Chemistry:Anandamide

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Short description: Chemical compound (fatty acid neurotransmitter)
Anandamide
Anandamide skeletal.svg
Names
Preferred IUPAC name
(5Z,8Z,11Z,14Z)-N-(2-hydroxyethyl)icosa-5,8,11,14-tetraenamide
Other names
N-arachidonoylethanolamine
arachidonoylethanolamide
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
MeSH Anandamide
UNII
Properties
C22H37NO2
Molar mass 347.53 g/mol
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Infobox references

Anandamide (ANA), also known as N-arachidonoylethanolamine (AEA), an N-acylethanolamine (NAE), is a fatty acid neurotransmitter. Anandamide was the first endocannabinoid to be discovered: it participates in the body's endocannabinoid system by binding to cannabinoid receptors, the same receptors that the psychoactive compound THC in cannabis acts on. Anandamide is found in nearly all tissues in a wide range of animals.[1][2] Anandamide has also been found in plants, including small amounts in chocolate.[3] The name 'anandamide' is taken from the Sanskrit word ananda, which means "joy, bliss, delight", plus amide.[1][4]

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.[5] 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 therapeutic use.[6][7]

Anandamide is also being explored for its role in diabetic neuropathy/neuropathy, as cannabinoids as well as exogenous or endogenous anandamide, demonstrate broad-spectrum antinociceptive properties in a model of painful diabetic neuropathy, mediated through peripheral activation of both cannabinoid receptors, i.e. CB1 and CB2,[8][9] beside involvement of transient receptor vanilloid type-1 (TRPV1) channels in the pain modulation, as endovanilloid signalling modulates local pain,[10] as well as in reduction of inflammation associated with renal injury.[11]

Physiological functions

Anandamide's effects can occur in either the central or peripheral nervous system. These distinct effects are mediated primarily by CB1 cannabinoid receptors in the central nervous system, and CB2 cannabinoid receptors in the periphery.[12] The latter are mainly involved in functions of the immune system. Cannabinoid receptors were originally discovered as being sensitive to Δ9-tetrahydrocannabinol (Δ9-THC, commonly called THC), which is the primary psychoactive cannabinoid found in cannabis. The discovery of anandamide came from research into CB1 and CB2, as it was inevitable that a naturally occurring (endogenous) chemical would be found to affect these receptors.

Anandamide is also important for the implantation of the early stage embryo in its blastocyst form into the uterus. Therefore, cannabinoids such as Δ9-THC might influence processes during the earliest stages of human pregnancy.[13] Peak plasma anandamide occurs at ovulation and positively correlates with peak estradiol and gonadotrophin levels, suggesting that these may be involved in the regulation of anandamide levels.[14] Subsequently, anandamide has been proposed as a biomarker of infertility, but so far lacks any predictive values in order to be used clinically.[15]

The acute beneficial effects of exercise (termed as runner's high) seem to be mediated by anandamide in mice.[16] Anandamide is the precursor of a class of physiologically active substances, the prostamides.[17] Anandamide was found in 2007 to inhibit the proliferation of certain human breast cancer cell lines in vitro.[18]

Anandamide is found in chocolate together with two substances that might mimic the effects of anandamide, N-oleoylethanolamine and N-linoleoylethanolamine.[19]

Additionally, anandamide and other endocannabinoids are found in the model organism Drosophila melanogaster (fruit fly), although no CB receptors have been found in any insects.[20][21]

Effects on behavior

Both the CB1 and CB2 receptors (the bonding site of anandamide) seem to play a role in the identification of positive and negative interpretation of environment and setting.[22] In animal models, anandamide mediates the interpretation of stimulus; specifically, optimism and pessimism in the presence of an ambiguous cue.[23] Anandamide has been shown to impair working memory in rats,[24] while THC (the compound in cannabis that binds to the CB1 and CB2 receptors) also shows a deficit in working memory.[25]

This binding relationship of anandamide and the CB1/CB2 may affect neurotransmission of dopamine, serotonin, GABA, and glutamate.[26] There is currently encouraging, albeit embryonic, evidence for medicinal cannabis in the treatment of a range of psychiatric disorders. Supportive findings are emerging for some key isolates, however, clinicians need to be mindful of a range of prescriptive and occupational safety considerations, especially if initiating higher dose THC formulas.[27]

