Search

N-arachidonoylethanolamine (also known as anandamide) and 2-arachidonoylglycerol are activators of the cannabinoid receptors. The endocannabinoid system also includes structurally and functionally related lipid mediators that do not target cannabinoid receptors, such as oleoylethanolamide, palmitoylethanolamide, and stearoylethanolamide. These bioactive lipids are involved in various physiological processes, including regulation of pain. The primary aim of the study was to analyze associations between serum levels of these lipids and pain in participants in the Pain in Neuropathy Study, an observational, cross-sectional, multicentre, research project in which diabetic patients with painless or painful neuropathy underwent deep phenotyping. Our hypothesis was that painful neuropathy would be associated with higher levels of the 5 lipids compared with painless neuropathy. Secondary aims were to analyze other patient-reported outcome measures and clinical data in relationship to lipid levels. The lipid mediators were analyzed in serum samples using liquid chromatography tandem mass spectrometry (LC-MS/MS). Serum levels of anandamide were significantly higher in the painful group, but the effect size was small (Cohen d = 0.31). Using cluster analysis of lipid data, patients were dichotomized into a "high-level" endocannabinoid group and a "low-level" group. In the high-level group, 61% of patients had painful neuropathy, compared with 45% in the low-level group (P = 0.039). This work is of a correlative nature only, and the relevance of these findings to the search for analgesics targeting the endocannabinoid system needs to be determined in future studies., Funding Agencies|NEURO Sweden; ALF Grants; Swedish Research Council [2018-02470]; MRC and vs Arthritis [MR/W002388/1]; European Union [FP7/2007-2013]; European Commission Horizon 2020 [ID633491]; Novo Nordisk Foundation Challenge Program grant [NNF14OC0011633]; Academy of Medical Sciences Starter Grant [SGL022\1086]; Honorary Senior Research Fellow and Carnegie-Wits Diaspora Fellow; Wellcome Trust [083259]

Childhood maltreatment (CM) is a risk factor for substance use disorders (SUD) in adulthood. Understanding the mechanisms by which people are susceptible or resilient to developing SUD after exposure to CM is important for improving intervention. This case-control study investigated the impact of prospectively assessed CM on biomarkers of endocannabinoid function and emotion regulation in relation to the susceptibility or resilience to developing SUD. Four groups were defined across the dimensions of CM and lifetime SUD (N = 101 in total). After screening, participants completed two experimental sessions on separate days, aimed at assessing the behavioral, physiological, and neural mechanisms involved in emotion regulation. In the first session, participants engaged in tasks assessing biochemical (i.e., cortisol, endocannabinoids), behavioral, and psychophysiological indices of stress and affective reactivity. During the second session, the behavioral and brain mechanisms associated with emotion regulation and negative affect were investigated using magnetic resonance imaging. CM-exposed adults who did not develop SUD, operationally defined as resilient to developing SUD, had higher peripheral levels of the endocannabinoid anandamide at baseline and during stress exposure, compared to controls. Similarly, this group had increased activity in salience and emotion regulation regions in task-based measures of emotion regulation compared to controls, and CM-exposed adults with lifetime SUD. At rest, the resilient group also showed significantly greater negative connectivity between ventromedial prefrontal cortex and anterior insula compared to controls and CM-exposed adults with lifetime SUD. Collectively, these peripheral and central findings point to mechanisms of potential resilience to developing SUD after documented CM exposure., Funding Agencies|Swedish Research Council for Infrastructures and Science for Life Laboratory, Sweden; Swedish Research Council [2013-07434]; Medical Training and Research Agreement in Ostergotland Region [ALF 2017: LIO-599451, ALF 2018: LIO-692621, ALF 2019: LIO-791581, ALF 2020: RO-888021, ALF 2021: RO-935602]; Systembolagets alkoholforskningsrad [2016-0018, 2017-0075, 2018-0030, 2019-0007]; Brain & Behavior Research Foundation NARSAD Young Investigator Grant [27094]

Childhood maltreatment (CM) is a risk factor for substance use disorders (SUD) in adulthood. Understanding the mechanisms by which people are susceptible or resilient to developing SUD after exposure to CM is important for improving intervention. This case-control study investigated the impact of prospectively assessed CM on biomarkers of endocannabinoid function and emotion regulation in relation to the susceptibility or resilience to developing SUD. Four groups were defined across the dimensions of CM and lifetime SUD (N = 101 in total). After screening, participants completed two experimental sessions on separate days, aimed at assessing the behavioral, physiological, and neural mechanisms involved in emotion regulation. In the first session, participants engaged in tasks assessing biochemical (i.e., cortisol, endocannabinoids), behavioral, and psychophysiological indices of stress and affective reactivity. During the second session, the behavioral and brain mechanisms associated with emotion regulation and negative affect were investigated using magnetic resonance imaging. CM-exposed adults who did not develop SUD, operationally defined as resilient to developing SUD, had higher peripheral levels of the endocannabinoid anandamide at baseline and during stress exposure, compared to controls. Similarly, this group had increased activity in salience and emotion regulation regions in task-based measures of emotion regulation compared to controls, and CM-exposed adults with lifetime SUD. At rest, the resilient group also showed significantly greater negative connectivity between ventromedial prefrontal cortex and anterior insula compared to controls and CM-exposed adults with lifetime SUD. Collectively, these peripheral and central findings point to mechanisms of potential resilience to developing SUD after documented CM exposure., Funding Agencies|Swedish Research Council for Infrastructures and Science for Life Laboratory, Sweden; Swedish Research Council [2013-07434]; Medical Training and Research Agreement in Ostergotland Region [ALF 2017: LIO-599451, ALF 2018: LIO-692621, ALF 2019: LIO-791581, ALF 2020: RO-888021, ALF 2021: RO-935602]; Systembolagets alkoholforskningsrad [2016-0018, 2017-0075, 2018-0030, 2019-0007]; Brain & Behavior Research Foundation NARSAD Young Investigator Grant [27094]

