatidic acid receptor-knockout (LPA1 -/-) mice but is not reversed by systemic or brain treatment with morphine. We investigated two issues in the present study: (1) whether chronic pain mechanisms and lack of brain morphine analgesia are associated in the ICS model and (2) what mechanisms are involved in the lack of morphine analgesia. ICS-induced hyperalgesia was not affected in µ-opioid receptor-knockout (MOPr -/-) mice, whereas the lack of brain morphine analgesia remained unchanged in LPA1 -/- mice, which completely abolished the hyperalgesia in the ICS model. In contrast, the lack of morphine analgesia was abolished in NR2A-NMDA receptor-knockout (NR2A -/- ) mice and blocked by intracerebroventricular (i.c.v.) injection of (R)-CPP, an NR2A antagonist, or by microinjection of siRNA NR2A into the periaqueductal gray matter region, whereas no change was observed with Ro 04-5595, an NMDA receptor subtype 2B antagonist (i.c.v.). The lack of morphine analgesia was also reversed by concomitant treatment with 1 mg/kg intraperitoneal (i.p.) of dextromethorphan, which possesses NMDA receptor antagonist activity but no analgesic activity. Finally, the hyperalgesia was completely reversed by methadone, which possesses both MOPr agonist and NMDA receptor antagonist activity. Indeed, methadone analgesia was abolished in MOPr -/- mice. These results suggest that chronic pain status and lack of morphine analgesia are independent of each other, and that lack of morphine analgesia is mediated by activation of the NR2A-NMDA receptor system. SIGNIFICANCE STATEMENT: This study reports that a type of intermittently repeated stress causes widespread pain that does not respond to morphine. Because this lack of morphine analgesia is not affected in mice, in which chronic pain is abolished, the mechanisms underlying chronic pain and lack of morphine analgesia are independent of each other. Through speculation that a lack of morphine analgesia may be a secondary event to endogenous opioid analgesic tolerance, the authors demonstrate that an antiopioid N-methyl-D-aspartate receptor system counterbalances the µ-opioid receptor-mediated analgesic mechanisms in the intermittent cold stress model.

Activation of acid-sensing ion channel 3 by lysophosphatidylcholine 16:0 mediates psychological stress-induced fibromyalgia-like pain.

OBJECTIVES: Fibromyalgia is commonly considered a stress-related chronic pain disorder, and daily stressors are known triggers. However, the relation between stress and pain development remains poorly defined by clinical approaches. Also, the aetiology remains largely unknown. METHODS: We used a newly developed mouse model and lipidomic approaches to probe the causation and explore the biological plausibility for how perceived stress translates into chronic non-inflammatory pain. Clinical and lipidomic investigations of fibromyalgia were conducted for human validation. RESULTS: Using non-painful sound stimuli as psychological stressors, we demonstrated that mice developed long-lasting non-inflammatory hyperalgesia after repeated and intermittent sound stress exposure. Elevated serum malondialdehyde level in stressed mice indicated excessive oxidative stress and lipid oxidative damage. Lipidomics revealed upregulation of lysophosphatidylcholine 16:0 (LPC16:0), a product of lipid oxidisation, in stressed mice. Intramuscular LPC16:0 injection triggered nociceptive responses and a hyperalgesic priming-like effect that caused long-lasting hypersensitivity. Pharmacological or genetic inhibition of acid-sensing ion channel 3 impeded the development of LPC16:0-induced chronic hyperalgesia. Darapladib and antioxidants could effectively alleviate the stress-induced hyperalgesia by inhibiting LPC16:0 synthesis. Clinical investigations showed that excessive oxidative stress and LPC16:0 expression also exist in patients with fibromyalgia. Moreover, LPC16:0 expression was correlated with pain symptoms in patients with high oxidative stress and disease severity. CONCLUSIONS: Our study provides experimental evidence for the causal effect of psychological stressors on chronic pain development. The findings identify a possible pathophysiological mechanism of stress-induced chronic non-inflammatory pain at molecular, behavioural and clinical levels that might indicate a new therapeutic approach for fibromyalgia.

The Comparison of the Biological Rhythms of Patients with Fibromyalgia Syndrome with Biological Rhythms of Healthy Controls.

