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| Anandamide (ANA), also referred to as N-arachidonoylethanolamine (AEA) is a fatty acid neurotransmitter belonging to the fatty acid derivative group known as N-acylethanolamine (NAE). Anandamide takes its name from the Sanskrit word ananda (आनन्द), meaning "joy, bliss, delight," plus amide. Anandamide, the first discovered endocannabinoid, engages with the body's endocannabinoid system by binding to the same cannabinoid receptors that THC found in cannabis acts on. Anandamide can be found within tissues in a wide range of animals. It has also been found in plants, such as the cacao tree.
Anandamide is derived from the non-oxidative metabolism of arachidonic acid, an essential omega-6 fatty acid. It is synthesized from N-arachidonoyl phosphatidylethanolamine by multiple pathways. It is degraded primarily by the fatty acid amide hydrolase (FAAH) enzyme, which converts anandamide into ethanolamine and arachidonic acid. As such, inhibitors of FAAH lead to elevated anandamide levels and are being pursued for possible therapeutic use. |
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Read full article at Wikipedia
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InChI=1S/C22H37NO2/c1- 2-3-4-5-6-7-8-9-10-11-12-13-14-15-16-17-18-19-22(25)23-20-21-24/h6-7,9-10,12-13,15-16,24H,2-5,8,11,14,17-21H2,1H3,(H,23,25)/b7-6-,10-9-,13-12-,16-15- |
| LGEQQWMQCRIYKG-DOFZRALJSA-N |
| CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(=O)NCCO |
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Homo sapiens
(NCBI:txid9606)
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See:
DOI
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Homo sapiens
(NCBI:txid9606)
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Found in
blood
(UBERON:0000178).
See:
PubMed
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Homo sapiens
(NCBI:txid9606)
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Found in
cerebrospinal fluid
(UBERON:0001359).
See:
PubMed
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Bronsted base
A molecular entity capable of accepting a hydron from a donor (Bronsted acid).
(via organic amino compound )
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human blood serum metabolite
Any metabolite (endogenous or exogenous) found in human blood serum samples.
neurotransmitter
An endogenous compound that is used to transmit information across the synapse between a neuron and another cell.
metabolite
Any intermediate or product resulting from metabolism. The term 'metabolite' subsumes the classes commonly known as primary and secondary metabolites.
(via endocannabinoid )
cannabinoid receptor agonist
An agonist that binds to and activates cannabinoid receptors.
(via cannabinoid )
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vasodilator agent
A drug used to cause dilation of the blood vessels.
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View more via ChEBI Ontology
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Outgoing
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anandamide
(CHEBI:2700)
has functional parent
arachidonic acid
(CHEBI:15843)
anandamide
(CHEBI:2700)
has role
human blood serum metabolite
(CHEBI:85234)
anandamide
(CHEBI:2700)
has role
neurotransmitter
(CHEBI:25512)
anandamide
(CHEBI:2700)
has role
vasodilator agent
(CHEBI:35620)
anandamide
(CHEBI:2700)
is a
N-acylethanolamine 20:4
(CHEBI:134161)
anandamide
(CHEBI:2700)
is a
endocannabinoid
(CHEBI:67197)
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Incoming
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N-(20-hydroxyarachidonoyl)ethanolamine
(CHEBI:136992)
has functional parent
anandamide
(CHEBI:2700)
N-[(5Z,11Z,14Z)-8,9-epoxyicosatrienoyl]ethanolamine
(CHEBI:136989)
has functional parent
anandamide
(CHEBI:2700)
N-[(5Z,8Z,11Z)-14,15-epoxyicosatrienoyl]ethanolamine
(CHEBI:136991)
has functional parent
anandamide
(CHEBI:2700)
N-[(5Z,8Z,14Z)-11,12-epoxyicosatrienoyl]ethanolamine
(CHEBI:136990)
has functional parent
anandamide
(CHEBI:2700)
N-[(8Z,11Z,14Z)-5,6-epoxyicosatrienoyl]ethanolamine
(CHEBI:136988)
has functional parent
anandamide
(CHEBI:2700)
N-arachidonoylethanolamine phosphate(2−)
(CHEBI:131894)
has functional parent
anandamide
(CHEBI:2700)
O-oleoylanandamide
(CHEBI:76070)
has functional parent
anandamide
(CHEBI:2700)
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(5Z,8Z,11Z,14Z)-N-(2-hydroxyethyl)icosa-5,8,11,14-tetraenamide
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(5Z,8Z,11Z,14Z)-N-(2-hydroxyethyl)-5,8,11,14-eicosatetraenamide
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ChemIDplus
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(all-Z)-N-(2-hydroxyethyl)-5,8,11,14-eicosatetraenamide
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ChemIDplus
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AEA
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KEGG COMPOUND
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Anandamide
