RESUMO
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.
RESUMO
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.
Assuntos
Dor Crônica , Fibromialgia , Humanos , Fibromialgia/complicações , Fibromialgia/diagnóstico por imagem , Córtex Pré-Frontal Dorsolateral , Percepção da Dor/fisiologia , Encéfalo , Imageamento por Ressonância Magnética/métodos , Córtex Pré-Frontal/patologiaRESUMO
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.
Assuntos
Fibromialgia , Humanos , Animais , Camundongos , Fibromialgia/diagnóstico , Dor , Autoanticorpos , Imunoglobulina G , Inquéritos e QuestionáriosRESUMO
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.
Assuntos
Fibromialgia , Humanos , Fibromialgia/genética , Analgésicos Opioides , Receptor 5-HT1A de Serotonina/genética , Limiar da Dor/fisiologia , Dor/genética , Receptores Opioides mu/genética , Genótipo , Polimorfismo de Nucleotídeo ÚnicoRESUMO
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.
Assuntos
Fibromialgia , Receptores de GABA , Encéfalo , Ácido Glutâmico/genética , Ácido Glutâmico/metabolismo , Voluntários Saudáveis , Humanos , Neuroimagem , Dor/diagnóstico por imagem , Dor/genética , Dor/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Receptores de GABA/genética , Receptores de GABA/metabolismo , Ácido gama-Aminobutírico/metabolismoRESUMO
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.
Assuntos
Fibromialgia/imunologia , Fibromialgia/fisiopatologia , Animais , Estudos de Casos e Controles , Modelos Animais de Doenças , Feminino , Fibromialgia/etiologia , Gânglios Espinais/fisiopatologia , Humanos , Imunização Passiva , Imunoglobulina G/administração & dosagem , Imunoglobulina G/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nociceptores/imunologia , Nociceptores/fisiologia , Dor/fisiopatologia , Limiar da Dor/fisiologiaRESUMO
The neurotransmitter serotonin, involved in the regulation of pain and emotion, is critically regulated by the 5-HT1A autoreceptor and the serotonin transporter (5-HTT). Polymorphisms of these genes affect mood and endogenous pain modulation, both demonstrated to be altered in fibromyalgia subjects (FMS). Here, we tested the effects of genetic variants of the 5-HT1A receptor (CC/G-carriers) and 5-HTT (high/intermediate/low expression) on mood, pain sensitivity, cerebral processing of evoked pain (functional MRI) and concentrations of GABA and glutamate (MR spectroscopy) in rostral anterior cingulate cortex (rACC) and thalamus in FMS and healthy controls (HC). Interactions between serotonin-relevant genes were found in affective characteristics, with genetically inferred high serotonergic signalling (5-HT1A CC/5-HTThigh genotypes) being more favourable across groups. Additionally, 5-HT1A CC homozygotes displayed higher pain thresholds than G-carriers in HC but not in FMS. Cerebral processing of evoked pressure pain differed between groups in thalamus with HC showing more deactivation than FMS, but was not influenced by serotonin-relevant genotypes. In thalamus, we observed a 5-HT1A-by-5-HTT and group-by-5-HTT interaction in GABA concentrations, with the 5-HTT high expressing genotype differing between groups and 5-HT1A genotypes. No significant effects were seen for glutamate or in rACC. To our knowledge, this is the first report of this serotonergic gene-to-gene interaction associated with mood, both among FMS (depression) and across groups (anxiety). Additionally, our findings provide evidence of an association between the serotonergic system and thalamic GABA concentrations, with individuals possessing genetically inferred high serotonergic signalling exhibiting the highest GABA concentrations, possibly enhancing GABAergic inhibitory effects via 5-HT.
