Pain and beyond: fatty acid amides and fatty acid amide hydrolase inhibitors in cardiovascular and metabolic diseases

Pillarisetti, Sivaram; Alexander, Christopher; Khanna, Ish

doi:10.1016/j.drudis.2009.08.002

Cited by 25 publications

(11 citation statements)

References 162 publications

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“…Acyl-amides and mono-acyl glycerols are also common components of blood with an equally broad spectrum of actions [70]. These functionalized lipids play important roles in regulating cell proliferation, apoptosis, tissue repair, blood clotting, blood vessel permeability, inflammation, pain perception, pancreatic function, and energy regulation at various levels [71], [72], [73], [74], [75].…”

Section: Resultsmentioning

confidence: 99%

The Human Serum Metabolome

et al. 2011

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Continuing improvements in analytical technology along with an increased interest in performing comprehensive, quantitative metabolic profiling, is leading to increased interest pressures within the metabolomics community to develop centralized metabolite reference resources for certain clinically important biofluids, such as cerebrospinal fluid, urine and blood. As part of an ongoing effort to systematically characterize the human metabolome through the Human Metabolome Project, we have undertaken the task of characterizing the human serum metabolome. In doing so, we have combined targeted and non-targeted NMR, GC-MS and LC-MS methods with computer-aided literature mining to identify and quantify a comprehensive, if not absolutely complete, set of metabolites commonly detected and quantified (with today's technology) in the human serum metabolome. Our use of multiple metabolomics platforms and technologies allowed us to substantially enhance the level of metabolome coverage while critically assessing the relative strengths and weaknesses of these platforms or technologies. Tables containing the complete set of 4229 confirmed and highly probable human serum compounds, their concentrations, related literature references and links to their known disease associations are freely available at http://www.serummetabolome.ca.

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Section: Resultsmentioning

confidence: 99%

The Human Serum Metabolome

et al. 2011

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“…Therefore, in future pharmacological studies, it is recommended to pay particular attention to their pharmacokinetic properties. In addition to their administration as single compounds, combinations with FAAH inhibitors (Pillarisetti et al, 2009) and (or) their fatty acid precursors could be of interest to further increase (local) concentrations.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

N‐acyl amines of docosahexaenoic acid and other n–3 polyunsatured fatty acids – from fishy endocannabinoids to potential leads

Meijerink

Balvers

Witkamp

2013

British J Pharmacology

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N–3 long‐chain polyunsaturated fatty acids (n–3 LC‐PUFAs), in particular α‐linolenic acid (18:3n‐3), eicosapentaenoic acid (EPA; 20:5n‐3) and docosahexaenoic acid (DHA; 22:6n‐3) are receiving much attention because of their presumed beneficial health effects. To explain these, a variety of mechanisms have been proposed, but their interactions with the endocannabinoid system have received relatively little attention so far. However, it has already been shown some time ago that consumption of n–3 LC‐PUFAs not only affects the synthesis of prototypic endocannabinoids like anandamide but also stimulates the formation of specific n–3 LC‐PUFA‐derived conjugates with ethanolamine, dopamine, serotonin or other amines. Some of these fatty amides show overlapping biological activities with those of typical endocannabinoids, whereas others possess distinct and sometimes largely unknown receptor affinities and other properties. The ethanolamine and dopamine conjugates of DHA have been the most investigated thus far. These mediators may provide promising new leads to the field of inflammatory and neurological disorders and for other pharmacological applications, including their use as carrier molecules for neurotransmitters to target the brain. Furthermore, combinations of n–3 LC‐PUFA‐derived fatty acid amides, their precursors and FAAH inhibitors offer possibilities to optimise their effects in health and disease. Linked Articles This article is part of a themed section on Cannabinoids. To view the other articles in this section visit &

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“…Peripheral CB1 receptors may modulate pain sensation and transmission [2, 3]. Ongoing studies are evaluating endocannabinoid‐modulating drugs for the treatment of pain syndromes [4, 5]. Moreover, endocannabinoids may be affected by anaesthesia.…”

Section: Introductionmentioning

confidence: 99%

Changes of blood endocannabinoids during anaesthesia: a special case for fatty acid amide hydrolase inhibition by propofol?

Jarzimski¹,

Karst²,

Zoerner³

et al. 2012

Brit J Clinical Pharma

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Available data from animal studies suggest that the narcotic drug propofol interacts with the endocannabinoid system. Inhibition of enzymatic degradation of anandamide could explain some of the characteristics of propofol. Direct measurements have not been reported yet in humans. WHAT THIS STUDY ADDS• Propofol does not change the time course of anandamide plasma concentrations during anaesthesia. Furthermore, propofol does not inhibit fatty acid amide hydrolase activity ex vivo or in vitro. Thus, specific characteristics of the narcotic drug propofol cannot be explained by peripheral inhibition of anandamide degradation in humans. AIMSThe aim of our study was to describe the time course of endocannabinoids during different anaesthesia protocols in more detail, and to challenge the hypothesis that propofol acts as a FAAH inhibitor. METHODSEndocannabinoids were measured during the first hour of anaesthesia in 14 women and 14 men undergoing general anaesthesia with propofol and in 14 women and 14 men receiving thiopental/sevoflurane. We also incubated whole human blood samples ex vivo with propofol and the known FAAH inhibitor oloxa and determined FAAH enzyme kinetics. RESULTSPlasma anandamide decreased similarly with propofol and thiopental/sevoflurane anaesthesia, and reached a nadir after 10 min. Areas under the curve for anandamide (mean and 95% CI) were 53.3 (47.4, 59.2) nmol l -1 60 min with propofol and 48.5 (43.1, 53.8) nmol l -1 60 min with thiopental/sevoflurane (P = NS). Anandamide and propofol plasma concentrations were not correlated at any time point. Ex vivo FAAH activity was not inhibited by propofol. Enzyme kinetics (mean Ϯ SD) of recombinant human FAAH were Km = 16.9 Ϯ 8.8 mmol l -1 and Vmax = 44.6 Ϯ 15.8 nmol mg -1 min -1 FAAH without, and Km = 16.6 Ϯ 4.0 mmol l -1 and Vmax = 44.0 Ϯ 7.6 nmol mg -1 min -1 FAAH with 50 mmol l -1 propofol (P = NS for both). CONCLUSIONSOur findings challenge the idea that propofol anaesthesia and also propofol addiction are directly mediated by FAAH inhibition, but we cannot exclude other indirect actions on cannabinoid receptors.

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Pain and beyond: fatty acid amides and fatty acid amide hydrolase inhibitors in cardiovascular and metabolic diseases

Cited by 25 publications

References 162 publications

The Human Serum Metabolome

The Human Serum Metabolome

N‐acyl amines of docosahexaenoic acid and other n–3 polyunsatured fatty acids – from fishy endocannabinoids to potential leads

Changes of blood endocannabinoids during anaesthesia: a special case for fatty acid amide hydrolase inhibition by propofol?

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