Childhood maltreatment (CM) is a risk factor for substance use disorders (SUD) in adulthood. Understanding the mechanisms by which people are susceptible or resilient to developing SUD after exposure to CM is important for improving intervention. This case-control study investigated the impact of prospectively assessed CM on biomarkers of endocannabinoid function and emotion regulation in relation to the susceptibility or resilience to developing SUD. Four groups were defined across the dimensions of CM and lifetime SUD (N = 101 in total). After screening, participants completed two experimental sessions on separate days, aimed at assessing the behavioral, physiological, and neural mechanisms involved in emotion regulation. In the first session, participants engaged in tasks assessing biochemical (i.e., cortisol, endocannabinoids), behavioral, and psychophysiological indices of stress and affective reactivity. During the second session, the behavioral and brain mechanisms associated with emotion regulation and negative affect were investigated using magnetic resonance imaging. CM-exposed adults who did not develop SUD, operationally defined as resilient to developing SUD, had higher peripheral levels of the endocannabinoid anandamide at baseline and during stress exposure, compared to controls. Similarly, this group had increased activity in salience and emotion regulation regions in task-based measures of emotion regulation compared to controls, and CM-exposed adults with lifetime SUD. At rest, the resilient group also showed significantly greater negative connectivity between ventromedial prefrontal cortex and anterior insula compared to controls and CM-exposed adults with lifetime SUD. Collectively, these peripheral and central findings point to mechanisms of potential resilience to developing SUD after documented CM exposure., Funding Agencies|Swedish Research Council for Infrastructures and Science for Life Laboratory, Sweden; Swedish Research Council [2013-07434]; Medical Training and Research Agreement in Ostergotland Region [ALF 2017: LIO-599451, ALF 2018: LIO-692621, ALF 2019: LIO-791581, ALF 2020: RO-888021, ALF 2021: RO-935602]; Systembolagets alkoholforskningsrad [2016-0018, 2017-0075, 2018-0030, 2019-0007]; Brain & Behavior Research Foundation NARSAD Young Investigator Grant [27094]

Childhood maltreatment (CM) is a risk factor for substance use disorders (SUD) in adulthood. Understanding the mechanisms by which people are susceptible or resilient to developing SUD after exposure to CM is important for improving intervention. This case-control study investigated the impact of prospectively assessed CM on biomarkers of endocannabinoid function and emotion regulation in relation to the susceptibility or resilience to developing SUD. Four groups were defined across the dimensions of CM and lifetime SUD (N = 101 in total). After screening, participants completed two experimental sessions on separate days, aimed at assessing the behavioral, physiological, and neural mechanisms involved in emotion regulation. In the first session, participants engaged in tasks assessing biochemical (i.e., cortisol, endocannabinoids), behavioral, and psychophysiological indices of stress and affective reactivity. During the second session, the behavioral and brain mechanisms associated with emotion regulation and negative affect were investigated using magnetic resonance imaging. CM-exposed adults who did not develop SUD, operationally defined as resilient to developing SUD, had higher peripheral levels of the endocannabinoid anandamide at baseline and during stress exposure, compared to controls. Similarly, this group had increased activity in salience and emotion regulation regions in task-based measures of emotion regulation compared to controls, and CM-exposed adults with lifetime SUD. At rest, the resilient group also showed significantly greater negative connectivity between ventromedial prefrontal cortex and anterior insula compared to controls and CM-exposed adults with lifetime SUD. Collectively, these peripheral and central findings point to mechanisms of potential resilience to developing SUD after documented CM exposure., Funding Agencies|Swedish Research Council for Infrastructures and Science for Life Laboratory, Sweden; Swedish Research Council [2013-07434]; Medical Training and Research Agreement in Ostergotland Region [ALF 2017: LIO-599451, ALF 2018: LIO-692621, ALF 2019: LIO-791581, ALF 2020: RO-888021, ALF 2021: RO-935602]; Systembolagets alkoholforskningsrad [2016-0018, 2017-0075, 2018-0030, 2019-0007]; Brain & Behavior Research Foundation NARSAD Young Investigator Grant [27094]

Childhood maltreatment (CM) is a risk factor for substance use disorders (SUD) in adulthood. Understanding the mechanisms by which people are susceptible or resilient to developing SUD after exposure to CM is important for improving intervention. This case-control study investigated the impact of prospectively assessed CM on biomarkers of endocannabinoid function and emotion regulation in relation to the susceptibility or resilience to developing SUD. Four groups were defined across the dimensions of CM and lifetime SUD (N = 101 in total). After screening, participants completed two experimental sessions on separate days, aimed at assessing the behavioral, physiological, and neural mechanisms involved in emotion regulation. In the first session, participants engaged in tasks assessing biochemical (i.e., cortisol, endocannabinoids), behavioral, and psychophysiological indices of stress and affective reactivity. During the second session, the behavioral and brain mechanisms associated with emotion regulation and negative affect were investigated using magnetic resonance imaging. CM-exposed adults who did not develop SUD, operationally defined as resilient to developing SUD, had higher peripheral levels of the endocannabinoid anandamide at baseline and during stress exposure, compared to controls. Similarly, this group had increased activity in salience and emotion regulation regions in task-based measures of emotion regulation compared to controls, and CM-exposed adults with lifetime SUD. At rest, the resilient group also showed significantly greater negative connectivity between ventromedial prefrontal cortex and anterior insula compared to controls and CM-exposed adults with lifetime SUD. Collectively, these peripheral and central findings point to mechanisms of potential resilience to developing SUD after documented CM exposure., Funding Agencies|Swedish Research Council for Infrastructures and Science for Life Laboratory, Sweden; Swedish Research Council [2013-07434]; Medical Training and Research Agreement in Ostergotland Region [ALF 2017: LIO-599451, ALF 2018: LIO-692621, ALF 2019: LIO-791581, ALF 2020: RO-888021, ALF 2021: RO-935602]; Systembolagets alkoholforskningsrad [2016-0018, 2017-0075, 2018-0030, 2019-0007]; Brain & Behavior Research Foundation NARSAD Young Investigator Grant [27094]

