| 11. |
- Kadetoff, Diana
(författare)
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Implications of autonomic nervous system and central inflammatory parameters for the perception of pain in fibromyalgia patients
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Dysfunctions of the autonomic nervous system and of endogenous pain modulation have been reported in fibromyalgia (FM) patients. The dysregulation of the autonomic nervous system, i.e., increased sympathetic activity at baseline and hyporeactivity during exercise and stress, could contribute to muscle ischemia as well as to the exercise intolerance that is typically seen in FM patients. Isometric contractions are potent stimuli to provoke muscle ischemia, increased muscle pain, heart rate (HR) and blood pressure (BP). In our first two studies we used isometric contractions to investigate the interaction between cardiovascular regulation and pain perception and to assess activation of the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis (HPA-axis) in FM patients. Glia cell activation has been suggested as a possible pathophysiological mechanism in FM and can be linked to dysfunction of autonomic nervous system. Increased levels of pro-inflammatory cytokines have been reported in the blood of FM patients, but cytokines have, to our knowledge, never been studied in the cerebrospinal fluid (CSF) in FM. In study three and four, we investigated pro-inflammatory cytokines in the CSF of patients with FM, rheumatoid arthritis (RA) and controls. In study 1 we assessed the interactions between cardiovascular regulation and pain perception during static muscle contractions in FM patients and healthy controls. We found that systolic and diastolic BP increased during contraction and decreased following contraction in both groups alike. A significant increase in HR was seen during contraction in FM patients, but not in healthy controls. The rated exertion/fatigue and pain intensity increased more during contraction and remained elevated longer following contraction in the patient group. Pressure pain thresholds (PPTs) were lower in patients compared to controls at all times. 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 de-conditioning. No exercise related change in PPTs was seen in either group, most likely due to insufficient exercise intensity, but the pain induced by contraction was more pronounced in FM patients. In study 2 we investigated activation of the sympathetic nervous system and the HPA-axis during static contractions in FM patients and healthy controls. BP and HR increased during contraction and decreased following contraction in both groups alike. Compared to baseline, plasma catecholamines increased during contraction in both groups alike but FM patients had lower levels of plasma adrenaline and a non-significant tendency to lower plasma noradrenaline at all times. No baseline group differences in adrenocorticotropic hormone (ACTH) were found. ACTH increased at exhaustion in controls, but not in FM patients and FM patients had lower ACTH at exhaustion compared to controls. High sensitivity C-reactive protein (CRP) was elevated in FM patients compared to controls. In conclusion, FM patients exhibited a hypoactive sympatho-adrenal system as well as a hypo-reactive HPA-axis during static exercise. In study 3 we assessed pro-inflammatory cytokines in the CSF and serum in FM patients and headache controls. We reported elevated CSF and serum concentrations of interleukin-8 (IL-8), but not IL-1b, in FM patients. Our conclusion was that the cytokine profile was in accordance with FM symptoms being mediated by abnormal activity in the sympathetic nervous system rather than dependent on prostaglandin associated mechanisms. The results support the hypothesis of glia cell activation in FM. In study 4 CSF and serum concentrations of pro- and anti-inflammatory cytokines in our FM cohort were compared to patients with an inflammatory rheumatic disease, i.e., rheumatoid arthritis (RA). We found different CSF cytokine profiles with higher concentrations of the pro-inflammatory IL-1b and lower concentrations of the anti-inflammatory IL-1Ra, IL-4 and IL-10 in the CSF of RA patients, compared to FM. FM patients had higher CSF and serum IL-8 concentrations than RA patients. Our results indicate different profiles of central cytokine release, i.e., IL-1b in patients with inflammatory, prostaglandin associated pain (RA) and IL-8 in patients with dysfunctional, possibly sympathetically mediated pain (FM).
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| 12. |
- Kadetoff, Diana, et al.
(författare)
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The effects of static muscular contraction on blood pressure, heart rate, pain ratings and pressure pain thresholds in healthy individuals and patients with fibromyalgia.
- 2007
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Ingår i: European Journal of Pain. - : Wiley. - 1090-3801 .- 1532-2149. ; 11:1, s. 39-47
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 13. |
- Kosek, Eva, et al.
(författare)
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Evidence of different mediators of central inflammation in dysfunctional and inflammatory pain--interleukin-8 in fibromyalgia and interleukin-1 β in rheumatoid arthritis.
- 2015
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Ingår i: Journal of Neuroimmunology. - : Elsevier BV. - 0165-5728 .- 1872-8421. ; 280, s. 49-55
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Tidskriftsartikel (refereegranskat)abstract
- 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)-1β 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-1β in inflammatory pain (RA) and elevated IL-8 in dysfunctional pain (FM).
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| 14. |
- Krock, Emerson, et al.
(författare)
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Fibromyalgia patients with elevated levels of anti-satellite glia cell immunoglobulin G antibodies present with more severe symptoms
- 2023
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Ingår i: Pain. - : Ovid Technologies (Wolters Kluwer Health). - 0304-3959 .- 1872-6623. ; 164:8, s. 1828-1840
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Tidskriftsartikel (refereegranskat)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.
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| 15. |
- Lampa, Jon, et al.
(författare)
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Peripheral inflammatory disease associated with centrally activated IL-1 system in humans and mice.
- 2012
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 109:31, s. 12728-33
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Tidskriftsartikel (refereegranskat)abstract
- 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-1β, 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)-1β 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-1β, 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-1β and fatigue assessments. Next, spinal inflammation in experimental arthritis was investigated. A marked increase of IL-1β, 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.
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| 16. |
- Sandström, Angelica, et al.
(författare)
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Dysfunctional Activation of the Dorsolateral Prefrontal Cortex During Pain Anticipation Is Associated With Altered Subsequent Pain Experience in Fibromyalgia Patients
- 2023
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Ingår i: Journal of Pain. - : Elsevier. - 1526-5900 .- 1528-8447. ; 24:9, s. 1731-1743
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 17. |
- Sandström, Angelica, et al.
(författare)
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Neural correlates of conditioned pain responses in fibromyalgia subjects indicate preferential formation of new pain associations rather than extinction of irrelevant ones.
- 2020
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Ingår i: Pain. - : Ovid Technologies (Wolters Kluwer Health). - 0304-3959 .- 1872-6623. ; 161:9, s. 2079-2088
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 18. |
- Tour, Jeanette, et al.
(författare)
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The OPRM1 gene and interactions with the 5-HT1a gene regulate conditioned pain modulation in fibromyalgia patients and healthy controls
- 2022
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 17:11
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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