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KEGG COMPOUND
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Anandamide (20.4, N-6)
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HMDB
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Anandamide(20:4, N-6)
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HMDB
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Arachidonic acid N-(hydroxyethyl)amide
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HMDB
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arachidonoyl ethanolamide
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ChemIDplus
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Arachidonylethanolamide
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KEGG COMPOUND
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N-(2-Hydroxyethyl)anachidonamide
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HMDB
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N-(5Z,8Z,11Z,14Z-Eicosatetraenoyl)-ethanolamine
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HMDB
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N-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-ethanolamine
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UniProt
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N-(5Z,8Z,11Z,14Z-icosatetraenoyl)-ethanolamide
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KEGG COMPOUND
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N-arachidonoyl ethanolamine
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HMDB
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N-arachidonoyl-2-hydroxyethylamide
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ChemIDplus
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N-arachidonoylethanolamine
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ChEBI
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7079463
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Reaxys Registry Number
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Reaxys
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94421-68-8
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CAS Registry Number
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KEGG COMPOUND
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94421-68-8
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CAS Registry Number
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ChemIDplus
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Ramadan A, Khalaf AR, El Ray A, Saad Y (2021)
Serum anandamide level as a potential indicator for nonalcoholic fatty liver disease severity.
European journal of gastroenterology & hepatology 33, e363-e367 [PubMed:33731590]
[show Abstract]
Introduction and aimNonalcoholic fatty liver disease (NAFLD) is a very common disease, ranging from simple steatosis to nonalcoholic steatohepatitis (NASH) and is considered the hepatic expression of metabolic syndrome. Liver biopsy is currently considered the gold standard in diagnosis of NAFLD; however, it is an invasive technique and carries many risks. The serum anandamide level is recently discovered to play an important role as the potential indicator for NAFLD severity. The purpose of the study is to determine the association of endocannabinoid metabolite anandamide and NAFLD severity and to investigate its association with anthropometric and metabolic features in NAFLD patients.MethodologyA case-control study on 36 NAFLD biopsy-proven NAFLD patients and 15 healthy volunteers. They were subjected to full clinical history and examination, laboratory tests, abdominal ultrasound and serological testing of anadamide.ResultsThe anadamide level was significantly higher among NAFLD subgroups (simple steatosis and NASH) vs. the normal group (1.1, 0.29 vs. 0.2 P value = 0.00085), with cutoff 0.58 in the NASH group (accuracy 89%; sensitivity 66% and specificity 100%) (P value < 0.01).ConclusionAnandamide could be a specific serum marker for NASH and can be used to detect NAFLD severity. | Biringer RG (2021)
The rise and fall of anandamide: processes that control synthesis, degradation, and storage.
Molecular and cellular biochemistry 476, 2753-2775 [PubMed:33713246]
[show Abstract]
Anandamide is an endocannabinoid derived from arachidonic acid-containing membrane lipids and has numerous biological functions. Its effects are primarily mediated by the cannabinoid receptors CB1 and CB2, and the vanilloid TRPV1 receptor. Anandamide is known to be involved in sleeping and eating patterns as well as pleasure enhancement and pain relief. This manuscript provides a review of anandamide synthesis, degradation, and storage and hence the homeostasis of the anandamide signaling system. | Fonseca BM, Moreira-Pinto B, Costa L, Felgueira E, Oliveira P, Rebelo I (2021)
Concentrations of the endocannabinoid N-arachidonoylethanolamine in the follicular fluid of women with endometriosis: the role of M1 polarised macrophages.
