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Stensson, Niclas
Publications (7 of 7) Show all publications
Stensson, N. (2018). Endocannabinoids and Related Lipids in Chronic Pain: Analytical and Clinical Aspects. (Doctoral dissertation). Linköping: Linköping University Electronic Press
Open this publication in new window or tab >>Endocannabinoids and Related Lipids in Chronic Pain: Analytical and Clinical Aspects
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In Europe, approximately one in five adults experience chronic pain, pain that lasts more than three months. Chronic pain is a significant problem not only for those people suffering from chronic pain but also for society. The prevalence of chronic pain is higher in women and lower socioeconomic groups. Although chronic pain often originates in a specific site, it may eventually spread to several sites, transforming into chronic widespread pain (CWP), a condition evident in about 10% of the adult population. Approximately 1.2-5.4% are classified with fibromyalgia (FM). In addition to CWP, common symptoms of FM include, stiffness, fatigue, sleep disturbances, and cognitive dysfunction and common co-morbidities include depression and anxiety. Although FM/CWP has been reported to alter both central and peripheral nociceptive mechanisms, no objective biomarkers have been found that correlate with CWP/FM and no standard examinations such as blood test, X-ray or computed tomography can provide support for a diagnosis. Because there are no objective biomarkers that correlate with the pathophysiological processes associated with CWP/FM, this debilitating disease is difficult to diagnose and ultimately treat. However, there are some promising therapeutic targets for chronic pain with inter alia analgesic, anti-inflammatory, and stress modulating properties: the endocannabinoids (ECs) arachidonoylethanolamide (AEA) and 2-arachidonoylglycerol (2-AG) and their related lipids oleoylethanolamide (OEA), palmitoylethanolamide (PEA), and stearoylethanolamide (SEA).

This thesis investigates whether ECs and the related N-acylethanolamines (NAEs) can be used as potential biomarkers for CWP/FM. Specifically, the studies compared the peripheral and systemic levels of ECs and NAEs in 121 women with CWP/FM and in 137 healthy controls in two different cohorts. In addition, the correlation between lipid levels and common pain characteristics such as intensity, sensitivity, and duration were investigated. The EC and related lipid levels were measured using liquid chromatography in combination with tandem mass spectrometry. Multivariate data analysis was used for biomarker evaluation.

Compared to the healthy controls, the CWP/FM patients had significantly higher concentrations of OEA, PEA, and SEA in muscle and plasma (p ≤ 0.05) and significantly higher 2-AG in plasma (p ≤ 0.01). These results may indicate that NAEs, are mobilized differently in painful muscles compared with pain free muscles. Moreover, increased systemic levels of NAEs and 2-AG in patients might be signs of ongoing low-grade inflammation in

CWP/FM. These findings contribute to a better understanding of how peripheral and systemic factors maintain and activate chronic pain. Although the investigated lipids have statistically significant effects but biologically uncertain role in the clinical manifestations of CWP/FM. Thus plasma lipids are not a good biomarker for CWP/FM. Nevertheless, increased lipid levels indicate a metabolic asymmetry in CWP/FM, a finding that could serve as a basis for more research on pain management.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2018. p. 85
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1619
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:liu:diva-147653 (URN)10.3384/diss.diva-147653 (DOI)9789176853191 (ISBN)
Public defence
2018-06-01, Berzeliussalen, Campus US, Linköping, 09:00 (English)
Opponent
Supervisors
Available from: 2018-05-03 Created: 2018-05-03 Last updated: 2019-09-30Bibliographically approved
Mayo, L. M., Asratian, A., Lindé, J., Holm, L., Nätt, D., Augier, G., . . . Heilig, M. (2018). Protective effects of elevated anandamide on stress and fear-related behaviors: translational evidence from humans and mice. Molecular Psychiatry
Open this publication in new window or tab >>Protective effects of elevated anandamide on stress and fear-related behaviors: translational evidence from humans and mice
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2018 (English)In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578Article in journal (Refereed) Epub ahead of print
Abstract [en]