Anandamide injected directly into the forebrain reward-related brain structure nucleus accumbens enhances the pleasurable responses of rats to a rewarding sucrose taste, and enhances food intake as well.[28] Increasing anandamide seems to increase the intrinsic value of food, not necessarily by stimulation of appetite or hunger.[29]

Anandamide may affect hunger, sleep, pain modulation, working memory, identification of novelty, and interpretation of environment.[citation needed]

Synthesis and degradation

In humans, anandamide is biosynthesized from N-arachidonoyl phosphatidylethanolamine (NAPE). In turn NAPE arises by transfer of arachidonic acid from lecithin to the free amine of cephalin through an N-acyltransferase enzyme.[30][31] Anandamide synthesis from NAPE occurs via multiple pathways and includes enzymes such as phospholipase A2, phospholipase C and N-acetylphosphatidylethanolamine-hydrolysing phospholipase D (NAPE-PLD).[5]

The crystal structure of NAPE-PLD in complex with phosphatidylethanolamine and deoxycholate shows how the cannabinoid anandamide is generated from membrane N-acylphosphatidylethanolamines (NAPEs), and reveals that bile acids – which are mainly involved in the absorption of lipids in the small intestine – modulate its biogenesis.[32]

Endogenous anandamide is present at very low levels and has a very short half-life due to the action of the enzyme fatty acid amide hydrolase (FAAH), which breaks it down into free arachidonic acid and ethanolamine. Studies of piglets show that dietary levels of arachidonic acid and other essential fatty acids affect the levels of anandamide and other endocannabinoids in the brain.[33] High fat diet feeding in mice increases levels of anandamide in the liver and increases lipogenesis.[34] Anandamide may be relevant to the development of obesity, at least in rodents.

Paracetamol (called acetaminophen in the US and Canada) is metabolically combined with arachidonic acid by FAAH to form AM404.[35] This metabolite of paracetamol is a potent agonist at the TRPV1 vanilloid receptor, a weak agonist at both CB1 and CB2 receptors, and an inhibitor of anandamide reuptake. As a result, anandamide levels in the body and brain are elevated. In this fashion, paracetamol acts as a pro-drug for a cannabimimetic metabolite. This action may be partially or fully responsible for the analgesic effects of paracetamol.[36][37]

Endocannabinoid transporters for anandamide and 2-arachidonoylglycerol include the heat shock proteins (Hsp70s) and fatty acid binding proteins (FABPs).[38][39]

It is found that anandamide prefers cholesterol and ceramide more than other membrane lipids, and cholesterol can behave as a binding partner for it, and following an initial interaction mediated by the establishment of a hydrogen bond, the endocannabinoid is attracted towards the membrane interior, where it forms a molecular complex with cholesterol after a functional conformation adaptation to the apolar membrane milieu, and from there, the complex is further directed to the cannabinoid receptor (CB1) and out.[40]

Research and production

Black pepper contains the alkaloid guineesine, which is an anandamide reuptake inhibitor. It may therefore increase anandamide's physiological effects.[41]

Low-dose anandamide has an anxiolytic effect, while in one study, high doses injected directly into the cerebral fluid of the brain of mice shows evident cell apoptosis (programmed cell death) in vitro as opposed to necrosis.[42] That being said, another study conducted under similar conditions demonstrated neuronal growth both in vitro and in vivo.[43]

Endocannabinoids may disturb homeostasis in several ways: by enhancing hunger sensations, encouraging increased food intake, and shifting energy balance towards energy storage. A resultant decrease in energy expenditure is observed.[44]

Another study with rats found that reductions in AEA signaling through FAAH overexpression within the basolateral complex of amygdala (BLA) appeared to reliably reduce measurements of anxiety and overall levels of corticosterone, a primary glucocorticoid in animals like birds, rodents, reptiles and amphibians responsible for energy regulation, immune and stress responses. This is similar to the main glucocorticoid cortisol in humans. Reduction of AEA in the BLA has been shown to suppress fear behavior and promote fear extinction. This suggests possible involvement of AEA intervention in the future for the treatment of psychological disorders. However, further work in this area of study is needed, as reduced anandamide signaling is believed at this moment to involve CB1 receptors as well as GABAergic and glutamatergic interactions.[45]