Reproduction, fertility, and development 33, 270-278 [PubMed:33551019]
[show Abstract]
Although N-arachidonoylethanolamine (AEA; also known as anandamide) is present in human follicular fluid (FF), its regulation remains unknown. Therefore, the aims of the present study were to: (1) investigate the relationships between FF AEA concentrations in women undergoing assisted reproductive technology and their age, body mass index, ART characteristics and fertility treatment outcomes; and (2) assess how different inflammatory patterns may trigger AEA production by human granulosa cells (hGCs). FF AEA concentrations were higher in women undergoing IVF than in those undergoing intracytoplasmic sperm injection group. FF AEA median concentrations were lower in women undergoing ART because of male factor infertility than in women with endometriosis (1.6 vs 2.5nM respectively), but not women with tubal, hormonal or unexplained infertility (1.6, 2.4 and 1.9nM respectively). To evaluate the effects of macrophages on AEA production by hGCs, hGCs were cocultured with monocyte-derived macrophages. The conditioned medium from M1 polarised macrophages increased AEA production by hGCs. This was accompanied by an increase in AEA-metabolising enzymes, particularly N-acyl phosphatidylethanolamine-specific phospholipase D. The results of the present study show that high FF AEA concentrations in patients with endometriosis may be associated with the recruitment of inflammatory chemokines within the ovary, which together may contribute to the decreased reproductive potential of women with endometriosis. Collectively, these findings add a new player to the hormone and cytokine networks that regulate fertility in women. | Hanlon EC (2020)
Impact of circadian rhythmicity and sleep restriction on circulating endocannabinoid (eCB) N-arachidonoylethanolamine (anandamide).
Psychoneuroendocrinology 111, 104471 [PubMed:31610409]
[show Abstract]
ObjectiveThe endocannabinoid (eCB) system is involved in diverse aspects of human physiology and behavior but little is known about the impact of circadian rhythmicity on the system. The two most studied endocannabinoids, AEA (ananamide) and 2-AG (2-arachidonoylglycerol), can be measured in peripheral blood however the functional relevance of peripheral eCB levels is not clear. Having previously detailed the 24-h profile of serum 2-AG, here we report the 24-h serum profile of AEA to determine if these two endocannabinoids vary in parallel across the biological day including a nocturnal 8.5-h sleep period. Further, we assessed and compared the effect of a physiological challenge, in the form of sleep restriction to 4.5-h, on these two profiles.MethodsIn this randomized crossover study, we examined serum concentrations of AEA across a 24-h period in fourteen young adults. Congeners of AEA, the structural analogs oleoylethanolamide (OEA) and palmitoylethanolamide (PEA) were simultaneously assayed. Prior to 24-h blood sampling, each participant was exposed to two nights of normal (8.5 h) or restricted sleep (4.5 h). The two sleep conditions were separated by at least one month. In both sleep conditions, during the period of blood sampling, each individual ate the same high-carbohydrate meal at 0900, 1400, and 1900.ResultsMean 24-h concentrations of AEA were 0.697 ± 0.11 pmol/ml. A reproducible biphasic 24-h profile of AEA was observed with a first peak occurring during early sleep (0200) and a second peak in the mid-afternoon (1500) while a nadir was detected in the mid-morning (1000). The 24-h profiles for both OEA and PEA followed a similar pattern to that observed for AEA. AEA, OEA, and PEA levels were not affected by sleep restriction at any time of day, contrasting with the elevation of early afternoon levels previously observed for 2-AG.ConclusionsThe 24-h rhythm of AEA is markedly different from that of 2-AG, being of lesser amplitude and biphasic, rather than monophasic. These observations suggest distinct regulatory pathways of the two eCB and indicate that time of day needs to be carefully controlled in studies attempting to delineate their relative roles. Moreover, unlike 2-AG, AEA is not altered by sleep restriction, suggesting that physiological perturbations may affect AEA and 2-AG differently. Similar 24-h profiles were observed for OEA and PEA following normal and restricted sleep, further corroborating the validity of the wave-shape and lack of response to sleep loss observed for the AEA profile. Therapeutic approaches involving agonism or antagonism of peripheral eCB signaling will likely need to be tailored according to time of day. | Lee SA, Yang KJZ, Brun PJ, Silvaroli JA, Yuen JJ, Shmarakov I, Jiang H, Feranil JB, Li X, Lackey AI, Krężel W, Leibel RL, Libien J, Storch J, Golczak M, Blaner WS (2020)
Retinol-binding protein 2 (RBP2) binds monoacylglycerols and modulates gut endocrine signaling and body weight.