Post-traumatic stress disorder (PTSD) is a common, debilitating condition with limited treatment options. Extinction of fear memories through prolonged exposure therapy, the primary evidence-based behavioral treatment for PTSD, has only partial efficacy. In mice, pharmacological inhibition of fatty acid amide hydrolase (FAAH) produces elevated levels of anandamide (AEA) and promotes fear extinction, suggesting that FAAH inhibitors may aid fear extinction-based treatments. A human FAAH 385C-greater thanA substitution encodes an FAAH enzyme with reduced catabolic efficacy. Individuals homozygous for the FAAH 385A allele may therefore offer a genetic model to evaluate the impact of elevations in AEA signaling in humans, helping to inform whether FAAH inhibitors have the potential to facilitate fear extinction therapy for PTSD. To overcome the challenge posed by low frequency of the AA genotype (appr. 5%), we prospectively genotyped 423 individuals to examine the balanced groups of CC, AC, and AA individuals (n = 25/group). Consistent with its loss-of-function nature, the A allele was dose dependently associated with elevated basal AEA levels, facilitated fear extinction, and enhanced the extinction recall. Moreover, the A-allele homozygotes were protected against stress-induced decreases in AEA and negative emotional consequences of stress. In a humanized mouse model, AA homozygous mice were similarly protected against stress-induced decreases in AEA, both in the periphery, and also in the amygdala and prefrontal cortex, brain structures critically involved in fear extinction and regulation of stress responses. Collectively, these data suggest that AEA signaling can temper aspects of the stress response and that FAAH inhibition may aid the treatment for stress-related psychiatric disorders, such as PTSD.

Place, publisher, year, edition, pages
Nature Publishing Group, 2018
National Category
Neurosciences
Identifiers
urn:nbn:se:liu:diva-154914 (URN)10.1038/s41380-018-0215-1 (DOI)30120421 (PubMedID)2-s2.0-85052287102 (Scopus ID)
Available from: 2019-03-05 Created: 2019-03-05 Last updated: 2019-05-01Bibliographically approved
Stensson, N., Ghafouri, N., Ernberg, M., Mannerkorpi, K., Kosek, E., Gerdle, B. & Ghafouri, B. (2018). The Relationship of Endocannabinoidome Lipid Mediators With Pain and Psychological Stress in Women With Fibromyalgia: A Case-Control Study. Journal of Pain, 19(11), 1318-1328
Open this publication in new window or tab >>The Relationship of Endocannabinoidome Lipid Mediators With Pain and Psychological Stress in Women With Fibromyalgia: A Case-Control Study
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2018 (English)In: Journal of Pain, ISSN 1526-5900, E-ISSN 1528-8447, Vol. 19, no 11, p. 1318-1328Article in journal (Refereed) Published
Abstract [en]

Characterized by chronic widespread pain, generalized hyperalgesia, and psychological stress, fibromyalgia (FM) is difficult to diagnose and lacks effective treatments. Endocannabinoids arachidonoylethanolamide (AEA), 2-arachidonoylglycerol (2-AG), and the related oleoylethanolamide (OEA), palmitoylethanolamide (PEA), and stearoylethanolamide (SEA) are endogenous lipid mediators with analgesic and anti-inflammatory characteristics, in company with psychological modulating properties (eg, stress and anxiety), and are included in a new emerging "ome," the endocannabinoidome. This case-control study compared the concentration differences of AEA, OEA, PEA, SEA, and 2 AG in 104 women with FM and 116 healthy control subjects. All participants rated their pain, anxiety, depression, and current health status. The relationships between the lipid concentrations and the clinical assessments were investigated using powerful multivariate data analysis and traditional bivariate statistics. The concentrations of OEA, PEA, SEA, and 2-AG were significantly higher in women with FM than in healthy control subjects; significance remained for OEA and SEA after controlling for body mass index and age. 2-AG correlated positively with FM duration and body mass index, and to some extent negatively with pain, anxiety, depression, and health status. In FM, AEA correlated positively with depression ratings. The elevated circulating levels of endocannabinoidome lipids suggest that these lipids play a role in the complex pathophysiology of FM and might be signs of ongoing low-grade inflammation in FM. Although the investigated lipids are significantly altered in FM, their biological roles are uncertain with respect to the clinical manifestations of FM. Thus plasma lipids alone are not good biomarkers for FM. Perspective: This study reports about elevated plasma levels of endocannabinoidome lipid mediators in FM. The lipids suitability to work as biomarkers for FM in the clinic were low; however, their altered levels indicate that a metabolic asymmetry is ongoing in FM, which could serve as a baseline during explorative FM pain management. (C) 2018 by the American Pain Society