Assuntos
Afeto/fisiologia , Epistasia Genética , Fibromialgia/genética , Dor/genética , Serotonina/metabolismo , Ácido gama-Aminobutírico/metabolismo , Análise de Variância , Ansiedade/complicações , Ansiedade/genética , Ansiedade/fisiopatologia , Estudos de Casos e Controles , Fibromialgia/diagnóstico por imagem , Fibromialgia/fisiopatologia , Fibromialgia/psicologia , Ácido Glutâmico/metabolismo , Humanos , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Oxigênio/sangue , Dor/complicações , Dor/diagnóstico por imagem , Dor/fisiopatologia , Limiar da Dor , Tálamo/metabolismoRESUMO
BACKGROUND: Dysregulation of the µ-opioid receptor has been reported in fibromyalgia (FM) and was linked to pain severity. Here, we investigated the effect of the functional genetic polymorphism of the µ-opioid receptor gene (OPRM1) (rs1799971) on symptom severity, pain sensitivity and cerebral pain processing in FM subjects and healthy controls (HC). METHODS: Symptom severity and pressure pain sensitivity was assessed in FM subjects (n = 70) and HC (n = 35). Cerebral pain-related activation was assessed by functional magnetic resonance imaging during individually calibrated painful pressure stimuli. RESULTS: Fibromyalgia subjects were more pain sensitive but no significant differences in pain sensitivity or pain ratings were observed between OPRM1 genotypes. A significant difference was found in cerebral pain processing, with carriers of at least one G-allele showing increased activation in posterior cingulate cortex (PCC) extending to precentral gyrus, compared to AA homozygotes. This effect was significant in FM subjects but not in healthy participants, however, between-group comparisons did not yield significant results. Seed-based functional connectivity analysis was performed with the seed based on differences in PCC/precentral gyrus activation between OPRM1 genotypes during evoked pain across groups. G-allele carriers displayed decreased functional connectivity between PCC/precentral gyrus and prefrontal cortex. CONCLUSIONS: G-allele carriers showed increased activation in PCC/precentral gyrus but decreased functional connectivity with the frontal control network during pressure stimulation, suggesting different pain modulatory processes between OPRM1 genotypes involving altered fronto-parietal network involvement. Furthermore, our results suggest that the overall effects of the OPRM1 G-allele may be driven by FM subjects. SIGNIFICANCE: We show that the functional polymorphism of the µ-opioid receptor gene OPRM1 was associated with alterations in the fronto-parietal network as well as with increased activation of posterior cingulum during evoked pain in FM. Thus, the OPRM1 polymorphism affects cerebral processing in brain regions implicated in salience, attention, and the default mode network. This finding is discussed in the light of pain and the opioid system, providing further evidence for a functional role of OPRM1 in cerebral pain processing.
Assuntos
Fibromialgia , Fibromialgia/diagnóstico por imagem , Fibromialgia/genética , Humanos , Imageamento por Ressonância Magnética , Dor/diagnóstico por imagem , Dor/genética , Limiar da Dor , Polimorfismo Genético/genética , Receptores Opioides mu/genéticaRESUMO
ABSTRACT: Behavioral studies have demonstrated aberrant safety processing in fibromyalgia subjects (FMSs) and suggested that patients accumulate new potential pain-related threats more effectively than extinguishing no longer relevant ones. The aim of the current study was to investigate the neural correlates of conditioned pain responses and their relationship with emotional distress in FMS (n = 67) and healthy controls (HCs, n = 34). Using functional magnetic resonance imaging, we traced conditioned pain responses to an identical moderately painful pressure (P30) depending on whether it was following a green (P30green) or a red (P30red) cue. The cues were previously associated with individually calibrated painful pressure stimuli of low and high intensity, corresponding to visual analogue scale 10 and 50 mm, respectively. Fibromyalgia subjects displayed increased P30green ratings over time, while P30red ratings remained elevated. Healthy controls adapted all pain ratings to resemble moderate pain. Fibromyalgia subjects exhibited increased activation for [P30green>P30red] in M1/anterior insula, whereas HC showed increased S2/mid-insula response to [P30red>P30green]. High pain catastrophizing scale (PCS) ratings in fibromyalgia (FM) covaried with heightened brain activation for [P30green] × PCS in left dorsolateral prefrontal cortex and medial prefrontal cortex/orbitofrontal cortex; and [P30green>P30red] × PCS in dorsal anterior cingulate cortex/mid-cingulate cortex; superior temporal pole, extending to anterior insula; bilateral thalamus; and posterior insula. Psychophysiological interaction analysis for FM [P30green>P30red] × PCS revealed a dissociation in functional connectivity between thalamus and bilateral inferior parietal lobe. In alignment with behavioral data, FMS displayed a cerebral response suggesting preferential formation of new pain-related associations while simultaneously maintaining no longer relevant ones. The opposite was observed in HC. Increased responses to pain-related threats in FM may contribute to dysfunctional pain-protective behaviors and disability.
