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Endocannabinoids and N-acylethanolamines in translational pain research: from monoacylglycerol lipase to muscle pain
Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In the early nineties cannabinoid receptors, the main target for Δ9-tetrahydrocannabinol (THC), the psychoactive component of marijuana were identified. Shortly after their endogenous ligands, N-arachidonoylethanolamine (anandamide, AEA) and 2-diacylglycerol (2-AG) were characterized. The enzymes primarily responsible for catalysing the degradation of AEA and 2-AG are fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MGL) respectively. AEA is a member of the N-acylethanolamine (NAE) class of lipids, which depending on the acyl chain length and number of double bonds can act as ligands for a variety of biological targets. Exogenous cannabinoids have long been reported to have analgesic effects, however the clinical usefulness of such substances is limited by their psychoactive effects. Inhibition of endocannabinoid degradation would mean enhancing the therapeutic effects without producing these unwanted side effects. In order to succeed in developing such compounds the pharmacology of the enzymes responsible for the degradation of endocannabinoids has to be thoroughly understood. When the preclinical part of this thesis was planned, FAAH had been well characterized whereas little was known as to the pharmacology of MGL. A series of compounds were tested in this first study aiming to find MGL-selective compounds. Although no compounds showed selectivity for MGL over FAAH, several interesting agents affecting both enzymes were identified.

In order to increase the knowledge concerning which patient group would benefit from such treatment strategies it is important to investigate in which pain states the endocannabinoids/NAEs are altered. Thus the general aim of the clinical part of this thesis was to investigate the levels of endocannabinoids/NAEs in the interstitium of the trapezius muscle in women suffering from chronic neck/shoulder pain (CNSP) and chronic wide spread pain (CWP) and in healthy pain-free controls. Furthermore for the CNSP the effect of training, which is a commonly recommended treatment for these patients, on the levels of endocannabinoids/NAEs was also investigated. Microdialysis technique in the trapezius muscle was used for sampling and masspectrometry was used for analysing. Two NAEs,

N-palmitoylethanolamine (PEA) and N-stearoylethanolamine (SEA), could be repeatedly measured. The levels of these two lipids were significantly higher in CNSP compared to CON. The result showed also that PEA and SEA mobilize differently in CWP compared to both CNSP and CON. Taken together the results presented in thesis represent an early characterization of the pharmacology of MGL and provides novel information on NAEs in chronic muscle pain.

Place, publisher, year, edition, pages
Umeå: Umeå Universitet , 2013. , 81 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1558
Keyword [en]
Monoacylglycerol lipase, endocannabinoid, palmitoylethanolamide, N-acylethanolamines, microdialysis, chronic widespread pain, muscle pain, trapezius
National Category
Pharmacology and Toxicology
Identifiers
URN: urn:nbn:se:umu:diva-67115ISBN: 978-91-7459-567-3 (print)OAI: oai:DiVA.org:umu-67115DiVA: diva2:611005
Public defence
2013-04-05, Berzeliussalen, Campus US, Ingång 64, plan 9, Linköping, 13:00 (English)
Opponent
Supervisors
Available from: 2013-03-19 Created: 2013-03-12 Last updated: 2013-03-19Bibliographically approved
List of papers
1. Inhibition of monoacylglycerol lipase and fatty acid amide hydrolase by analogues of 2-arachidonoylglycerol
Open this publication in new window or tab >>Inhibition of monoacylglycerol lipase and fatty acid amide hydrolase by analogues of 2-arachidonoylglycerol
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2004 (English)In: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 143, no 6, 774-784 p.Article in journal (Refereed) Published
Keyword
Amidohydrolases/*antagonists & inhibitors/metabolism, Animals, Arachidonic Acids/chemistry/*pharmacology, CHO Cells, Cerebellum/drug effects/enzymology, Cricetinae, Dose-Response Relationship; Drug, Enzyme Inhibitors/chemistry/*pharmacology, Glycerides/chemistry/*pharmacology, Monoacylglycerol Lipases/*antagonists & inhibitors/metabolism, Pain Measurement/drug effects/methods, Rats, Rats; Sprague-Dawley, Receptor; Cannabinoid; CB1/metabolism
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:umu:diva-5786 (URN)10.1038/sj.bjp.0705948 (DOI)15492019 (PubMedID)
Available from: 2008-01-11 Created: 2008-01-11 Last updated: 2017-12-14Bibliographically approved
2. High levels of N-palmitoylethanolamide and N-stearoylethanolamide in microdialysate samples from myalgic trapezius muscle in women
Open this publication in new window or tab >>High levels of N-palmitoylethanolamide and N-stearoylethanolamide in microdialysate samples from myalgic trapezius muscle in women
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2011 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 11, e27257- p.Article in journal (Refereed) Published
Abstract [en]

