Niclas Stensson

Palmitoylethanolamide and stearoylethanolamide levels in the interstitium of the trapezius muscle of women with chronic widespread pain and chronic neck-shoulder pain correlate with pain intensity and sensitivity.

Summary The levels of palmitoylethanolamide and stearoylethanolamide differ in women with chronic neck/shoulder pain and widespread pain in response to a low‐force exercise which induces pain. ABSTRACT Chronic widespread pain (CWP) is a complex condition characterized by central hyperexcitability and altered descending control of nociception. However, nociceptive input from deep tissues is suggested to be an important drive. N‐Acylethanolamines (NAEs) are endogenous lipid mediators involved in regulation of inflammation and pain. Previously we have reported elevated levels of the 2 NAEs, the peroxisome proliferator‐activated receptor type‐&agr; ligand N‐palmitoylethanolamine (PEA) and N‐stearoylethanolamine (SEA) in chronic neck/shoulder pain (CNSP). In the present study, the levels of PEA and SEA in women with CWP (n = 18), CNSP (n = 34) and healthy controls (CON, n = 24) were investigated. All subjects went through clinical examination, pressure pain threshold measurements and induction of experimental pain in the tibialis anterior muscle. Microdialysis dialysate of the trapezius was collected before and after subjects performed a repetitive low‐force exercise and analyzed by mass spectrometry. The levels of PEA and SEA in CNSP were significantly higher post exercise compared with CWP, and both pre and post exercise compared with CON. Levels of both NAEs decreased significantly pre to post exercise in CWP. Intercorrelations existed between aspects of pain intensity and sensitivity and the level of the 2 NAEs in CWP and CNSP. This is the first study demonstrating that CNSP and CWP differ in levels of NAEs in response to a low‐force exercise which induces pain. Increases in pain intensity as a consequence of low‐force exercise were associated with low levels of PEA and SEA in CNSP and CWP. These results indicate that PEA and SEA have antinociceptive roles in humans.

Chronic widespread pain: increased glutamate and lactate concentrations in the trapezius muscle and plasma.

Background:Chronic widespread pain (CWP), including fibromyalgia syndrome (FM), is associated with prominent negative consequences. CWP has been associated with alterations in the central processing of nociception. Whereas some researchers consider CWP/FM as a central hyperexcitability pain condition, others suggest that the central alterations are maintained by peripheral nociceptive input. Microdialysis can be used in vivo to study muscle alterations in chronic myalgia. Aim:The aim of the study was to investigate the plasma and interstitial concentrations of metabolites and algesics in the trapezius muscle of women with CWP and in pain-free women (CON). Materials and Methods:Seventeen women with CWP and 24 CON went through a clinical examination and completed a questionnaire; the pressure pain thresholds in the upper and lower extremities were registered. Microdialysis was conducted in the trapezius muscle, and a blood sample was drawn. Muscle blood flow, interstitial muscle concentrations, and plasma concentrations of lactate, pyruvate, glutamate, glucose, and glycerol (not in the plasma) were determined. Results:CWP patients had significantly increased interstitial muscle (P=0.02 to 0.001) and plasma (P=0.026 to 0.017) concentrations of lactate and glutamate. No significant differences existed in blood flow between CWP and CON. The interstitial concentrations—but not the plasma levels—of glutamate and lactate correlated significantly with aspects of pain such as pressure pain thresholds of the trapezius (R2=0.22) and tibialis anterior (R2=0.18) and the mean pain intensity (R2=0.10) in CWP but not in CON. Conclusions:The present study supports the suggestion that aspects of pain and central alterations in CWP/FM are influenced by peripheral tissue alterations.

Dopamine in plasma - a biomarker for myofascial TMD pain?

BackgroundDopaminergic pathways could be involved in the pathophysiology of myofascial temporomandibular disorders (M-TMD). This study investigated plasma levels of dopamine and serotonin (5-HT) in patients with M-TMD and in healthy subjects.MethodsFifteen patients with M-TMD and 15 age- and sex-matched healthy subjects participated. The patients had received an M-TMD diagnosis according to the Research Diagnostic Criteria for TMD. Perceived mental stress, pain intensity (0–100-mm visual analogue scale), and pressure pain thresholds (PPT, kPa) over the masseter muscles were assessed; a venous blood sample was taken.ResultsDopamine in plasma differed significantly between patients with M-TMD (4.98 ± 2.55 nM) and healthy controls (2.73 ± 1.24 nM; P < 0.01). No significant difference in plasma 5-HT was observed between the groups (P = 0.75). Patients reported significantly higher pain intensities (P < 0.001) and had lower PPTs (P < 0.01) compared with the healthy controls. Importantly, dopamine in plasma correlated significantly with present pain intensity (r = 0.53, n = 14, P < 0.05) and perceived mental stress (r = 0.34, n = 28, P < 0.05).ConclusionsThe results suggest that peripheral dopamine might be involved in modulating peripheral pain. This finding, in addition to reports in other studies, suggests that dopaminergic pathways could be implicated in the pathophysiology of M-TMD but also in other chronic pain conditions. More research is warranted to elucidate the role of peripheral dopamine in the pathophysiology of chronic pain.