Assuntos
Fibromialgia , Encéfalo/diagnóstico por imagem , Mapeamento Encefálico , Fibromialgia/complicações , Humanos , Imageamento por Ressonância Magnética , Dor/etiologiaRESUMO
Chronic pain represents one of the major medical challenges in the 21st century, affecting >1.5 billion of the world population. Overlapping and heterogenous symptoms of various chronic pain conditions complicate their diagnosis, emphasizing the need for more specific biomarkers to improve the diagnosis and understand the disease mechanisms. We have here investigated proteins found in human CSF with respect to known "pain" genes and in a cohort of patients with dysfunctional pain (fibromyalgia, FM), inflammatory pain (rheumatoid arthritis patients, RA) and non-pain controls utilized semi-quantitative proteomics using mass spectrometry (MS) to explore quantitative differences between these cohorts of patients. We found that "pain proteins" detected in CSF using MS are typically related to synaptic transmission, inflammatory responses, neuropeptide signaling- and hormonal activity. In addition, we found ten proteins potentially associated with chronic pain in FM and RA: neural cell adhesion molecule L1, complement C4-A, lysozyme C, receptor-type tyrosine-protein phosphatase zeta, apolipoprotein D, alpha-1-antichymotrypsin, granulins, calcium/calmodulin-dependent protein kinase type II subunit alpha, mast/stem cell growth factor receptor Kit, prolow-density lipoprotein receptor-related protein 1. These proteins might be of importance for understanding the mechanisms of dysfunctional/inflammatory chronic pain and also for use as potential biomarkers. SIGNIFICANCE: Chronic pain is a common disease and it poses a large burden on worldwide health. Fibromyalgia (FM) is a heterogeneous disease of unknown etiology characterized by chronic widespread pain (CWP). The diagnosis and treatment of FM is based on the analysis of clinical assessments and no measurable biomarkers are available. Cerebrospinal fluid (CSF) has been historically considered as a rich source of biomarkers for diseases of nervous system including chronic pain. Here, we explore CSF proteome of FM patients utilizing mass spectrometry based quantitative proteomics method combined with multivariate data analysis in order to monitor the dynamics of the CSF proteome. Our findings in this exploratory study support notable presence of pain related proteins in CSF yet with specific domains including inflammatory responses, neuropeptide signaling- and hormonal activity. We have investigated molecular functions of significantly altered proteins and demonstrate presence of 176 known pain related proteins in CSF. In addition, we found ten proteins potentially associated with pain in FM and RA: neural cell adhesion molecule L1, complement C4-A, lysozyme C, receptor-type tyrosine-protein phosphatase zeta, apolipoprotein D, alpha-1-antichymotrypsin, granulins, calcium/calmodulin-dependent protein kinase type II subunit alpha, mast/stem cell growth factor receptor Kit, prolow-density lipoprotein receptor-related protein 1. These proteins are novel in the context of FM but are known to be involved in pain mechanisms including inflammatory response and signal transduction. These results should be of clear significance and interest for researchers and clinicians working in the field of pain utilizing human CSF and MS based proteomics.