Background: N-acylethanolamines (NAEs) are endogenous compounds that regulate inflammation and pain. These include the cannabinoid ligand anandamide (AEA) and the peroxisome proliferator-activated receptor-a ligand palmitoylethanolamide (PEA). Little is known as to the levels of NAEs in pain states in human, particularly in the skeletal muscle. The aim of this study was to investigate the levels of these lipid mediators in muscle dialysate from women with chronic neck-/shoulder pain compared to healthy controls.

Methods: Eleven women with chronic neck-/shoulder pain and eleven healthy women participated in this study. All participants went through microdialysis procedures in the trapezius muscle. Muscle dialysate samples were collected during four hours and analysed by nano liquid chromatography tandem mass spectrometry (nLC-MS/MS).

Results: We were able to detect AEA, PEA, N-stearoylethanolamine (SEA) and 2-arachidonoylglycerol (2-AG) in a single chromatographic run. Of the NAEs studied, PEA and SEA were clearly detectable in the muscle microdialysate samples. The muscle dialysate levels of PEA and SEA were significantly higher in myalgic subjects compared to healthy controls.

Conclusion: This study demonstrates that microdialysis in combination with mass spectrometry can be used for analysing NAE's in human muscle tissue regularly over time. Furthermore the significant group differences in the concentration of PEA and SEA in this study might fill an important gap in our knowledge of mechanisms in chronic myalgia in humans. In the long run this expanded understanding of nociceptive and anitinociceptive processes in the muscle may provide a base for ameliorating treatment and rehabilitation of pain.

Place, publisher, year, edition, pages
San Fransisco: Public Library of Science, 2011
Keyword
whiplash-associated disorders; activated-receptor-alpha; fatty-acid amide; pain; hyperalgesia; trpv1; work; acylethanolamine; quantification; fibromyalgia
National Category
Biological Sciences
Identifiers
urn:nbn:se:umu:diva-50943 (URN)10.1371/journal.pone.0027257 (DOI)000297789200009 ()
Available from: 2012-01-05 Created: 2012-01-02 Last updated: 2017-12-08Bibliographically approved
3. Palmitoylethanolamide and stearoylethanolamide levels in the interstitium of the trapezius muscle of women with chronic widespread pain and chronic neck-shoulder pain
Open this publication in new window or tab >>Palmitoylethanolamide and stearoylethanolamide levels in the interstitium of the trapezius muscle of women with chronic widespread pain and chronic neck-shoulder pain
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(English)Manuscript (preprint) (Other academic)
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:umu:diva-67131 (URN)
Available from: 2013-03-14 Created: 2013-03-14 Last updated: 2013-03-14Bibliographically approved
4. Effects of two different specific neck training programs on palmitoylethanolamide and stearoylethanolamide concentrations in the interstitium of the trapezius muscle in women with chronic neck-shoulder pain
Open this publication in new window or tab >>Effects of two different specific neck training programs on palmitoylethanolamide and stearoylethanolamide concentrations in the interstitium of the trapezius muscle in women with chronic neck-shoulder pain
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(English)Manuscript (preprint) (Other academic)
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:umu:diva-67132 (URN)
Available from: 2013-03-14 Created: 2013-03-14 Last updated: 2013-03-14Bibliographically approved

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