Mechanism-based diagnosis and therapies for chronic pain are lacking. However, bio-psycho-social interventions such as interdisciplinary multimodal rehabilitation programs (IPRPs) have shown to be relatively effective treatments. In this context we aim to investigate the effects of IPRP on the changes in levels of bioactive lipids and telomerase activity in plasma, and if these changes are associated with changes in pain intensity and psychological distress. This exploratory study involves 18 patients with complex chronic pain participating in an IPRP. Self-reports of pain, psychological distress, physical activity, and blood samples were collected before the IPRP and at a six-month follow-up. Levels of arachidonoylethanolamide (AEA) and 2-arachidonoylglycerol (2-AG), palmitoylethanolamide (PEA), oleoylethanolamide (OEA), stearoylethanolamide (SEA), and telomerase activity were measured. Pain intensity was decreased, and SEA levels were increased at the six-month follow up. A significant correlation existed between changes in SEA levels and pain intensity. AEA levels, were inversely correlated with physical activity. Furthermore, 2-AG and telomerase activity was significantly correlated at the six-month follow-up. This study confirms that IPRP is relatively effective for reduction in chronic pain. Changes in SEA were correlated with changes in pain intensity, which might indicate that SEA changes reflect the pain reduction effects of IPRP., Funding Agencies|Swedish Research Council, Region Oestergoetland (Stiftelsefoervaltningen, Research-ALF)Swedish Research Council; Magnus Bergvalls foundation; ake Wiberg foundation

Mechanism-based diagnosis and therapies for chronic pain are lacking. However, bio-psycho-social interventions such as interdisciplinary multimodal rehabilitation programs (IPRPs) have shown to be relatively effective treatments. In this context we aim to investigate the effects of IPRP on the changes in levels of bioactive lipids and telomerase activity in plasma, and if these changes are associated with changes in pain intensity and psychological distress. This exploratory study involves 18 patients with complex chronic pain participating in an IPRP. Self-reports of pain, psychological distress, physical activity, and blood samples were collected before the IPRP and at a six-month follow-up. Levels of arachidonoylethanolamide (AEA) and 2-arachidonoylglycerol (2-AG), palmitoylethanolamide (PEA), oleoylethanolamide (OEA), stearoylethanolamide (SEA), and telomerase activity were measured. Pain intensity was decreased, and SEA levels were increased at the six-month follow up. A significant correlation existed between changes in SEA levels and pain intensity. AEA levels, were inversely correlated with physical activity. Furthermore, 2-AG and telomerase activity was significantly correlated at the six-month follow-up. This study confirms that IPRP is relatively effective for reduction in chronic pain. Changes in SEA were correlated with changes in pain intensity, which might indicate that SEA changes reflect the pain reduction effects of IPRP., Funding Agencies|Swedish Research Council, Region Oestergoetland (Stiftelsefoervaltningen, Research-ALF)Swedish Research Council; Magnus Bergvalls foundation; ake Wiberg foundation

Mechanism-based diagnosis and therapies for chronic pain are lacking. However, bio-psycho-social interventions such as interdisciplinary multimodal rehabilitation programs (IPRPs) have shown to be relatively effective treatments. In this context we aim to investigate the effects of IPRP on the changes in levels of bioactive lipids and telomerase activity in plasma, and if these changes are associated with changes in pain intensity and psychological distress. This exploratory study involves 18 patients with complex chronic pain participating in an IPRP. Self-reports of pain, psychological distress, physical activity, and blood samples were collected before the IPRP and at a six-month follow-up. Levels of arachidonoylethanolamide (AEA) and 2-arachidonoylglycerol (2-AG), palmitoylethanolamide (PEA), oleoylethanolamide (OEA), stearoylethanolamide (SEA), and telomerase activity were measured. Pain intensity was decreased, and SEA levels were increased at the six-month follow up. A significant correlation existed between changes in SEA levels and pain intensity. AEA levels, were inversely correlated with physical activity. Furthermore, 2-AG and telomerase activity was significantly correlated at the six-month follow-up. This study confirms that IPRP is relatively effective for reduction in chronic pain. Changes in SEA were correlated with changes in pain intensity, which might indicate that SEA changes reflect the pain reduction effects of IPRP., Funding Agencies|Swedish Research Council, Region Oestergoetland (Stiftelsefoervaltningen, Research-ALF)Swedish Research Council; Magnus Bergvalls foundation; ake Wiberg foundation

Background: Although neuropathic pain is a significant problem in polyneuropathy, the underlying molecular mechanisms are poorly understood. The endogenous bioactive lipids 2-arachidonoyl-glycerol (2-AG), oleoylethanolamide (OEA), palmitoylethanolamide (PEA), and stearoylethanolamide (SEA) are known to influence pain and inflammation in the peripheral nervous system. The aim of this study was to explore the plasma levels of endocannabinoids and related lipids and health-related quality of life in patients with polyneuropathy with and without pain. Methods: Patients (n = 48) with Chronic Idiopathic Axonal Neuropathy were included. Clinical data were retrieved from medical files. All patients filled out the SF-36 and EQ-5D questionnaires. In addition, blood samples were analyzed for 2-AG, OEA, PEA, and SEA. Results: Neuropathic pain was reported in 21 of the patients. There were significantly lower levels of 2-AG in patients with neuropathic pain (P = 0.03), but there were no significant differences in OEA (P = 0.61), PEA (P = 0.95), or SEA (P = 0.97) levels. The patients reporting pain in the hands had significantly lower SEA levels, 10.0 versus 15.0 (P = 0.03). The levels of 2-AG were significantly higher among patients reporting paresthesia in their feet (80.1 vs. 56.3; P = 0.02). Levels of PEA, SEA, and 2-AG were decreased in patients with loss of vibration. PEA and SEA were decreased in patients with loss of pain and temperature, and SEA decreased in patients with loss of sense of touch. However, the differences in the levels of bioactive endogenous lipids were not statistically significant when corrected for multiple comparisons. Conclusion: Alterations of 2-AG levels between polyneuropathy patients with and without neurogenic pain indicate that it could play an essential role. Further studies are warranted.

