Department of pharmacology and Clinical Neuroscience
Umeå University Umeå 2013
Umeå University Medical Dissertations, New Series No 1558
Endocannabinoids and N-acylethanolamines in
translational pain research: from monoacylglycerol lipase to muscle pain
Nazdar Ghafouri
Akademisk avhandling
som med vederbörligt tillstånd av Rektor vid Umeå universitet för avläggande av medicine doktorsexamen framläggs till offentligt försvar i Berzeliussalen, Campus US, Ingång 64, plan 9, Linköping
Fredagen den 5e april, kl. 13:00
Avhandlingen kommer att försvaras på engelska
Fakultetsopponent: Professor Andrew S.C. Rice, Pain Medicine and
Intensive Care, Department of Surgery and Cancer, Imperial College
London, UK
Organization Document type Date of publication
Umeå University Doctoral thesis 14-03-2013
Department of pharmacology and Clinical Neuroscience
Author
Nazdar Ghafouri Title
Endocannabinoids and N-acylethanolamines in translational pain research: from monoacylglycerol lipase to muscle pain
Abstract
In the early nineties cannabinoid receptors, the main target for ∆9-tetrahydrocannabinol (THC), the psychoactive component of marijuana were identified. Shortly after their endogenous ligands, N-arachidonoylethanolamine (anandamide, AEA) and 2-diacyl- glycerol (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-Acyl- ethanolamine (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.
Keywords: Monoacylglycerol lipase, endocannabinoid, palmitoylethanolamide, N- acylethanolamines, microdialysis, chronic widespread pain, muscle pain, trapezius
Language ISBN ISSN Number of pages
English 978-91-7459-567-3 0346-6612 81 + 4 papers