BACKGROUND Fibromyalgia syndrome (FMS) is a rheumatic disease characterized by diffuse body pain and decreased muscle function. The aim of the present study was to compare the biological rhythms of patients with fibromyalgia syndrome with the biological rhythms of healthy controls. MATERIAL AND METHODS This was a cross-sectional, single blind, and single center case-control study. The patients with fibromyalgia were evaluated using a Fibromyalgia Impact Questionnaire (FIQ), Biological Rhythms Interview of Assessment in Neuropsychiatry (BRIAN) Scale, Visual Analog Scale (VAS), Pittsburg Sleep Quality Index (PSQI) and Beck Depression Inventory (BDI). RESULTS The study included 77 female patients with FMS, and 32 healthy female individuals as the control group. We found that the patients in the FMS group achieved higher scores in VAS, BDI, PSQI, and the BRIAN scale than the patients in the control group (P<0.001). An evaluation of the relationship between FMS evaluation parameters and biological rhythm scores in patients with FMS revealed a significant positive correlation between total BRAIN and VAS, FIQ, BDI, and PSQI scores. When the relationship between FMS evaluation parameters and biological rhythm scores was evaluated in patients with FMS, a significant positive correlation was found between total BRAIN and VAS, FIQ, BDI, and PSQI scores (r=0.555, P<0.001; r=0.461, P<0.001; r=0.630, P<0.001; and r=0.551, P<0.001 respectively). CONCLUSIONS We consider that an evaluation of the biological rhythm of female patients with FMS, and appropriate treatment when required, would contribute significantly to the treatment and follow-up process of the patients.

Determining the association between fibromyalgia, the gut microbiome and its biomarkers: A systematic review.

BACKGROUND: The association between fibromyalgia and irritable bowel syndrome is well-established. Alterations in the composition and diversity of the gut microbiome in irritable bowel syndrome have been reported, however, this association is poorly understood in fibromyalgia. Our aim was to summarise the research reporting on the gastrointestinal microbiome and its biomarkers in people with fibromyalgia. METHODS: A systematic review of published original research reporting on the gastrointestinal microbiota and its biomarkers in adults with a diagnosis of fibromyalgia was undertaken. RESULTS: From 4771 studies, 11 met our inclusion criteria and were separated into four main groups: papers reporting Helicobacter pylori; other gut bacterial markers; metabolomics and other biomarkers, which included intestinal permeability and small intestinal bacterial overgrowth. CONCLUSION: The results suggest there is a paucity of quality research in this area, with indications that the gut microbiota may play a role in fibromyalgia within the emerging field of the gut-musculoskeletal axis. Further investigations into the relationship between the gut microbiota, gut dysfunction and fibromyalgia are warranted.

Commonalities and differences in abnormal peripheral metabolites between patients with fibromyalgia and complex regional pain syndrome.

Background: Fibromyalgia (FM) and complex regional pain syndrome (CRPS) share many pathological mechanisms related to chronic pain that could contribute to multifactorial pathological mechanisms.Methods: We investigated peripheral metabolites in FM and CRPS patients compared to healthy controls based on cross-sectional study.Results: Mean corpuscular hemoglobin (p < 0.001), mean corpuscular volume (p = 0.014), and total bilirubin levels (p = 0.017) were lower in FM patients than in healthy controls. On the other hand, CRPS patients showed lower levels of total bilirubin than healthy controls (p = 0.037). Creatinine level was lower in FM patients (p = 0.057) compared to healthy controls, particularly when comparing the low-hemoglobin subgroup among FM patients (p = 0.035) with the low-hemoglobin subgroup among healthy controls. Red blood cell count (r = -0.620, p = 0.031), hematocrit (r = -0.593, p = 0.042), and creatinine level (r = -0.598, p = 0.040) showed negative correlations with McGill Pain Questionnaire-Affective (MPQ-A) scores in FM patients. A negative correlation was observed between MCV and McGill Pain Questionnaire-Sensory scores (r = -0.680, p = 0.015) in CRPS patients.Conclusion: We found specific peripheral metabolites that may exhibit different tendency between FM and CRPS patients as well as some common metabolites, which may be associated with peripheral pathology in the patients. Considering this study had a few limitations such as a small sample sizes and using a liberal threshold of significance in the correlation analysis, future studies with larger sample sizes may be needed to generalize these findings.

The GC-MS metabolomics signature in patients with fibromyalgia syndrome directs to dysbiosis as an aspect contributing factor of FMS pathophysiology.