Background: Although neuropathic pain is a significant problem in polyneuropathy, the underlying molecular mechanisms are poorly understood. The endogenous bioactive lipids 2-arachidonoyl-glycerol (2-AG), oleoylethanolamide (OEA), palmitoylethanolamide (PEA), and stearoylethanolamide (SEA) are known to influence pain and inflammation in the peripheral nervous system. The aim of this study was to explore the plasma levels of endocannabinoids and related lipids and health-related quality of life in patients with polyneuropathy with and without pain. Methods: Patients (n = 48) with Chronic Idiopathic Axonal Neuropathy were included. Clinical data were retrieved from medical files. All patients filled out the SF-36 and EQ-5D questionnaires. In addition, blood samples were analyzed for 2-AG, OEA, PEA, and SEA. Results: Neuropathic pain was reported in 21 of the patients. There were significantly lower levels of 2-AG in patients with neuropathic pain (P = 0.03), but there were no significant differences in OEA (P = 0.61), PEA (P = 0.95), or SEA (P = 0.97) levels. The patients reporting pain in the hands had significantly lower SEA levels, 10.0 versus 15.0 (P = 0.03). The levels of 2-AG were significantly higher among patients reporting paresthesia in their feet (80.1 vs. 56.3; P = 0.02). Levels of PEA, SEA, and 2-AG were decreased in patients with loss of vibration. PEA and SEA were decreased in patients with loss of pain and temperature, and SEA decreased in patients with loss of sense of touch. However, the differences in the levels of bioactive endogenous lipids were not statistically significant when corrected for multiple comparisons. Conclusion: Alterations of 2-AG levels between polyneuropathy patients with and without neurogenic pain indicate that it could play an essential role. Further studies are warranted.

Background: Although neuropathic pain is a significant problem in polyneuropathy, the underlying molecular mechanisms are poorly understood. The endogenous bioactive lipids 2-arachidonoyl-glycerol (2-AG), oleoylethanolamide (OEA), palmitoylethanolamide (PEA), and stearoylethanolamide (SEA) are known to influence pain and inflammation in the peripheral nervous system. The aim of this study was to explore the plasma levels of endocannabinoids and related lipids and health-related quality of life in patients with polyneuropathy with and without pain. Methods: Patients (n = 48) with Chronic Idiopathic Axonal Neuropathy were included. Clinical data were retrieved from medical files. All patients filled out the SF-36 and EQ-5D questionnaires. In addition, blood samples were analyzed for 2-AG, OEA, PEA, and SEA. Results: Neuropathic pain was reported in 21 of the patients. There were significantly lower levels of 2-AG in patients with neuropathic pain (P = 0.03), but there were no significant differences in OEA (P = 0.61), PEA (P = 0.95), or SEA (P = 0.97) levels. The patients reporting pain in the hands had significantly lower SEA levels, 10.0 versus 15.0 (P = 0.03). The levels of 2-AG were significantly higher among patients reporting paresthesia in their feet (80.1 vs. 56.3; P = 0.02). Levels of PEA, SEA, and 2-AG were decreased in patients with loss of vibration. PEA and SEA were decreased in patients with loss of pain and temperature, and SEA decreased in patients with loss of sense of touch. However, the differences in the levels of bioactive endogenous lipids were not statistically significant when corrected for multiple comparisons. Conclusion: Alterations of 2-AG levels between polyneuropathy patients with and without neurogenic pain indicate that it could play an essential role. Further studies are warranted.

Mechanism-based diagnosis and therapies for chronic pain are lacking. However, bio-psycho-social interventions such as interdisciplinary multimodal rehabilitation programs (IPRPs) have shown to be relatively effective treatments. In this context we aim to investigate the effects of IPRP on the changes in levels of bioactive lipids and telomerase activity in plasma, and if these changes are associated with changes in pain intensity and psychological distress. This exploratory study involves 18 patients with complex chronic pain participating in an IPRP. Self-reports of pain, psychological distress, physical activity, and blood samples were collected before the IPRP and at a six-month follow-up. Levels of arachidonoylethanolamide (AEA) and 2-arachidonoylglycerol (2-AG), palmitoylethanolamide (PEA), oleoylethanolamide (OEA), stearoylethanolamide (SEA), and telomerase activity were measured. Pain intensity was decreased, and SEA levels were increased at the six-month follow up. A significant correlation existed between changes in SEA levels and pain intensity. AEA levels, were inversely correlated with physical activity. Furthermore, 2-AG and telomerase activity was significantly correlated at the six-month follow-up. This study confirms that IPRP is relatively effective for reduction in chronic pain. Changes in SEA were correlated with changes in pain intensity, which might indicate that SEA changes reflect the pain reduction effects of IPRP., Funding Agencies|Swedish Research Council, Region Oestergoetland (Stiftelsefoervaltningen, Research-ALF)Swedish Research Council; Magnus Bergvalls foundation; ake Wiberg foundation

Background: Although neuropathic pain is a significant problem in polyneuropathy, the underlying molecular mechanisms are poorly understood. The endogenous bioactive lipids 2-arachidonoyl-glycerol (2-AG), oleoylethanolamide (OEA), palmitoylethanolamide (PEA), and stearoylethanolamide (SEA) are known to influence pain and inflammation in the peripheral nervous system. The aim of this study was to explore the plasma levels of endocannabinoids and related lipids and health-related quality of life in patients with polyneuropathy with and without pain. Methods: Patients (n = 48) with Chronic Idiopathic Axonal Neuropathy were included. Clinical data were retrieved from medical files. All patients filled out the SF-36 and EQ-5D questionnaires. In addition, blood samples were analyzed for 2-AG, OEA, PEA, and SEA. Results: Neuropathic pain was reported in 21 of the patients. There were significantly lower levels of 2-AG in patients with neuropathic pain (P = 0.03), but there were no significant differences in OEA (P = 0.61), PEA (P = 0.95), or SEA (P = 0.97) levels. The patients reporting pain in the hands had significantly lower SEA levels, 10.0 versus 15.0 (P = 0.03). The levels of 2-AG were significantly higher among patients reporting paresthesia in their feet (80.1 vs. 56.3; P = 0.02). Levels of PEA, SEA, and 2-AG were decreased in patients with loss of vibration. PEA and SEA were decreased in patients with loss of pain and temperature, and SEA decreased in patients with loss of sense of touch. However, the differences in the levels of bioactive endogenous lipids were not statistically significant when corrected for multiple comparisons. Conclusion: Alterations of 2-AG levels between polyneuropathy patients with and without neurogenic pain indicate that it could play an essential role. Further studies are warranted.