Assuntos
Proteínas do Líquido Cefalorraquidiano/análise , Dor Crônica/diagnóstico , Proteoma/análise , Proteômica/métodos , Adulto , Artrite Reumatoide/líquido cefalorraquidiano , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/patologia , Biomarcadores/líquido cefalorraquidiano , Feminino , Fibromialgia/líquido cefalorraquidiano , Fibromialgia/diagnóstico , Fibromialgia/patologia , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
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 usingâ¯λâ¯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'sâ¯≥â¯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'sâ¯<â¯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.
Assuntos
Fibromialgia/diagnóstico por imagem , Fibromialgia/metabolismo , Neuroglia/metabolismo , Acetamidas/metabolismo , Adulto , Astrócitos/metabolismo , Encéfalo/metabolismo , Radioisótopos de Carbono/metabolismo , Feminino , Fibromialgia/fisiopatologia , Humanos , Masculino , Microglia/metabolismo , Pessoa de Meia-Idade , Neuroglia/fisiologia , Neuroimunomodulação/fisiologia , Dor/metabolismo , Dor/fisiopatologia , Tomografia por Emissão de Pósitrons/métodos , Piridinas/metabolismo , Receptores de GABA/metabolismoRESUMO
The purpose of this study was to relate central inflammation to autonomic activity (heart rate variability (HRV)) in patients with rheumatoid arthritis (RA) and fibromyalgia (FM). RA patients had reduced parasympathetic activity and FM patients had increased sympathetic activity compared to healthy controls. Comparisons between RA and FM showed higher cerebrospinal fluid (CSF) interleukin (IL)-1ß inversely correlated to parasympathetic activity in RA. The FM patients had higher concentrations of CSF IL-8, IL-1Ra, IL-4 and IL-10, but none of these cytokines correlated with HRV. In conclusion, we found different profiles of central cytokines, i.e., elevated IL-1ß in inflammatory pain (RA) and elevated IL-8 in dysfunctional pain (FM).
Assuntos
Artrite Reumatoide , Fibromialgia , Interleucina-1beta/sangue , Interleucina-1beta/líquido cefalorraquidiano , Interleucina-8/sangue , Interleucina-8/líquido cefalorraquidiano , Adulto , Artrite Reumatoide/sangue , Artrite Reumatoide/líquido cefalorraquidiano , Artrite Reumatoide/fisiopatologia , Sistema Nervoso Autônomo/fisiopatologia , Citocinas/sangue , Citocinas/líquido cefalorraquidiano , Feminino , Fibromialgia/líquido cefalorraquidiano , Fibromialgia/metabolismo , Fibromialgia/fisiopatologia , Frequência Cardíaca/fisiologia , Humanos , Pessoa de Meia-Idade , Dor/etiologia , Medição da Dor , Radioimunoensaio , Punção Espinal , Estatísticas não ParamétricasRESUMO
During peripheral immune activation caused by an infection or an inflammatory condition, the innate immune response signals to the brain and causes an up-regulation of central nervous system (CNS) cytokine production. Central actions of proinflammatory cytokines, in particular IL-1ß, are pivotal for the induction of fever and fatigue. In the present study, the influence of peripheral chronic joint inflammatory disease in rheumatoid arthritis (RA) on CNS inflammation was investigated. Intrathecal interleukin (IL)-1ß concentrations were markedly elevated in RA patients compared with controls or with patients with multiple sclerosis. Conversely, the anti-inflammatory IL-1 receptor antagonist and IL-4 were decreased in RA cerebrospinal fluid (CSF). Tumor necrosis factor and IL-6 levels in the CSF did not differ between patients and controls. Concerning IL-1ß, CSF concentrations in RA patients were higher than in serum, indicating local production in the CNS, and there was a positive correlation between CSF IL-1ß and fatigue assessments. Next, spinal inflammation in experimental arthritis was investigated. A marked increase of IL-1ß, IL-18, and tumor necrosis factor, but not IL-6 mRNA production, in the spinal cord was observed, coinciding with increased arthritis scores in the KBxN serum transfer model. These data provide evidence that peripheral inflammation such as arthritis is associated with an immunological activation in the CNS in both humans and mice, suggesting a possible therapeutic target for centrally affecting conditions as fatigue in chronic inflammatory diseases, for which to date there are no specific treatments.