Alterations of anti-inflammatory lipids in plasma from women with chronic widespread pain - a case control study

BackgroundChronic widespread pain conditions (CWP) such as the pain associated with fibromyalgia syndrome (FMS) are significant health problems with unclear aetiology. Although CWP and FMS can alter both central and peripheral pain mechanisms, there are no validated markers for such alterations. Pro- and anti-inflammatory components of the immune system such as cytokines and endogenous lipid mediators could serve as systemic markers of alterations in chronic pain. Lipid mediators associated with anti-inflammatory qualities – e.g., oleoylethanolamide (OEA), palmitoylethanolamide (PEA), and stearoylethanolamide (SEA) – belong to N-acylethanolamines (NAEs). Previous studies have concluded that these lipid mediators may modulate pain and inflammation via the activation of peroxisome proliferator activating receptors (PPARs) and the activation of PPARs may regulate gene transcriptional factors that control the expression of distinct cytokines.MethodsThis study investigates NAEs and cytokines in 17 women with CWP and 21 healthy controls. Plasma levels of the anti-inflammatory lipids OEA, PEA, and SEA, the pro-inflammatory cytokines TNF-α, IL-1β, IL-6, and IL-8, and the anti-inflammatory cytokine IL-10 were investigated. T-test of independent samples was used for group comparisons. Bivariate correlation analyses, and multivariate regression analysis were performed between lipids, cytokines, and pain intensity of the participants.ResultsSignificantly higher levels of OEA and PEA in plasma were found in CWP. No alterations in the levels of cytokines existed and no correlations between levels of lipids and cytokines were found.ConclusionsWe conclude that altered levels of OEA and PEA might indicate the presence of systemic inflammation in CWP. In addition, we believe our findings contribute to the understanding of the biochemical mechanisms involved in chronic musculoskeletal pain.

High levels of endogenous lipid mediators (N-acylethanolamines) in women with chronic widespread pain during acute tissue trauma.

Although chronic widespread musculoskeletal pain is a significant health problem, the molecular mechanisms involved in developing and maintaining chronic widespread musculoskeletal pain are poorly understood. Central sensitization mechanisms maintained by stimuli from peripheral tissues such as muscle have been suggested. Lipid mediators with anti-inflammatory characteristics such as endogenous ligands of peroxisome proliferator activating receptor-α, oleoylethanolamide, and palmitoylethanolamide are suggested to regulate nociceptive transmission from peripheral locations on route towards the central nervous system. This case–control study investigates the levels of anti-inflammatory lipids in microdialysis samples collected during the first 2 h after microdialysis probe insertion and explores the association of these lipids with different pain characteristics in women with chronic widespread musculoskeletal pain (n = 17) and female healthy controls (n = 19). The levels of oleoylethanolamide, palmitoylethanolamide, and stearoylethanolamide were determined. During sampling of dialysate, pain ratings were conducted using a numeric rating scale. Pain thresholds were registered from upper and lower parts of the body. Oleoylethanolamide and stearoylethanolamide levels were significantly higher (p ≤ 0.05) in chronic widespread musculoskeletal pain at all time points. Numeric rating scale correlated with levels of stearoylethanolamide in chronic widespread musculoskeletal pain. Higher levels of lipid mediators could reflect an altered tissue reactivity in response to microdialysis probe insertion in chronic widespread musculoskeletal pain.

Identification of Lipid Mediators in Peripheral Human Tissues Using an Integrative In Vivo Microdialysis Approach

Endocannabinoids and related N-acylethanolamines (NAEs) are lipid mediators involved in a number of physiological and pathological mechanisms in peripheral tissues. Microdialysis (MD) technique all ...

Levels of N-acylethanolamines in the interstitium of trapezius muscle during the tissue trauma: A microdialysis study on women with chronic widespread pain

Abstract Aims Since the insertion of MD probes causes an acute tissue trauma, analyses of microdialysates during this period has previously been disregarded in favour of waiting until stable baselines are achieved. The aim of this study is to compare the levels of NAEs in women with chronic widespread pain (CWP) to the healthy controls (CON) during the tissue trauma period. Methods 18 women with CWP were included in this study. Inclusion criteria were female sex, age range 20–65 years, and widespread pain according to the American College of Rheumatology (ACR) classification. 20 CON were recruited. Inclusion criteria were female sex age range 20–65 years, and pain-free. All participants were examined by a standard and validated clinical examination of the upper extremities. MD was conducted in trapezius muscle and dialysate were sampled every 20 min, and the samples of interest in this study were collected in the two first hour after catheter insertion. CMA 63 (catheter: membrane 30 mm length, 0.5 mm diameter, 20 kDa cut-off, flow rate: 5 μl/min) was used. The levels of NAEs were analyzed by liquid chromatography tandem mass spectrometry (LC–MS/MS). Results Oleoylethanolamine (OEA) and Palmitoylethanolamine (PEA) levels were significantly higher in CWP compered to CON during tissue trauma period (Mann–Whitney U-test: P > 0.001 for OEA and P ≤ 0.05 for PEA). Conclusions Previous biochemical studies of patients with CWP have often focused on sensitizing substances. Here we investigated the levels of lipid signaling molecules, with anti-inflammatory and pain-relieving properties, during acute tissue trauma. The results demonstrate that the levels of OEA and PEA differ significantly between CWP and CON. A better understanding of the interplay between these lipids and peripheral pain signaling might provide new therapeutic opportunities for patients with CWP.