Place, publisher, year, edition, pages
CHURCHILL LIVINGSTONE, 2018
Keywords
Fibromyalgia; chronic; widespread pain; anxiety; depression; endocannabinoidome; 2-arachidonoylglycerol; N-acylethanolamines
National Category
Neurology
Identifiers
urn:nbn:se:liu:diva-153180 (URN)10.1016/j.jpain.2018.05.008 (DOI)000450244400008 ()29885369 (PubMedID)
Note

Funding Agencies|Swedish Rheumatism Association; Health and Medical Care Executive Board of Vastra Gotaland Region; ALF-LUA at Sahlgrenska University Hospital; Region Ostergotland (ALF); Swedish Research Council [K2013-52X-22199-01-3, K2015-99x-21874-05-4, 521-2010-2893]; Karolinska Institute Foundation; AFA Insurance [140341]; Stockholm County Council (ALF); Linkoping University Hospital Research

Available from: 2018-12-01 Created: 2018-12-01 Last updated: 2019-05-01
Stensson, N., Ghafouri, B., Gerdle, B. & Ghafouri, N. (2017). Alterations of anti-inflammatory lipids in plasma from women with chronic widespread pain - a case control study. Lipids in Health and Disease, 16, Article ID 112.
Open this publication in new window or tab >>Alterations of anti-inflammatory lipids in plasma from women with chronic widespread pain - a case control study
2017 (English)In: Lipids in Health and Disease, ISSN 1476-511X, E-ISSN 1476-511X, Vol. 16, article id 112Article in journal (Refereed) Published
Abstract [en]

Background: Chronic 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. Methods: This 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-alpha, IL-1 beta, 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. Results: Significantly 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. Conclusions: We 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.

Place, publisher, year, edition, pages
BIOMED CENTRAL LTD, 2017
Keywords
Chronic widespread pain; Inflammation; N acylethanolamines; Palmitoylethanolamide; Oleoylethanolamide; Cytokines
National Category
Other Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-138888 (URN)10.1186/s12944-017-0505-7 (DOI)000403043600002 ()28606089 (PubMedID)
Note

Funding Agencies|Swedish Research Council [K2015-99x-21, 874-05-4]; Swedish Council for Working Life and Social Research [2010-0913]; AFA Insurance; Region Ostergotland foundation; Ake Wiberg foundation

Available from: 2017-06-27 Created: 2017-06-27 Last updated: 2018-05-03
Shimada, A., Baad-Hansen, L., Castrillon, E., Ghafouri, B., Stensson, N., Gerdle, B., . . . Svensson Odont, P. (2015). Differential effects of repetitive oral administration of monosodium glutamate on interstitial glutamate concentration and muscle pain sensitivity. Nutrition (Burbank, Los Angeles County, Calif.), 31(2), 315-323
Open this publication in new window or tab >>Differential effects of repetitive oral administration of monosodium glutamate on interstitial glutamate concentration and muscle pain sensitivity
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2015 (English)In: Nutrition (Burbank, Los Angeles County, Calif.), ISSN 0899-9007, E-ISSN 1873-1244, Vol. 31, no 2, p. 315-323Article in journal (Refereed) Published
Abstract [en]