Assuntos
Artrite Reumatoide/líquido cefalorraquidiano , Sistema Nervoso Central/metabolismo , Regulação da Expressão Gênica , Interleucina-1beta/líquido cefalorraquidiano , Esclerose Múltipla/líquido cefalorraquidiano , Adulto , Animais , Modelos Animais de Doenças , Feminino , Humanos , Proteína Antagonista do Receptor de Interleucina 1/líquido cefalorraquidiano , Interleucina-18/líquido cefalorraquidiano , Interleucina-4/líquido cefalorraquidiano , Interleucina-6/líquido cefalorraquidiano , Camundongos , Camundongos Endogâmicos NOD , Pessoa de Meia-Idade , Fator de Necrose Tumoral alfa/líquido cefalorraquidianoRESUMO
Interventions based on Cognitive Behavioral Therapy (CBT) are widely used to treat chronic pain, but the brain mechanisms responsible for these treatment effects are poorly understood. The aim of this study was to validate the relevance of the cortical control theory in response to an exposure-based form of CBT, Acceptance and Commitment Therapy, in patients with chronic pain. Forty-three female patients diagnosed with fibromyalgia syndrome were enrolled in a randomized, 12-week, waiting-list controlled clinical trial (CBT n=25; controls n=18). CBT was administered in groups of six patients during 12 weekly sessions. Functional magnetic resonance imaging (fMRI) during pressure-evoked pain was assessed before and after treatment or the 12-week period. Self-report questionnaires of depression and anxiety were administered pre- and posttreatment as well as 3 months following end of treatment. Patients treated with CBT reported larger improvement of fibromyalgia on the Patient Global Impression of Change measure, and improved depression and anxiety symptoms, compared to the waiting-list controls. However, there were no effects on clinical pain or pain sensitivity measures. An analysis of fMRI scans revealed that CBT led to increased activations in the ventrolateral prefrontal/lateral orbitofrontal cortex; regions associated with executive cognitive control. We suggest that CBT changes the brain's processing of pain through an altered cerebral loop between pain signals, emotions, and cognitions; leading to increased access to executive regions for reappraisal of pain. Our data thereby support our hypothesis about the activation of a cortical control mechanism in response to CBT treatment in chronic pain.
Assuntos
Dor Crônica/etiologia , Terapia Cognitivo-Comportamental , Fibromialgia/terapia , Córtex Pré-Frontal/fisiopatologia , Adulto , Ansiedade/psicologia , Dor Crônica/fisiopatologia , Depressão/psicologia , Feminino , Fibromialgia/complicações , Fibromialgia/psicologia , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Medição da Dor/psicologia , Limiar da Dor/fisiologia , Inquéritos e Questionários , Resultado do TratamentoRESUMO
Activation of glia cells resulting in intrathecal elevation of cytokines and chemokines has been hypothesized in chronic pain syndromes such as fibromyalgia. To our knowledge, this is the first study assessing intrathecal concentrations of pro-inflammatory substances in fibromyalgia. We report elevated cerebrospinal fluid and serum concentrations of interleukin-8, but not interleukin-1beta, in FM patients. This profile is in accordance with FM symptoms being mediated by sympathetic activity rather than dependent on prostaglandin associated mechanisms and supports the hypothesis of glia cell activation in response to pain mechanisms.