Science advances 6, eaay8937 [PubMed:32195347]
[show Abstract]
Expressed in the small intestine, retinol-binding protein 2 (RBP2) facilitates dietary retinoid absorption. Rbp2-deficient (Rbp2-/- ) mice fed a chow diet exhibit by 6-7 months-of-age higher body weights, impaired glucose metabolism, and greater hepatic triglyceride levels compared to controls. These phenotypes are also observed when young Rbp2-/- mice are fed a high fat diet. Retinoids do not account for the phenotypes. Rather, RBP2 is a previously unidentified monoacylglycerol (MAG)-binding protein, interacting with the endocannabinoid 2-arachidonoylglycerol (2-AG) and other MAGs with affinities comparable to retinol. X-ray crystallographic studies show that MAGs bind in the retinol binding pocket. When challenged with an oil gavage, Rbp2-/- mice show elevated mucosal levels of 2-MAGs. This is accompanied by significantly elevated blood levels of the gut hormone GIP (glucose-dependent insulinotropic polypeptide). Thus, RBP2, in addition to facilitating dietary retinoid absorption, modulates MAG metabolism and likely signaling, playing a heretofore unknown role in systemic energy balance. | Rand AA, Helmer PO, Inceoglu B, Hammock BD, Morisseau C (2018)
LC-MS/MS Analysis of the Epoxides and Diols Derived from the Endocannabinoid Arachidonoyl Ethanolamide.
Methods in molecular biology (Clifton, N.J.) 1730, 123-133 [PubMed:29363071]
[show Abstract]
Liquid chromatography-tandem mass spectrometry (LC-MS/MS) is a useful tool to characterize the behavior of natural lipids within biological matrices. We report a LC-MS/MS method developed specifically to analyze CYP products of the arachidonoyl ethanolamide (anandamide, AEA), the epoxyeicosatrienoic acid ethanolamides (EET-EAs) and their hydrolyzed metabolites, and the dihydroxyeicosatrienoic acid ethanolamides (DHET-EAs). This method was used to measure EET-EA biotransformation to DHET-EAs by two human epoxide hydrolases: the soluble EH (sEH) and the microsomal EH (mEH). In general, sEH and mEH substrate preference was similar, based on kcat/KM. The 14,15-EET-EA and 11,12-EET-EA were the most efficiently hydrolyzed, followed by 8,9-EET-EA and 5,6-EET-EA. The method was also used to detect endogenous levels of these lipids in mouse tissues, although levels were below the instrumental detection limit (0.1-3.4 nM). Because both AEA and EETs are biologically active, the method described herein will be invaluable in revealing the role(s) of EET-EAs in vivo. | Wingenfeld K, Dettenborn L, Kirschbaum C, Gao W, Otte C, Roepke S (2018)
Reduced levels of the endocannabinoid arachidonylethanolamide (AEA) in hair in patients with borderline personality disorder - a pilot study.