Background: Although neuropathic pain is a significant problem in polyneuropathy, the underlying molecular mechanisms are poorly understood. The endogenous bioactive lipids 2-arachidonoyl-glycerol (2-AG), oleoylethanolamide (OEA), palmitoylethanolamide (PEA), and stearoylethanolamide (SEA) are known to influence pain and inflammation in the peripheral nervous system. The aim of this study was to explore the plasma levels of endocannabinoids and related lipids and health-related quality of life in patients with polyneuropathy with and without pain. Methods: Patients (n = 48) with Chronic Idiopathic Axonal Neuropathy were included. Clinical data were retrieved from medical files. All patients filled out the SF-36 and EQ-5D questionnaires. In addition, blood samples were analyzed for 2-AG, OEA, PEA, and SEA. Results: Neuropathic pain was reported in 21 of the patients. There were significantly lower levels of 2-AG in patients with neuropathic pain (P = 0.03), but there were no significant differences in OEA (P = 0.61), PEA (P = 0.95), or SEA (P = 0.97) levels. The patients reporting pain in the hands had significantly lower SEA levels, 10.0 versus 15.0 (P = 0.03). The levels of 2-AG were significantly higher among patients reporting paresthesia in their feet (80.1 vs. 56.3; P = 0.02). Levels of PEA, SEA, and 2-AG were decreased in patients with loss of vibration. PEA and SEA were decreased in patients with loss of pain and temperature, and SEA decreased in patients with loss of sense of touch. However, the differences in the levels of bioactive endogenous lipids were not statistically significant when corrected for multiple comparisons. Conclusion: Alterations of 2-AG levels between polyneuropathy patients with and without neurogenic pain indicate that it could play an essential role. Further studies are warranted.

Mechanism-based diagnosis and therapies for chronic pain are lacking. However, bio-psycho-social interventions such as interdisciplinary multimodal rehabilitation programs (IPRPs) have shown to be relatively effective treatments. In this context we aim to investigate the effects of IPRP on the changes in levels of bioactive lipids and telomerase activity in plasma, and if these changes are associated with changes in pain intensity and psychological distress. This exploratory study involves 18 patients with complex chronic pain participating in an IPRP. Self-reports of pain, psychological distress, physical activity, and blood samples were collected before the IPRP and at a six-month follow-up. Levels of arachidonoylethanolamide (AEA) and 2-arachidonoylglycerol (2-AG), palmitoylethanolamide (PEA), oleoylethanolamide (OEA), stearoylethanolamide (SEA), and telomerase activity were measured. Pain intensity was decreased, and SEA levels were increased at the six-month follow up. A significant correlation existed between changes in SEA levels and pain intensity. AEA levels, were inversely correlated with physical activity. Furthermore, 2-AG and telomerase activity was significantly correlated at the six-month follow-up. This study confirms that IPRP is relatively effective for reduction in chronic pain. Changes in SEA were correlated with changes in pain intensity, which might indicate that SEA changes reflect the pain reduction effects of IPRP., Funding Agencies|Swedish Research Council, Region Oestergoetland (Stiftelsefoervaltningen, Research-ALF)Swedish Research Council; Magnus Bergvalls foundation; ake Wiberg foundation

PURPOSE: Physical exercise is increasingly being promoted by health care for chronic pain conditions with beneficial outcomes, such as pain and fatigue reduction, and increased quality of life. Nevertheless, knowledge about biochemical consequences of physical exercise in chronic pain is still relatively poor. The endocannabinoid system has been suggested to play a role for acute exercise-induced reward and pain inhibition. The aim of this study is to investigate the chronic outcomes of resistance exercise on levels of endocannabinoids and related lipids in fibromyalgia (FM). METHODS: This study examine the outcomes of a 15-wk person-centered resistance exercise program on plasma levels of the lipid mediators; anandamide, 2-arachidonoylglycerol (2-AG), oleoylethanolamide, palmitoylethanolamide, and stearoylethanolamide (SEA) sampled from 37 women with FM and 33 healthy controls. The associations between clinical scorings of pain, depression, anxiety, fatigue, and muscle strength with levels of these lipid mediators before and after the exercise program are also analyzed. RESULTS: After the 15-wk exercise program, anandamide levels were significantly increased, and SEA levels significantly decreased in FM. Pain intensity and depression scorings decreased and muscle strength increased, and in a multivariate context, muscle strength was positively associated with 2-AG levels after the resistance exercise program in FM. CONCLUSIONS: The increased anandamide and decreased SEA in women with FM after the 15-wk program might point to a chronic effect of resistance exercise. Pain and depression scorings decreased in the FM group after the program, but no associations between pain, depression, and lipid level changes were assured.

Purpose Physical exercise is increasingly being promoted by health care for chronic pain conditions with beneficial outcomes, such as pain and fatigue reduction, and increased quality of life. Nevertheless, knowledge about biochemical consequences of physical exercise in chronic pain is still relatively poor. The endocannabinoid system has been suggested to play a role for acute exercise-induced reward and pain inhibition. The aim of this study is to investigate the chronic outcomes of resistance exercise on levels of endocannabinoids and related lipids in fibromyalgia (FM). Methods This study examine the outcomes of a 15-wk person-centered resistance exercise program on plasma levels of the lipid mediators; anandamide, 2-arachidonoylglycerol (2-AG), oleoylethanolamide, palmitoylethanolamide, and stearoylethanolamide (SEA) sampled from 37 women with FM and 33 healthy controls. The associations between clinical scorings of pain, depression, anxiety, fatigue, and muscle strength with levels of these lipid mediators before and after the exercise program are also analyzed. Results After the 15-wk exercise program, anandamide levels were significantly increased, and SEA levels significantly decreased in FM. Pain intensity and depression scorings decreased and muscle strength increased, and in a multivariate context, muscle strength was positively associated with 2-AG levels after the resistance exercise program in FM. Conclusions The increased anandamide and decreased SEA in women with FM after the 15-wk program might point to a chronic effect of resistance exercise. Pain and depression scorings decreased in the FM group after the program, but no associations between pain, depression, and lipid level changes were assured., Funding Agencies|Swedish Rheumatism Association; Swedish Research CouncilSwedish Research Council [K2009-52P-20943-03-2]; County Council of ostergotland (Research-ALF); Magnus Bergvall foundation [2016-01733]; Ake Wiberg foundation [M16-0134]; AFA insurance