Assuntos
Fibromialgia/líquido cefalorraquidiano , Fibromialgia/imunologia , Mediadores da Inflamação/líquido cefalorraquidiano , Mediadores da Inflamação/fisiologia , Interleucina-8/líquido cefalorraquidiano , Adulto , Feminino , Fibromialgia/patologia , Humanos , Inflamação/sangue , Inflamação/líquido cefalorraquidiano , Inflamação/imunologia , Mediadores da Inflamação/sangue , Interleucina-1beta/biossíntese , Interleucina-1beta/sangue , Interleucina-1beta/líquido cefalorraquidiano , Interleucina-8/biossíntese , Interleucina-8/sangue , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: To assess activation of the sympathetic nervous system and the hypothalamic-pituitary-adrenocortical axis during static exercise in patients with fibromyalgia. PATIENTS AND METHODS: Sixteen patients with fibromyalgia and 16 healthy controls performed a static knee extension until exhaustion. Plasma catecholamines, adrenocorticotropic hormone and cortisol, as well as blood pressure and heart rate, were assessed before, during and following contraction. Plasma C reactive protein was analysed at baseline. RESULTS: Blood pressure and heart rate increased during contraction (p < 0.001) and decreased following contraction (p < 0.001) in both groups alike. Compared with baseline, plasma catecholamines increased during contraction in both groups (p < 0.001), but patients with fibromyalgia had lower levels of plasma adrenaline (p < 0.04) and noradrenaline (p < 0.08) at all times. Adrenocorticotropic hormone increased at exhaustion in controls (p < 0.001), but not in patients with fibromyalgia, who also had lower adrenocorticotropic hormone at exhaustion (p < 0.02) compared with controls. There were no group differences, or changes over time in plasma cortisol. High sensitivity C reactive protein was higher in patients with fibromyalgia compared with controls (p < 0.02). CONCLUSION: Patients with fibromyalgia exhibited a hypoactive sympatho-adrenal system as well as a hypo-reactive hypothalamic-pituitary axis during static exercise.
Assuntos
Exercício Físico/fisiologia , Fibromialgia/fisiopatologia , Sistema Hipotálamo-Hipofisário/fisiologia , Sistema Hipófise-Suprarrenal/fisiologia , Hormônio Adrenocorticotrópico/sangue , Adulto , Sistema Nervoso Autônomo/fisiologia , Sistema Nervoso Autônomo/fisiopatologia , Pressão Sanguínea/fisiologia , Proteína C-Reativa/análise , Epinefrina/sangue , Feminino , Fibromialgia/sangue , Frequência Cardíaca/fisiologia , Humanos , Hidrocortisona/sangue , Sistema Hipotálamo-Hipofisário/fisiopatologia , Pessoa de Meia-Idade , Contração Muscular/fisiologia , Sistema Hipófise-Suprarrenal/fisiopatologia , Sistema Nervoso Simpático/fisiologia , Sistema Nervoso Simpático/fisiopatologiaRESUMO
Aberrations of cardiovascular regulation and dysfunction of endogenous pain modulation have been reported in fibromyalgia (FM) patients. This study aimed at investigating the interactions between cardiovascular regulation and pain perception during static muscle contractions. Seventeen FM patients and 17 healthy controls performed a standardised static contraction (m. quadriceps femoris dx) until exhaustion. Blood pressure (BP), heart rate (HR), ratings of exertion/fatigue and pain intensity as well as pressure pain thresholds (PPTs) (at m. quadriceps dx and m. deltoideus dx) were assessed before, during and 15 min following contraction. Systolic and diastolic BP increased during contraction (p<0.001) and decreased following contraction (p<0.001) in both groups alike. A significant increase in HR was seen during contraction in FM patients (p<0.001), but not in healthy controls (difference between groups p<0.02). The rated exertion/fatigue and pain intensity increased more during contraction and remained elevated longer following contraction in the patient group. PPTs were lower in patients compared to controls at both sites at all times (p<0.001). No group differences in PPT changes over time were found. In conclusion, no indication of an attenuated cardiovascular response to exercise was found in our FM patients. The more pronounced HR increase in patients during contraction was most likely due to deconditioning. No exercise related change in PPTs was seen in either group, most likely due to insufficient exercise intensity, but the contraction induced pain was more pronounced in the FM patients.