Stress (Amsterdam, Netherlands) 21, 366-369 [PubMed:29546791]
[show Abstract]
Endocannabinoids are involved in depressive and anxious symptoms and might play a role in stress-associated psychiatric disorders. While alterations in the endogenous cannabinoid system have been repeatedly found in patients with posttraumatic stress disorder (PTSD), this system has been mostly neglected in borderline personality disorder (BPD). However, there is first evidence for elevated serum levels of the endocannabinoids arachidonylethanolamide (AEA) and 2-arachidonyl-sn-glycerol (2-AG) in BPD patients compared to healthy controls and PTSD patients. In this study, hair endocannabinoids were analyzed, reflecting long-term endocannabinoid concentrations. We assessed AEA concentrations as well as 2-AG and the 2-AG main isomer 1-AG (1-AG/2-AG) in hair in women with BPD (n = 15) and age- and education-matched healthy women (n = 16). We found significantly reduced log AEA in BPD patients compared to healthy women (p = .03) but no differences in log 1-AG/2-AG concentrations. In addition, there was no association between 1-AG/2-AG and hair cortisol, but we found a non-significant correlation between hair concentrations of AEA and cortisol (p = .06). Our data indicate altered long-term release of endogenous cannabinoids in women with BPD depending on type of endocannabinoid. AEA has been suggested to modulate the basal activity of the endocannabinoid system and seems to attenuate depressive and anxious symptoms. Thus, chronically reduced AEA might contribute to psychiatric symptoms in BPD. | Clapper JR, Mangieri RA, Piomelli D (2009)
The endocannabinoid system as a target for the treatment of cannabis dependence.
Neuropharmacology 56 Suppl 1, 235-243 [PubMed:18691603]
[show Abstract]
The endocannabinoid system modulates neurotransmission at inhibitory and excitatory synapses in brain regions relevant to the regulation of pain, emotion, motivation, and cognition. This signaling system is engaged by the active component of cannabis, Delta9-tetrahydrocannabinol (Delta9-THC), which exerts its pharmacological effects by activation of G protein-coupled type-1 (CB1) and type-2 (CB2) cannabinoid receptors. During frequent cannabis use a series of poorly understood neuroplastic changes occur, which lead to the development of dependence. Abstinence in cannabinoid-dependent individuals elicits withdrawal symptoms that promote relapse into drug use, suggesting that pharmacological strategies aimed at alleviating cannabis withdrawal might prevent relapse and reduce dependence. Cannabinoid replacement therapy and CB1 receptor antagonism are two potential treatments for cannabis dependence that are currently under investigation. However, abuse liability and adverse side-effects may limit the scope of each of these approaches. A potential alternative stems from the recognition that (i) frequent cannabis use may cause an adaptive down-regulation of brain endocannabinoid signaling, and (ii) that genetic traits that favor hyperactivity of the endocannabinoid system in humans may decrease susceptibility to cannabis dependence. These findings suggest in turn that pharmacological agents that elevate brain levels of the endocannabinoid neurotransmitters, anandamide and 2-arachidonoylglycerol (2-AG), might alleviate cannabis withdrawal and dependence. One such agent, the fatty-acid amide hydrolase (FAAH) inhibitor URB597, selectively increases anandamide levels in the brain of rodents and primates. Preclinical studies show that URB597 produces analgesic, anxiolytic-like and antidepressant-like effects in rodents, which are not accompanied by overt signs of abuse liability. In this article, we review evidence suggesting that (i) cannabis influences brain endocannabinoid signaling and (ii) FAAH inhibitors such as URB597 might offer a possible therapeutic avenue for the treatment of cannabis withdrawal. | Di Pasquale E, Chahinian H, Sanchez P, Fantini J (2009)
The insertion and transport of anandamide in synthetic lipid membranes are both cholesterol-dependent.
PloS one 4, e4989 [PubMed:19330032]
[show Abstract]
BackgroundAnandamide is a lipid neurotransmitter which belongs to a class of molecules termed the endocannabinoids involved in multiple physiological functions. Anandamide is readily taken up into cells, but there is considerable controversy as to the nature of this transport process (passive diffusion through the lipid bilayer vs. involvement of putative proteic transporters). This issue is of major importance since anandamide transport through the plasma membrane is crucial for its biological activity and intracellular degradation. The aim of the present study was to evaluate the involvement of cholesterol in membrane uptake and transport of anandamide.Methodology/principal findingsMolecular modeling simulations suggested that anandamide can adopt a shape that is remarkably complementary to cholesterol. Physicochemical studies showed that in the nanomolar concentration range, anandamide strongly interacted with cholesterol monolayers at the air-water interface. The specificity of this interaction was assessed by: i) the lack of activity of structurally related unsaturated fatty acids (oleic acid and arachidonic acid at 50 nM) on cholesterol monolayers, and ii) the weak insertion of anandamide into phosphatidylcholine or sphingomyelin monolayers. In agreement with these data, the presence of cholesterol in reconstituted planar lipid bilayers triggered the stable insertion of anandamide detected as an increase in bilayer capacitance. Kinetics transport studies showed that pure phosphatidylcholine bilayers were weakly permeable to anandamide. The incorporation of cholesterol in phosphatidylcholine bilayers dose-dependently stimulated the translocation of anandamide.Conclusions/significanceOur results demonstrate that cholesterol stimulates both the insertion of anandamide into synthetic lipid monolayers and bilayers, and its transport across bilayer membranes. In this respect, we suggest that besides putative anandamide protein-transporters, cholesterol could be an important component of the anandamide transport machinery. Finally, this study provides a mechanistic explanation for the key regulatory activity played by membrane cholesterol in the responsiveness of cells to anandamide. | Simon GM, Cravatt BF (2008)
Anandamide biosynthesis catalyzed by the phosphodiesterase GDE1 and detection of glycerophospho-N-acyl ethanolamine precursors in mouse brain.