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., Funding agencies: Swedish Research CouncilSwedish Research Council [2013-7434]; Canadian Institutes of Health Research (CIHR)Canadian Institutes of Health Research (CIHR); Alberta Innovates and BranchOut Neurological Foundation

The insufficient knowledge of biochemical mechanisms behind the emergence and maintenance of chronic musculoskeletal pain conditions constrains the development of diagnostic and therapeutic tools for clinical use. However, physical activity and exercise may improve pain severity and physical function during chronic pain conditions. Nevertheless, the biochemical consequences of physical activity and exercise in chronic pain need to be elucidated to increase the precision of this therapeutic tool in chronic pain treatment. The endocannabinoid system has been suggested to play an important role in exercise-induced reward and pain inhibition. Moreover, glutamatergic signalling has been suggested as an important factor for sensation and transmission of pain. In addition, a link has been established between the endocannabinoid system and glutamatergic pathways. This study examines the effect of dynamic load arm cycling (30 min) on levels of lipid mediators related to the endocannabinoid system and glutamate in plasma of chronic pain subjects and pain-free controls. Pain assessments and plasma levels of arachidonoylethanolamide (anandamide), 2-aracidonoylglycerol, oleoylethanolamide, palmitoylethanolamide, stearoylethanolamide and glutamate from 21 subjects with chronic neck pain (chronic pain group) and 11 healthy controls were analysed pre and post intervention of dynamic load arm cycling. Pain intensity was significantly different between groups pre and post exercise. Post exercise, anandamide levels were significantly decreased in health controls but not in the chronic pain group. A strong positive correlation existed between anandamide and glutamate in the control group post exercise but not in the chronic pain group. Moreover, the glutamate/anandamide ratio increased significantly in the control group and differed significantly with the chronic pain group post exercise. The altered relationship between anandamide and glutamate after the intervention in the chronic pa, Funding Agencies|Royal Society of Arts and Sciences in Gothenburg; Lions Medical Research Foundation

The insufficient knowledge of biochemical mechanisms behind the emergence and maintenance of chronic musculoskeletal pain conditions constrains the development of diagnostic and therapeutic tools for clinical use. However, physical activity and exercise may improve pain severity and physical function during chronic pain conditions. Nevertheless, the biochemical consequences of physical activity and exercise in chronic pain need to be elucidated to increase the precision of this therapeutic tool in chronic pain treatment. The endocannabinoid system has been suggested to play an important role in exercise-induced reward and pain inhibition. Moreover, glutamatergic signalling has been suggested as an important factor for sensation and transmission of pain. In addition, a link has been established between the endocannabinoid system and glutamatergic pathways. This study examines the effect of dynamic load arm cycling (30 min) on levels of lipid mediators related to the endocannabinoid system and glutamate in plasma of chronic pain subjects and pain-free controls. Pain assessments and plasma levels of arachidonoylethanolamide (anandamide), 2-aracidonoylglycerol, oleoylethanolamide, palmitoylethanolamide, stearoylethanolamide and glutamate from 21 subjects with chronic neck pain (chronic pain group) and 11 healthy controls were analysed pre and post intervention of dynamic load arm cycling. Pain intensity was significantly different between groups pre and post exercise. Post exercise, anandamide levels were significantly decreased in health controls but not in the chronic pain group. A strong positive correlation existed between anandamide and glutamate in the control group post exercise but not in the chronic pain group. Moreover, the glutamate/anandamide ratio increased significantly in the control group and differed significantly with the chronic pain group post exercise. The altered relationship between anandamide and glutamate after the intervention in the chronic pa, Funding Agencies|Royal Society of Arts and Sciences in Gothenburg; Lions Medical Research Foundation

The insufficient knowledge of biochemical mechanisms behind the emergence and maintenance of chronic musculoskeletal pain conditions constrains the development of diagnostic and therapeutic tools for clinical use. However, physical activity and exercise may improve pain severity and physical function during chronic pain conditions. Nevertheless, the biochemical consequences of physical activity and exercise in chronic pain need to be elucidated to increase the precision of this therapeutic tool in chronic pain treatment. The endocannabinoid system has been suggested to play an important role in exercise-induced reward and pain inhibition. Moreover, glutamatergic signalling has been suggested as an important factor for sensation and transmission of pain. In addition, a link has been established between the endocannabinoid system and glutamatergic pathways. This study examines the effect of dynamic load arm cycling (30 min) on levels of lipid mediators related to the endocannabinoid system and glutamate in plasma of chronic pain subjects and pain-free controls. Pain assessments and plasma levels of arachidonoylethanolamide (anandamide), 2-aracidonoylglycerol, oleoylethanolamide, palmitoylethanolamide, stearoylethanolamide and glutamate from 21 subjects with chronic neck pain (chronic pain group) and 11 healthy controls were analysed pre and post intervention of dynamic load arm cycling. Pain intensity was significantly different between groups pre and post exercise. Post exercise, anandamide levels were significantly decreased in health controls but not in the chronic pain group. A strong positive correlation existed between anandamide and glutamate in the control group post exercise but not in the chronic pain group. Moreover, the glutamate/anandamide ratio increased significantly in the control group and differed significantly with the chronic pain group post exercise. The altered relationship between anandamide and glutamate after the intervention in the chronic pa, Funding Agencies|Royal Society of Arts and Sciences in Gothenburg; Lions Medical Research Foundation

The insufficient knowledge of biochemical mechanisms behind the emergence and maintenance of chronic musculoskeletal pain conditions constrains the development of diagnostic and therapeutic tools for clinical use. However, physical activity and exercise may improve pain severity and physical function during chronic pain conditions. Nevertheless, the biochemical consequences of physical activity and exercise in chronic pain need to be elucidated to increase the precision of this therapeutic tool in chronic pain treatment. The endocannabinoid system has been suggested to play an important role in exercise-induced reward and pain inhibition. Moreover, glutamatergic signalling has been suggested as an important factor for sensation and transmission of pain. In addition, a link has been established between the endocannabinoid system and glutamatergic pathways. This study examines the effect of dynamic load arm cycling (30 min) on levels of lipid mediators related to the endocannabinoid system and glutamate in plasma of chronic pain subjects and pain-free controls. Pain assessments and plasma levels of arachidonoylethanolamide (anandamide), 2-aracidonoylglycerol, oleoylethanolamide, palmitoylethanolamide, stearoylethanolamide and glutamate from 21 subjects with chronic neck pain (chronic pain group) and 11 healthy controls were analysed pre and post intervention of dynamic load arm cycling. Pain intensity was significantly different between groups pre and post exercise. Post exercise, anandamide levels were significantly decreased in health controls but not in the chronic pain group. A strong positive correlation existed between anandamide and glutamate in the control group post exercise but not in the chronic pain group. Moreover, the glutamate/anandamide ratio increased significantly in the control group and differed significantly with the chronic pain group post exercise. The altered relationship between anandamide and glutamate after the intervention in the chronic pa, Funding Agencies|Royal Society of Arts and Sciences in Gothenburg; Lions Medical Research Foundation