Cortical glutamatergic transmission may be modulated by endocannabinoids during stress and fear habituation.[46] Glutamatergic interaction in the BLA believed to be responsible for changes in anxiety, appears to normalize stress-induced anxiety-like behavior. A study indicated that infusion of the GluK1 receptor agonist ATPA into the BLA enhanced GABAergic neurotransmission, which is currently believed to have a large role in the reduction of anxiety symptoms.[47]

Additionally, the ECs, along with AEA, have been highlighted for their potential involvement in obesity development and harmful effects on lipid and glucose metabolism, which may contribute to insulin resistance and deficiency, both of which are major risk factors for developing type 2 diabetes mellitus. Blockade of CB1 receptors was found significantly to improve lipid resistance and lipid profile in obese subjects, but also has potential to increase fat accumulation through increased food intake, favored lipogenesis and reduced energy expenditure. This may affect downstream systems like the pancreas, liver, adipose tissue, and skeletal muscle, with inflammation and apoptosis in the case of the pancreas. CB1R inhibition with peripherally restricted antagonists and inverse agonists may aid in the treatment of diabetic neuropathy and neuropathy. CB2R agonists may show promise for the treatment of inflammation, which contributes to renal injury.[48]

AEA was associated with nonalcoholic fatty liver disease, nonalcoholic steatohepatitis (NASH), and liver fibrosis. Data suggests AEA as a marker for cardiometabolic disease and NAFLD severity. NAFLD can progress to more severe diseases, like NASH, cirrhosis, and hepatocellular carcinoma.[49]

A Scottish woman with a rare mutation in her FAAH gene that resulted in elevated anandamide levels was reported to be immune to anxiety, unable to experience fear, and insensitive to pain. The frequent burns and cuts she suffered due to her hypoalgesia healed more rapidly than was expected.[50][51][52]

Topical Anandamide was found to reduce peripheral neuropathic pain by interaction with peripheral cannabinoid receptors.[53]

The American Academy of Dermatology has named topical Anandamide a promising therapy for cutaneous lupus erythematosus. [54][55]