The Journal of biological chemistry 283, 9341-9349 [PubMed:18227059]
[show Abstract]
Anandamide (AEA) is an endogenous ligand of cannabinoid receptors and a well characterized mediator of many physiological processes including inflammation, pain, and appetite. The biosynthetic pathway(s) for anandamide and its N-acyl ethanolamine (NAE) congeners remain enigmatic. Previously, we proposed an enzymatic route for producing NAEs that involves the double-O-deacylation of N-acyl phosphatidylethanolamines (NAPEs) by alpha/beta-hydrolase 4 (ABDH4 or Abh4) to form glycerophospho (GP)-NAEs, followed by conversion of these intermediates to NAEs by an unidentified phosphodiesterase. Here, we report the detection and measurement of GP-NAEs, including the anandamide precursor glycerophospho-N-arachidonoylethanolamine (GP-NArE), as endogenous constituents of mouse brain tissue. Inhibition of the phosphodiesterase-mediated degradation of GP-NAEs ex vivo resulted in a striking accumulation of these lipids in brain extracts, suggesting a rapid endogenous flux through this pathway. Furthermore, we identify the glycerophosphodiesterase GDE1, also known as MIR16, as a broadly expressed membrane enzyme with robust GP-NAE phosphodiesterase activity. Together, these data provide evidence for a multistep pathway for the production of anandamide in the nervous system by the sequential actions of Abh4 and GDE1. | Sang N, Chen C (2006)
Lipid signaling and synaptic plasticity.
The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry 12, 425-434 [PubMed:16957004]
[show Abstract]
Lipids are essential components of plasma- and organelle-membranes, not only providing a frame for embedded proteins (e.g., receptors and ion channels) but also functioning as reservoirs for lipid mediators. Increasing evidence indicates that bioactive lipids such as eicosanoids, endocannabinoids, and lysophospholipids serve as intercellular and intracellular signaling molecules participating in physiological and pathological functions in the brain. The discovery of some of these lipid receptors and novel lipid signaling mediators has sparked an intense interest in lipidomic neurobiology research. Classic prostaglandins (PGD(2), PGE(2), PGF(2alpha), PGI(2), and TXA(2)), catalyzed by cyclooxygenases (COX), are synthesized from arachidonic acid (AA). Experimental studies demonstrate that prostaglandin E(2) (PGE(2)), mainly derived from the COX-2 reaction, is an important mediator, acting as a retrograde messenger via a presynaptic PGE(2) subtype 2 receptor (EP(2)) in modulation of synaptic events. Novel prostaglandins (prostaglandin glycerol esters and prostaglandin ethanolamides) are COX-2 oxidative metabolites of endogenous cannabinoids (2-arachidonyl glycerol and arachidonyl ethanolamide). Recent evidence suggests that these new types of prostaglandins are likely novel signaling mediators involved in synaptic transmission and plasticity. This means that COX- 2 plays a central role in metabolisms of AA and endocannabinoids (eCBs) and productions of AA- and eCB- derived prostaglandins. Thus, in the present review article, the authors will mainly discuss COX-2 regulation of prostaglandin signaling in modulation of hippocampal synaptic transmission and plasticity. | Movahed P, Evilevitch V, Andersson TL, Jönsson BA, Wollmer P, Zygmunt PM, Högestätt ED (2005)
Vascular effects of anandamide and N-acylvanillylamines in the human forearm and skin microcirculation.