The insufficient knowledge of biochemical mechanisms behind the emergence and maintenance of chronic musculoskeletal pain conditions constrains the development of diagnostic and therapeutic tools for clinical use. However, physical activity and exercise may improve pain severity and physical function during chronic pain conditions. Nevertheless, the biochemical consequences of physical activity and exercise in chronic pain need to be elucidated to increase the precision of this therapeutic tool in chronic pain treatment. The endocannabinoid system has been suggested to play an important role in exercise-induced reward and pain inhibition. Moreover, glutamatergic signalling has been suggested as an important factor for sensation and transmission of pain. In addition, a link has been established between the endocannabinoid system and glutamatergic pathways. This study examines the effect of dynamic load arm cycling (30 min) on levels of lipid mediators related to the endocannabinoid system and glutamate in plasma of chronic pain subjects and pain-free controls. Pain assessments and plasma levels of arachidonoylethanolamide (anandamide), 2-aracidonoylglycerol, oleoylethanolamide, palmitoylethanolamide, stearoylethanolamide and glutamate from 21 subjects with chronic neck pain (chronic pain group) and 11 healthy controls were analysed pre and post intervention of dynamic load arm cycling. Pain intensity was significantly different between groups pre and post exercise. Post exercise, anandamide levels were significantly decreased in health controls but not in the chronic pain group. A strong positive correlation existed between anandamide and glutamate in the control group post exercise but not in the chronic pain group. Moreover, the glutamate/anandamide ratio increased significantly in the control group and differed significantly with the chronic pain group post exercise. The altered relationship between anandamide and glutamate after the intervention in the chronic pa, Funding Agencies|Royal Society of Arts and Sciences in Gothenburg; Lions Medical Research Foundation

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

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

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

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

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

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

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, 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

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., 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

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., 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

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., 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

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., 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

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., 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

BACKGROUND: Dopaminergic 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. METHODS: Fifteen 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. RESULTS: Dopamine 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). CONCLUSIONS: The 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.

BACKGROUND: Dopaminergic 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. METHODS: Fifteen 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. RESULTS: Dopamine 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). CONCLUSIONS: The 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.

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-alpha, 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 amp;lt;= 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., Funding Agencies|Swedish Research Council [K2015-99x-21874-05-4]; Swedish Council for Working Life and Social Research [2010-0913]; County Council of Ostergotland; AFA Insurance

Endocannabinoids and related N-acylethanolamines (NAEs) are lipid mediators involved in a number of physiological and pathological mechanisms in peripheral tissues. Microdialysis (MD) technique allows continues sampling of endogenous substances in the interstitial fluids of the tissues. The main limitation of MD sampling of lipophilic compounds is low recovery due to adsorption to the MD system and particularly to the catheter membranes. In this in vivo study microdialysate samples were collected from human trapezius muscle and forearm skin. The levels of arachidonoylethanolamide (AEA), 2-arachidonoylglycerol (2-AG), oleoylethanolamide (OEA), palmitoylethanolamide (PEA), and stearoylethanolamide (SEA) were analyzed in both microdialysate and in catheter membrane samples using liquid chromatography tandem mass spectrometry. OEA, PEA and SEA were identified in all microdialysate and catheter membrane samples from trapezius and skin. 2-AG was found in all catheter membrane samples from both tissues but not in the actual microdialysate. In conclusion sampling of OEA, PEA and SEA was achievable from trapezius and skin with the presented MD set-up. 2-AG is present in both trapezius muscle and skin tissue but adsorbs to the membranes in a higher extent than the NAEs. Furthermore, consideration of data conserved in the membrane during an MD experiment could be a relevant and more broadly applicable extension of MD sampling methodology which could fill an "information gap" and enhance an adequate interpretation of microdialysate data outcomes.

Background: Dopaminergic 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. Methods: Fifteen 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. Results: Dopamine in plasma differed significantly between patients with M-TMD (4.98 +/- 2.55 nM) and healthy controls (2.73 +/- 1.24 nM; P amp;lt; 0.01). No significant difference in plasma 5-HT was observed between the groups (P = 0.75). Patients reported significantly higher pain intensities (P amp;lt; 0.001) and had lower PPTs (P amp;lt; 0.01) compared with the healthy controls. Importantly, dopamine in plasma correlated significantly with present pain intensity (r = 0.53, n = 14, P amp;lt; 0.05) and perceived mental stress (r = 0.34, n = 28, P amp;lt; 0.05). Conclusions: The 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., Funding Agencies|Faculty of Odontology at Malmo University; Swedish Dental Society

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-alpha, 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 amp;lt;= 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., Funding Agencies|Swedish Research Council [K2015-99x-21874-05-4]; Swedish Council for Working Life and Social Research [2010-0913]; County Council of Ostergotland; AFA Insurance

Endocannabinoids and related N-acylethanolamines (NAEs) are lipid mediators involved in a number of physiological and pathological mechanisms in peripheral tissues. Microdialysis (MD) technique allows continues sampling of endogenous substances in the interstitial fluids of the tissues. The main limitation of MD sampling of lipophilic compounds is low recovery due to adsorption to the MD system and particularly to the catheter membranes. In this in vivo study microdialysate samples were collected from human trapezius muscle and forearm skin. The levels of arachidonoylethanolamide (AEA), 2-arachidonoylglycerol (2-AG), oleoylethanolamide (OEA), palmitoylethanolamide (PEA), and stearoylethanolamide (SEA) were analyzed in both microdialysate and in catheter membrane samples using liquid chromatography tandem mass spectrometry. OEA, PEA and SEA were identified in all microdialysate and catheter membrane samples from trapezius and skin. 2-AG was found in all catheter membrane samples from both tissues but not in the actual microdialysate. In conclusion sampling of OEA, PEA and SEA was achievable from trapezius and skin with the presented MD set-up. 2-AG is present in both trapezius muscle and skin tissue but adsorbs to the membranes in a higher extent than the NAEs. Furthermore, consideration of data conserved in the membrane during an MD experiment could be a relevant and more broadly applicable extension of MD sampling methodology which could fill an "information gap" and enhance an adequate interpretation of microdialysate data outcomes.

