Implications of autonomic nervous system and central inflammatory parameters for the perception of pain in fibromyalgia patients

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 hypothalamicpituitary- 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 deconditioning. 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 5 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)

Passive transfer of fibromyalgia symptoms from patients to mice

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

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

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

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

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

Normalized pressure pain thresholds (PPTs) (mean ± SEM) at start, middle, end and 5 minutes after a standardized tourniquet test.

The conditioning pain was applied in the upper left arm and PPTs were assessed at the contralateral m. quadriceps in FM patients and healthy controls. There was a statistically significant difference between the groups at end (p<0.001) and after (p = 0.041) the assessment.</p

Schematic view of the assessment for conditioned pain modulation.

Schematic view of the assessment for conditioned pain modulation.</p

Descriptives of study population.

Descriptives of study population.</p

Genotype frequencies of the polymorphisms <i>rs1799971</i> (OPRM1), <i>rs6296</i> (5-HT_1A) and the triallelic 5-HTT for the whole group, as well as fibromyalgia (FM) patients and healthy controls (HC) separately.

Genotype frequencies of the polymorphisms rs1799971 (OPRM1), rs6296 (5-HT1A) and the triallelic 5-HTT for the whole group, as well as fibromyalgia (FM) patients and healthy controls (HC) separately.</p

Conditioned pain modulation (CPM) score based on OPRM1 genotype in the study group.

Fig 2A. Fibromyalgia patients and healthy controls pooled together split by OPRM1-AA versus G-genotype. Results showed significantly reduced CPM score in OPRM1 G-allele carriers (p = 0.019). Fig 2B. CPM score for HC and FM patients separately split by OPRM1-AA vs G-allele. A significant difference was seen for FM patients (p = 0.045) but not for HC. Notable, FM patients with the OPRM1 G-allele had the lowest CPM score among all four groups (indicating less efficient CPM).</p

Polymorphisms of the μ-opioid receptor gene influence cerebral pain processing in fibromyalgia

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