Objective: The aim of this study was to determine the relationship of high daily monosodium glutamate (MSG) consumption with glutamate concentrations in jaw muscle, saliva, and serum, and muscle pain sensitivity in healthy participants. Methods: A randomized, double-blinded, placebo-controlled study was conducted to investigate the effect of repetitive consumption of high-dose MSG on glutamate concentration in the masseter muscles measured by microdialysis and muscle pain sensitivity. In five contiguous experimental daily sessions, 32 healthy participants drank MSG (150 mg/kg) or NaCl (24 mg/kg) diluted with a 400 mL soda. The concentrations of glutamate before and after the ingestion were assessed in dialysate and plasma samples on the first and last days. Saliva glutamate concentration was assessed every day. Pressure pain threshold, pressure pain tolerance, autonomic parameters (heart rate, systolic and diastolic blood pressures) and reported side effects also were assessed. Results: No significant change was noted in the baseline concentration of glutamate in the masseter muscle, blood, or saliva, but the peak concentration in the masseter muscle increased significantly between day 1 and 5. A statistically significant increase in systolic and diastolic blood pressures after MSG administration was observed, as well as a significantly higher frequency of reports of nausea and headache in the MSG group. No robust effect of MSG on muscle sensitivity was found. Conclusion: Interstitial glutamate concentration in the masseter muscle is not highly disturbed by excessive repetitive intake of MSG in healthy man. (C) 2015 Elsevier Inc. All rights reserved.

Place, publisher, year, edition, pages
Elsevier, 2015
Keywords
Microdialysis; Mechanical muscle sensitivity; Monosodium glutamate; Myofascial temporomandibular disorders; Diet; Pain
National Category
Basic Medicine
Identifiers
urn:nbn:se:liu:diva-114991 (URN)10.1016/j.nut.2014.07.011 (DOI)000348633400008 ()25592010 (PubMedID)
Note

Funding Agencies|Danish Dental Association; Danish Medical Research Council

Available from: 2015-03-09 Created: 2015-03-06 Last updated: 2018-01-11
Gerdle, B., Larsson, B., Forsberg, F., Ghafouri, N., Karlsson, L., Stensson, N. & Ghafouri, B. (2014). Chronic Widespread Pain: Increased Glutamate and Lactate Concentrations in the Trapezius Muscle and Plasma. The Clinical Journal of Pain, 30(5), 409-420
Open this publication in new window or tab >>Chronic Widespread Pain: Increased Glutamate and Lactate Concentrations in the Trapezius Muscle and Plasma
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2014 (English)In: The Clinical Journal of Pain, ISSN 0749-8047, E-ISSN 1536-5409, Vol. 30, no 5, p. 409-420Article, review/survey (Refereed) Published
Abstract [en]

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 (R=0.22) and tibialis anterior (R=0.18) and the mean pain intensity (R=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.

Place, publisher, year, edition, pages
Lippincott Williams & Wilkins, 2014
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-103741 (URN)10.1097/AJP.0b013e31829e9d2a (DOI)000334597800005 ()23887335 (PubMedID)
Available from: 2014-01-24 Created: 2014-01-24 Last updated: 2017-12-06
Ghafouri, N., Ghafouri, B., Larsson, B., Stensson, N., Fowler, C. J. & Gerdle, B. (2013). 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. Pain, 154(9), 1649-1658
Open this publication in new window or tab >>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
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2013 (English)In: Pain, ISSN 0304-3959, E-ISSN 1872-6623, Vol. 154, no 9, p. 1649-1658Article in journal (Refereed) Published
Abstract [en]

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-alpha 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.

Place, publisher, year, edition, pages
Elsevier, 2013
Keywords
N-Acylethanolamines, Cannabinoid, Palmitoylethanolamide, Pain, Microdialysis, Myalgia, Widespread pain
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-97651 (URN)10.1016/j.pain.2013.05.002 (DOI)000323600000022 ()
Note

Funding Agencies|Swedish Council for Working Life and Social Research||Swedish Research Council||IngaBritt and Arne Lundberg foundation||

Available from: 2013-09-19 Created: 2013-09-19 Last updated: 2017-12-06
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