Background: Dopaminergic 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. Methods: Fifteen 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. Results: Dopamine in plasma differed significantly between patients with M-TMD (4.98 +/- 2.55 nM) and healthy controls (2.73 +/- 1.24 nM; P amp;lt; 0.01). No significant difference in plasma 5-HT was observed between the groups (P = 0.75). Patients reported significantly higher pain intensities (P amp;lt; 0.001) and had lower PPTs (P amp;lt; 0.01) compared with the healthy controls. Importantly, dopamine in plasma correlated significantly with present pain intensity (r = 0.53, n = 14, P amp;lt; 0.05) and perceived mental stress (r = 0.34, n = 28, P amp;lt; 0.05). Conclusions: The 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., Funding Agencies|Faculty of Odontology at Malmo University; Swedish Dental Society

Endocannabinoids and related N-acylethanolamines (NAEs) are lipid mediators involved in a number of physiological and pathological mechanisms in peripheral tissues. Microdialysis (MD) technique allows continues sampling of endogenous substances in the interstitial fluids of the tissues. The main limitation of MD sampling of lipophilic compounds is low recovery due to adsorption to the MD system and particularly to the catheter membranes. In this in vivo study microdialysate samples were collected from human trapezius muscle and forearm skin. The levels of arachidonoylethanolamide (AEA), 2-arachidonoylglycerol (2-AG), oleoylethanolamide (OEA), palmitoylethanolamide (PEA), and stearoylethanolamide (SEA) were analyzed in both microdialysate and in catheter membrane samples using liquid chromatography tandem mass spectrometry. OEA, PEA and SEA were identified in all microdialysate and catheter membrane samples from trapezius and skin. 2-AG was found in all catheter membrane samples from both tissues but not in the actual microdialysate. In conclusion sampling of OEA, PEA and SEA was achievable from trapezius and skin with the presented MD set-up. 2-AG is present in both trapezius muscle and skin tissue but adsorbs to the membranes in a higher extent than the NAEs. Furthermore, consideration of data conserved in the membrane during an MD experiment could be a relevant and more broadly applicable extension of MD sampling methodology which could fill an "information gap" and enhance an adequate interpretation of microdialysate data outcomes.

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-alpha, 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 amp;lt;= 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., Funding Agencies|Swedish Research Council [K2015-99x-21874-05-4]; Swedish Council for Working Life and Social Research [2010-0913]; County Council of Ostergotland; AFA Insurance

Background: Dopaminergic 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. Methods: Fifteen 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. Results: Dopamine in plasma differed significantly between patients with M-TMD (4.98 +/- 2.55 nM) and healthy controls (2.73 +/- 1.24 nM; P amp;lt; 0.01). No significant difference in plasma 5-HT was observed between the groups (P = 0.75). Patients reported significantly higher pain intensities (P amp;lt; 0.001) and had lower PPTs (P amp;lt; 0.01) compared with the healthy controls. Importantly, dopamine in plasma correlated significantly with present pain intensity (r = 0.53, n = 14, P amp;lt; 0.05) and perceived mental stress (r = 0.34, n = 28, P amp;lt; 0.05). Conclusions: The 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., Funding Agencies|Faculty of Odontology at Malmo University; Swedish Dental Society

Endocannabinoids and related N-acylethanolamines (NAEs) are lipid mediators involved in a number of physiological and pathological mechanisms in peripheral tissues. Microdialysis (MD) technique allows continues sampling of endogenous substances in the interstitial fluids of the tissues. The main limitation of MD sampling of lipophilic compounds is low recovery due to adsorption to the MD system and particularly to the catheter membranes. In this in vivo study microdialysate samples were collected from human trapezius muscle and forearm skin. The levels of arachidonoylethanolamide (AEA), 2-arachidonoylglycerol (2-AG), oleoylethanolamide (OEA), palmitoylethanolamide (PEA), and stearoylethanolamide (SEA) were analyzed in both microdialysate and in catheter membrane samples using liquid chromatography tandem mass spectrometry. OEA, PEA and SEA were identified in all microdialysate and catheter membrane samples from trapezius and skin. 2-AG was found in all catheter membrane samples from both tissues but not in the actual microdialysate. In conclusion sampling of OEA, PEA and SEA was achievable from trapezius and skin with the presented MD set-up. 2-AG is present in both trapezius muscle and skin tissue but adsorbs to the membranes in a higher extent than the NAEs. Furthermore, consideration of data conserved in the membrane during an MD experiment could be a relevant and more broadly applicable extension of MD sampling methodology which could fill an "information gap" and enhance an adequate interpretation of microdialysate data outcomes.

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-alpha, 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 amp;lt;= 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., Funding Agencies|Swedish Research Council [K2015-99x-21874-05-4]; Swedish Council for Working Life and Social Research [2010-0913]; County Council of Ostergotland; AFA Insurance

Background: Dopaminergic 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. Methods: Fifteen 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. Results: Dopamine in plasma differed significantly between patients with M-TMD (4.98 +/- 2.55 nM) and healthy controls (2.73 +/- 1.24 nM; P amp;lt; 0.01). No significant difference in plasma 5-HT was observed between the groups (P = 0.75). Patients reported significantly higher pain intensities (P amp;lt; 0.001) and had lower PPTs (P amp;lt; 0.01) compared with the healthy controls. Importantly, dopamine in plasma correlated significantly with present pain intensity (r = 0.53, n = 14, P amp;lt; 0.05) and perceived mental stress (r = 0.34, n = 28, P amp;lt; 0.05). Conclusions: The 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., Funding Agencies|Faculty of Odontology at Malmo University; Swedish Dental Society