INTRODUCTION: Fibromyalgia syndrome (FMS) is a chronic pain syndrome. Previous analyses of untargeted metabolomics data indicated altered metabolic profile in FMS patients. OBJECTIVES: We report a semi-targeted explorative metabolomics study on the urinary metabolite profile of FMS patients; exploring the potential of urinary metabolite information to augment existing medical diagnosis. METHODS: All cases were females. Patients had a medical history of persistent FMS (n = 18). Control groups were first-generation family members of the patients (n = 11), age-related individuals without indications of FMS (n = 10), and healthy, young (18-22 years) individuals (n = 41). The biofluid investigated was early morning urine samples. Data generation was done through gas chromatography-mass spectrometry (GC-MS) analysis and data processing and analyses were performed using Matlab, R, SPSS and SAS software. RESULTS: Quantitative analysis revealed the presence of 196 metabolites. Unsupervised and supervised multivariate analyses distinguished all three control groups and the FMS patients, which could be related to 14 significantly increased metabolites. These metabolites are associated with energy metabolism, digestion and metabolism of carbohydrates and other host and gut metabolites. CONCLUSIONS: Overall, urinary metabolite profiles in the FMS patients suggest: (1) energy utilization is a central aspect of this pain disorder, (2) dysbiosis seems to prevail in FMS patients, indicated by disrupted microbiota metabolites, supporting the model that microbiota may alter brain function through the gut-brain axis, with the gut being a gateway to generalized pain, and (3) screening of urine from FMS is an avenue to explore for adding non-invasive clinical information for diagnosis and treatment of FMS.

Patients with Fibromyalgia and Chronic Fatigue Syndrome show increased hsCRP compared to healthy controls.

Chronic Fatigue Syndrome (CFS) and Fibromyalgia (FM) are both chronic disorders that have a devastating effect on the lives of the affected patients and their families. Both conditions have overlapping clinical features that partly resemble those of inflammatory disorders. The etiology is still not understood, and it is suggested that the immune system might be a contributing factor. So far, the results are inconclusive. The purpose of this study was to compare the two conditions and investigate the level of the inflammatory marker high-sensitivity CRP (hsCRP) in CFS and FM patients compared to healthy controls. Female participants aged 18-60 years were enrolled in this study. The group consisted of 49 CFS patients, 57 FM patients, and 54 healthy controls. hsCRP levels were significantly higher for both the CFS and the FM groups compared to healthy controls when adjusting for age, smoking, and BMI (p < .001). There was no difference between the two patient groups. The level of hsCRP was affected by BMI but not by age and smoking. Patients with CFS and FM have higher concentrations of hsCRP compared to healthy controls. This remains significant even after adjusting for BMI. CFS and FM cannot be distinguished from each other on the basis of hsCRP in our study.

Brain glial activation in fibromyalgia - A multi-site positron emission tomography investigation.

Fibromyalgia (FM) is a poorly understood chronic condition characterized by widespread musculoskeletal pain, fatigue, and cognitive difficulties. While mounting evidence suggests a role for neuroinflammation, no study has directly provided evidence of brain glial activation in FM. In this study, we conducted a Positron Emission Tomography (PET) study using [11C]PBR28, which binds to the translocator protein (TSPO), a protein upregulated in activated microglia and astrocytes. To enhance statistical power and generalizability, we combined datasets collected independently at two separate institutions (Massachusetts General Hospital [MGH] and Karolinska Institutet [KI]). In an attempt to disentangle the contributions of different glial cell types to FM, a smaller sample was scanned at KI with [11C]-L-deprenyl-D2 PET, thought to primarily reflect astrocytic (but not microglial) signal. Thirty-one FM patients and 27 healthy controls (HC) were examined using [11C]PBR28 PET. 11 FM patients and 11 HC were scanned using [11C]-L-deprenyl-D2 PET. Standardized uptake values normalized by occipital cortex signal (SUVR) and distribution volume (VT) were computed from the [11C]PBR28 data. [11C]-L-deprenyl-D2 was quantified using λ k3. PET imaging metrics were compared across groups, and when differing across groups, against clinical variables. Compared to HC, FM patients demonstrated widespread cortical elevations, and no decreases, in [11C]PBR28 VT and SUVR, most pronounced in the medial and lateral walls of the frontal and parietal lobes. No regions showed significant group differences in [11C]-L-deprenyl-D2 signal, including those demonstrating elevated [11C]PBR28 signal in patients (p's ≥ 0.53, uncorrected). The elevations in [11C]PBR28 VT and SUVR were correlated both spatially (i.e., were observed in overlapping regions) and, in several areas, also in terms of magnitude. In exploratory, uncorrected analyses, higher subjective ratings of fatigue in FM patients were associated with higher [11C]PBR28 SUVR in the anterior and posterior middle cingulate cortices (p's < 0.03). SUVR was not significantly associated with any other clinical variable. Our work provides the first in vivo evidence supporting a role for glial activation in FM pathophysiology. Given that the elevations in [11C]PBR28 signal were not also accompanied by increased [11C]-L-deprenyl-D2 signal, our data suggests that microglia, but not astrocytes, may be driving the TSPO elevation in these regions. Although [11C]-L-deprenyl-D2 signal was not found to be increased in FM patients, larger studies are needed to further assess the role of possible astrocytic contributions in FM. Overall, our data support glial modulation as a potential therapeutic strategy for FM.