British journal of pharmacology 146, 171-179 [PubMed:15997233]
[show Abstract]
The endocannabinoid anandamide is an emerging potential signalling molecule in the cardiovascular system. Anandamide causes vasodilatation, bradycardia and hypotension in animals and has been implicated in the pathophysiology of endotoxic, haemorrhagic and cardiogenic shock, but its vascular effects have not been studied in man. Human forearm blood flow and skin microcirculatory flow were recorded using venous occlusion plethysmography and laser-Doppler perfusion imaging (LDPI), respectively. Each test drug was infused into the brachial artery or applied topically on the skin followed by a standardized pin-prick to disrupt the epidermal barrier. Anandamide failed to affect forearm blood flow when administered intra-arterially at infusion rates of 0.3-300 nmol min(-1). The highest infusion rate led to an anandamide concentration of approximately 1 microM in venous blood as measured by mass spectrometry. Dermal application of anandamide significantly increased skin microcirculatory flow and coapplication of the transient receptor potential vanilloid 1 (TRPV1) antagonist capsazepine inhibited this effect. The TRPV1 agonists capsaicin, olvanil and arvanil all induced concentration-dependent increases in skin blood flow and burning pain when administered dermally. Coapplication of capsazepine inhibited blood flow and pain responses to all three TRPV1 agonists. This study shows that locally applied anandamide is a vasodilator in the human skin microcirculation. The results are consistent with this lipid being an activator of TRPV1 on primary sensory nerves, but do not support a role for anandamide as a circulating vasoactive hormone in the human forearm vascular bed. | Chen P, Hu S, Yao J, Moore SA, Spector AA, Fang X (2005)
Induction of cyclooxygenase-2 by anandamide in cerebral microvascular endothelium.
Microvascular research 69, 28-35 [PubMed:15797258]
[show Abstract]
Anandamide (AEA), an endogenous cannabinoid receptor agonist, is a potent vasodilator in the cerebral microcirculation. AEA is converted to arachidonic acid (AA) by fatty acid amidohydrolase (FAAH), and the conversion of AA to prostaglandins has been proposed as a potential mechanism for the vasodilation. Although AEA stimulated prostaglandin production by mouse cerebral microvascular endothelial cells, no [(3)H]prostaglandins were produced when these cells were incubated with [3H]AEA. Incubation with R(+)-methanandamide (MAEA), a stable analogue of AEA that is not a substrate for FAAH, produced a similar increase in PGE2 production as AEA. The PGE2 production induced by either AEA or MAEA was completely inhibited by NS-398, a selective cyclooxygenase (COX)-2 inhibitor, suggesting that COX-2 was induced. AEA and MAEA increased the expression of COX-2 protein in a time-dependent manner. This increase occurred as early as 1 h and reached maximum at 2 h. Induction of COX-2 protein by AEA was partially inhibited by AM-251, a selective cannabinoid receptor-1 antagonist. Furthermore, AEA increased COX-2 promoter activity approximately twofold above baseline in a fragment ranging from -1432 to +59, the full-length of the COX-2 promoter, and the increase in COX-2 promoter activity produced by AEA was partially inhibited by AM-251. These results indicate that AEA increased COX-2 expression at the transcriptional level through, at least in part, a cannabinoid receptor-1-mediated mechanism in cerebral microvascular endothelium. | Justinova Z, Solinas M, Tanda G, Redhi GH, Goldberg SR (2005)
The endogenous cannabinoid anandamide and its synthetic analog R(+)-methanandamide are intravenously self-administered by squirrel monkeys.