See also

References

  1. ↑ 1.0 1.1 "Isolation and structure of a brain constituent that binds to the cannabinoid receptor". Science 258 (5090): 1946–1949. December 1992. doi:10.1126/science.1470919. PMID 1470919. Bibcode: 1992Sci...258.1946D. 
  2. ↑ "Discovery and characterization of endogenous cannabinoids". Life Sciences 65 (6–7): 573–595. 1999. doi:10.1016/S0024-3205(99)00281-7. PMID 10462059. 
  3. ↑ "Brain cannabinoids in chocolate". Nature 382 (6593): 677–678. August 1996. doi:10.1038/382677a0. PMID 8751435. Bibcode: 1996Natur.382..677D. https://escholarship.org/uc/item/2kk1604c. 
  4. ↑ Pertwee RG, ed (1995). "The unpaved road to the endogenous brain cannabinoid ligands, the anandamides". Cannabinoid receptors. Boston: Academic Press. pp. 233–258. ISBN 978-0-12-551460-6. 
  5. ↑ 5.0 5.1 "Biology of endocannabinoid synthesis system". Prostaglandins & Other Lipid Mediators 89 (3–4): 112–119. September 2009. doi:10.1016/j.prostaglandins.2008.12.002. PMID 19126434. 
  6. ↑ "The endocannabinoid system as a target for novel anxiolytic and antidepressant drugs". International Review of Neurobiology 85: 57–72. 2009. doi:10.1016/S0074-7742(09)85005-8. ISBN 9780123748935. PMID 19607961. 
  7. ↑ "Enhancement of endocannabinoid signaling by fatty acid amide hydrolase inhibition: a neuroprotective therapeutic modality". Life Sciences 86 (15–16): 615–623. April 2010. doi:10.1016/j.lfs.2009.06.003. PMID 19527737. 
  8. ↑ Schreiber, Anne K.; Neufeld, Manuele; Jesus, Carlos H. A.; Cunha, Joice M. (2012-12-01). "Peripheral antinociceptive effect of anandamide and drugs that affect the endocannabinoid system on the formalin test in normal and streptozotocin-diabetic rats" (in en). Neuropharmacology 63 (8): 1286–1297. doi:10.1016/j.neuropharm.2012.08.009. ISSN 0028-3908. PMID 22959964. https://www.sciencedirect.com/science/article/pii/S0028390812004455. 
  9. ↑ Ellington, Heather C; Cotter, Mary A; Cameron, Norman E; Ross, Ruth A (2002-06-01). "The effect of cannabinoids on capsaicin-evoked calcitonin gene-related peptide (CGRP) release from the isolated paw skin of diabetic and non-diabetic rats" (in en). Neuropharmacology 42 (7): 966–975. doi:10.1016/S0028-3908(02)00040-0. ISSN 0028-3908. PMID 12069907. https://www.sciencedirect.com/science/article/pii/S0028390802000400. 
  10. ↑ Silva, M.; Martins, D.; Charrua, A.; Piscitelli, F.; Tavares, I.; Morgado, C.; Di Marzo, V. (2016-08-01). "Endovanilloid control of pain modulation by the rostroventromedial medulla in an animal model of diabetic neuropathy" (in en). Neuropharmacology 107: 49–57. doi:10.1016/j.neuropharm.2016.03.007. ISSN 0028-3908. PMID 26965218. https://www.sciencedirect.com/science/article/pii/S002839081630079X. 
  11. ↑ Schreiber, Anne K.; Neufeld, Manuele; Jesus, Carlos H. A.; Cunha, Joice M. (2012-12-01). "Peripheral antinociceptive effect of anandamide and drugs that affect the endocannabinoid system on the formalin test in normal and streptozotocin-diabetic rats" (in en). Neuropharmacology 63 (8): 1286–1297. doi:10.1016/j.neuropharm.2012.08.009. ISSN 0028-3908. PMID 22959964. https://www.sciencedirect.com/science/article/pii/S0028390812004455. 
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  14. ↑ "The relationship between plasma levels of the endocannabinoid, anandamide, sex steroids, and gonadotrophins during the menstrual cycle". Fertility and Sterility 93 (6): 1989–1996. April 2010. doi:10.1016/j.fertnstert.2008.12.033. PMID 19200965. 
  15. ↑ "Endocannabinoids as biomarkers of human reproduction". Human Reproduction Update 20 (4): 501–516. 2014. doi:10.1093/humupd/dmu004. PMID 24516083. 
  16. ↑ "A runner's high depends on cannabinoid receptors in mice". Proceedings of the National Academy of Sciences of the United States of America 112 (42): 13105–13108. October 2015. doi:10.1073/pnas.1514996112. PMID 26438875. Bibcode: 2015PNAS..11213105F. 
  17. ↑ "Prostamides (prostaglandin-ethanolamides) and their pharmacology". British Journal of Pharmacology 153 (3): 410–419. February 2008. doi:10.1038/sj.bjp.0707434. PMID 17721551. 
  18. ↑ "The endogenous cannabinoid anandamide inhibits human breast cancer cell proliferation". Proceedings of the National Academy of Sciences of the United States of America 95 (14): 8375–8380. July 1998. doi:10.1073/pnas.95.14.8375. PMID 9653194. Bibcode: 1998PNAS...95.8375D. 
