Endocannabinoid and Cannabinoid-Like Fatty Acid Amide Levels Correlate with Pain-Related Symptoms in Patients with IBS-D and IBS-C: A Pilot Study

et al. (2013) Endocannabinoid and Cannabinoid-Like Fatty Acid Amide Levels Correlate with Pain-Related Symptoms in Patients with IBS-D and IBS-C: A Pilot Study. PLoS ONE 8(12): e85073. doi:10.1371/journal.pone.0085073 Endocannabinoid and Cannabinoid-Like Fatty Acid Amide Levels Correlate with Pain-Related Symptoms in Patients with IBS-D and IBS-C: A Pilot Study Jakub Fichna 0 JodiAnne T. Wood 0 Malvina Papanastasiou 0 Subramanian K. Vadivel 0 Piotr Oprocha 0 Maciej Saaga 0 Marta Sobczak 0 Anna Mokrowiecka 0 Adam I. Cygankiewicz 0 Piotr K. Zakrzewski 0 Ewa 0 Maecka-Panas 0 Wanda M. Krajewska 0 Piotr Kocielniak 0 Alexandros Makriyannis 0 Martin A. Storr 0 Michal Zmijewski, Medical University of Gdask, Poland 0 1 Snyder Institute for Chronic Diseases, University of Calgary , Calgary, Alberta , Canada , 2 Department of Medicine, Division of Gastroenterology, University of Calgary , Calgary, Alberta , Canada , 3 Department of Biomolecular Chemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland, 4 Department of Digestive Tract Diseases, Faculty of Medicine, Medical University of Lodz, Lodz, Poland, 5 Center for Drug Discovery, Northeastern University , Boston , Massachusetts, United States of America, 6 Faculty of Applied Mathematics, AGH University of Science and Technology , Cracow , Poland , 7 Department of Cytobiochemistry, Faculty of Biology and Environmental Protection, University of Lodz, Lodz, Poland, 8 Faculty of Mathematics and Computer Science, Jagiellonian University , Cracow , Poland , 9 Department of Medicine, Division of Gastroenterology, Ludwig Maximilians University of Munich , Munich , Germany Aims: Irritable bowel syndrome (IBS) is a functional gastrointestinal (GI) disorder, associated with alterations of bowel function, abdominal pain and other symptoms related to the GI tract. Recently the endogenous cannabinoid system (ECS) was shown to be involved in the physiological and pathophysiological control of the GI function. The aim of this pilot study was to investigate whether IBS defining symptoms correlate with changes in endocannabinoids or cannabinoid like fatty acid levels in IBS patients. Methods: AEA, 2-AG, OEA and PEA plasma levels were determined in diarrhoea-predominant (IBS-D) and constipation-predominant (IBS-C) patients and were compared to healthy subjects, following the establishment of correlations between biolipid contents and disease symptoms. FAAH mRNA levels were evaluated in colonic biopsies from IBS-D and IBS-C patients and matched controls. Results: Patients with IBS-D had higher levels of 2AG and lower levels of OEA and PEA. In contrast, patients with IBS-C had higher levels of OEA. Multivariate analysis found that lower PEA levels are associated with cramping abdominal pain. FAAH mRNA levels were lower in patients with IBS-C. Conclusion: IBS subtypes and their symptoms show distinct alterations of endocannabinoid and endocannabinoidlike fatty acid levels. These changes may partially result from reduced FAAH expression. The here reported changes support the notion that the ECS is involved in the pathophysiology of IBS and the development of IBS symptoms. - Funding: This work was supported by the University of Calgary Research Grant Committee (to MS), the Iuventus Plus program of the Polish Ministry of Science and Higher Education (0119/IP1/2011/71 and 0107/IP1/2013/72 to JF), and the Deutsche Forschungsgemeinschaft (STO 645/6-1 to MS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing interests: The authors have declared that no competing interests exist. Irritable bowel syndrome (IBS) is a functional gastrointestinal (GI) disorder, associated with alterations of bowel function and other symptoms related to the GI tract, such as abdominal pain or cramping (localized, intermittent pain), bloating or feeling of incomplete evacuation. The prevalence of IBS is estimated at up to 20% in the Western countries [1,2] and accounts for more than 50% of referrals to GI specialists [35]. IBS has a major impact on patients quality of life, and accounts for a heavy burden for, patients, health care providers and economies. Due to the lack of efficient treatments, there is an unmet need to develop novel anti-IBS strategies. The design of novel therapeutics to be used in IBS is impaired by our incomplete understanding of the pathophysiology of IBS and therefore the poor control of the changes in endogenous systems during IBS development. Therefore the systems that are well-known for their involvement in pain signalling and GI motility are currently regarded as being a main potential target for future anti-IBS drugs. The endogenous cannabinoid system (ECS), which consists of three principal pillars, i.e. classical cannabinoid (CB1, CB2) and non-classical (TRPV1, GPR55) receptors, endogenous ligands (anandamide, AEA; 2arachidonyloglycerol, 2-AG) and the cluster of enzymes, responsible for CB synthesis and degradation [6] has recently attracted much attention as a crucial site in IBS pathophysiology. The localization of CB1 and CB2 receptors and their endogenous ligands in the GI tract and in sensory endings on primary sensory afferents [711], as well as participation of the ECS in pain signalling, modulation of sensory afferent information and GI peristalsis (for review, see: [6,12]) have been well established. However, much attention has currently been given to the fatty acid amide hydrolase (FAAH) and its metabolites. FAAH is an intracellular enzyme, primarily located in the liver and the brain, as well as in peripheral organs, like the GI tract (for review, see: [13]). It is commonly accepted that AEA is the main substrate for FAAH, but a growing body of evidence points that 2-AG, although not exclusively, is also deactivated by this hydrolase [14]. FAAH is also involved in the degradation of several other biolipids, including palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), which may bind to both, classical and non-classical CB receptors. Therefore it has been suggested that the modulators of the FAAH activity, as potential anti-IBS therapeutics, may provide finer tuning of the ECS function than the CB receptor ligands, also in terms of peripheral vs. central site-dependent site effects. To further clarify whether the ECS is involved in IBS pathophysiology and whether changes in ECB or cannabinoidlike fatty acid amide levels contribute to clinical symptoms we established ECB and cannabinoid-like fatty acid amide levels in female patients with IBS. The levels where then correlated with IBS subtypes, namely IBS-D and IBS-C and, additionally, with the self-reported symptom scores and compared to agematched female control group. Finally, FAAH mRNA levels were evaluated in colonic biopsies from female IBS-D and IBSC patients and matched controls to investigate whether changes in FAAH expression at the transcription level contribut (...truncated)