The Journal of neuroscience : the official journal of the Society for Neuroscience 25, 5645-5650 [PubMed:15944392]
[show Abstract]
Anandamide, an endogenous ligand for brain cannabinoid CB(1) receptors, produces many behavioral effects similar to those of Delta(9)-tetrahydrocannabinol (THC), the main psychoactive ingredient in marijuana. Reinforcing effects of THC have been demonstrated in experimental animals, but there is only indirect evidence that endogenous cannabinoids such as anandamide participate in brain reward processes. We now show that anandamide serves as an effective reinforcer of drug-taking behavior when self-administered intravenously by squirrel monkeys. We also show that methanandamide, a synthetic long-lasting anandamide analog, similarly serves as a reinforcer of drug-taking behavior. Finally, we show that the reinforcing effects of both anandamide and methanandamide are blocked by pretreatment with the cannabinoid CB(1) receptor antagonist rimonabant (SR141716). These findings strongly suggest that release of endogenous cannabinoids is involved in brain reward processes and that activation of cannabinoid CB(1) receptors by anandamide could be part of the signaling of natural rewarding events. | McPartland JM, Giuffrida A, King J, Skinner E, Scotter J, Musty RE (2005)
Cannabimimetic effects of osteopathic manipulative treatment.
The Journal of the American Osteopathic Association 105, 283-291 [PubMed:16118355]
[show Abstract]
Endogenous cannabinoids activate cannabinoid receptors in the brain and elicit mood-altering effects. Parallel effects (eg, anxiolysis, analgesia, sedation) may be elicited by osteopathic manipulative treatment (OMT), and previous research has shown that the endorphin system is not responsible for OMT's mood-altering effects. The authors investigate whether OMT generated cannabimimetic effects for 31 healthy subjects in a dual-blind, randomized controlled trial that measured changes in subjects' scores on the 67-item Drug Reaction Scale (DRS). Chemical ionization gas chromatography and mass spectrometry were also used to determine changes in serum levels of anandamide (AEA), 2-arachidonoylglycerol (2-AG), and oleylethanolamide (OEA). In subjects receiving OMT, posttreatment DRS scores increased significantly for the cannabimimetic descriptors good, high, hungry, light-headed, and stoned, with significant score decreases for the descriptors inhibited, sober, and uncomfortable. Mean posttreatment AEA levels (8.01 pmol/mL) increased 168% over pretreatment levels (2.99 pmol/mL), mean OEA levels decreased 27%, and no changes occurred in 2-AG levels in the group receiving OMT. Subjects in the sham manipulative treatment group recorded mixed DRS responses, with both increases and decreases in scores for cannabimimetic and noncannabimimetic descriptors and no changes in sera levels. When changes in serum AEA were correlated with changes in subjects' DRS scores, increased AEA correlated best with an increase for the descriptors cold and rational, and decreased sensations for the descriptors bad, paranoid, and warm. The authors propose that healing modalities popularly associated with changes in the endorphin system, such as OMT, may actually be mediated by the endocannabinoid system. | Contassot E, Tenan M, Schnüriger V, Pelte MF, Dietrich PY (2004)
Arachidonyl ethanolamide induces apoptosis of uterine cervix cancer cells via aberrantly expressed vanilloid receptor-1.
Gynecologic oncology 93, 182-188 [PubMed:15047233]
[show Abstract]
ObjectivesDelta(9)-Tetrahydrocannabinol, the active agent of Cannabis sativa, exhibits well-documented antitumor properties, but little is known about the possible effects mediated by endogenous cannabinoids on human tumors. In the present study, we analyzed the effect of arachidonyl ethanolamide (AEA) on cervical carcinoma (CxCa) cell lines.MethodsTo assess the sensitivity of CxCa cells to AEA, we selected three cell lines that were exposed to increasing doses of AEA with or without antagonists to receptors to AEA. DNA fragmentation and caspase-7 activity were used as apoptosis markers. The expression of receptors to AEA were analyzed in CxCa cell lines as well as CxCa biopsies.ResultsThe major finding was that AEA induced apoptosis of CxCa cell lines via aberrantly expressed vanilloid receptor-1, whereas AEA binding to the classical CB1 and CB2 cannabinoid receptors mediated a protective effect. Furthermore, unexpectedly, a strong expression of the three forms of AEA receptors was observed in ex vivo CxCa biopsies.ConclusionsOverall, these data suggest that the specific targeting of VR1 by endogenous cannabinoids or synthetic molecules offers attractive opportunities for the development of novel potent anticancer drugs. |
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