  19. ↑ "Brain cannabinoids in chocolate". Nature 382 (6593): 677–678. August 1996. doi:10.1038/382677a0. PMID 8751435. Bibcode: 1996Natur.382..677D. https://escholarship.org/uc/item/2kk1604c. 
  20. ↑ "Drosophila melanogaster as a model system to study long-chain fatty acid amide metabolism". FEBS Letters 588 (9): 1596–1602. May 2014. doi:10.1016/j.febslet.2014.02.051. PMID 24650760. 
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  30. ↑ "N-Acylation of ethanolamine phospholipids in canine myocardium". Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism 712 (2): 342–355. August 1982. doi:10.1016/0005-2760(82)90352-6. PMID 7126608. 
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  32. ↑ "Structure of human N-acylphosphatidylethanolamine-hydrolyzing phospholipase D: regulation of fatty acid ethanolamide biosynthesis by bile acids". Structure 23 (3): 598–604. March 2015. doi:10.1016/j.str.2014.12.018. PMID 25684574. 
  33. ↑ "Anandamide and diet: inclusion of dietary arachidonate and docosahexaenoate leads to increased brain levels of the corresponding N-acylethanolamines in piglets". Proceedings of the National Academy of Sciences of the United States of America 98 (11): 6402–6406. May 2001. doi:10.1073/pnas.101119098. PMID 11353819. Bibcode: 2001PNAS...98.6402B. 
  34. ↑ "Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity". The Journal of Clinical Investigation 115 (5): 1298–1305. May 2005. doi:10.1172/JCI23057. PMID 15864349. 
  35. ↑ "Conversion of acetaminophen to the bioactive N-acylphenolamine AM404 via fatty acid amide hydrolase-dependent arachidonic acid conjugation in the nervous system". The Journal of Biological Chemistry 280 (36): 31405–31412. September 2005. doi:10.1074/jbc.M501489200. PMID 15987694. 
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  37. ↑ "New analgesics synthetically derived from the paracetamol metabolite N-(4-hydroxyphenyl)-(5Z,8Z,11Z,14Z)-icosatetra-5,8,11,14-enamide". Journal of Medicinal Chemistry 51 (24): 7800–7805. December 2008. doi:10.1021/jm800807k. PMID 19053765. 
  38. ↑ "Identification of intracellular carriers for the endocannabinoid anandamide". Proceedings of the National Academy of Sciences of the United States of America 106 (15): 6375–6380. April 2009. doi:10.1073/pnas.0901515106. PMID 19307565. Bibcode: 2009PNAS..106.6375K. 
  39. ↑ "Molecular identification of albumin and Hsp70 as cytosolic anandamide-binding proteins". Chemistry & Biology 16 (6): 624–632. June 2009. doi:10.1016/j.chembiol.2009.05.004. PMID 19481477. 
  40. ↑ "Anandamide Revisited: How Cholesterol and Ceramides Control Receptor-Dependent and Receptor-Independent Signal Transmission Pathways of a Lipid Neurotransmitter". Biomolecules 8 (2): 31. May 2018. doi:10.3390/biom8020031. PMID 29789479. 
  41. ↑ "Guineensine is a novel inhibitor of endocannabinoid uptake showing cannabimimetic behavioral effects in BALB/c mice". Pharmacological Research 80: 52–65. February 2014. doi:10.1016/j.phrs.2013.12.010. PMID 24412246. 
  42. ↑ "The "dark side" of endocannabinoids: a neurotoxic role for anandamide". Journal of Cerebral Blood Flow and Metabolism 24 (5): 564–578. May 2004. doi:10.1097/00004647-200405000-00011. PMID 15129189. 
  43. ↑ "Neuroprotection by the endogenous cannabinoid anandamide and arvanil against in vivo excitotoxicity in the rat: role of vanilloid receptors and lipoxygenases". The Journal of Neuroscience 23 (10): 4127–4133. May 2003. doi:10.1523/JNEUROSCI.23-10-04127.2003. PMID 12764100. 
  44. ↑ Schulz, Piotr; Hryhorowicz, Szymon; Rychter, Anna Maria; Zawada, Agnieszka; Słomski, Ryszard; Dobrowolska, Agnieszka; Krela-Kaźmierczak, Iwona (2021-01-26). "What Role Does the Endocannabinoid System Play in the Pathogenesis of Obesity?" (in en). Nutrients 13 (2): 373. doi:10.3390/nu13020373. ISSN 2072-6643. PMID 33530406. 
  45. ↑ Morena, Maria; Aukema, Robert J.; Leitl, Kira D.; Rashid, Asim J.; Vecchiarelli, Haley A.; Josselyn, Sheena A.; Hill, Matthew N. (2019-02-13). "Upregulation of Anandamide Hydrolysis in the Basolateral Complex of Amygdala Reduces Fear Memory Expression and Indices of Stress and Anxiety" (in en). The Journal of Neuroscience 39 (7): 1275–1292. doi:10.1523/JNEUROSCI.2251-18.2018. ISSN 0270-6474. PMID 30573646. 
  46. ↑ Kamprath, K.; Plendl, W.; Marsicano, G.; Deussing, J. M.; Wurst, W.; Lutz, B.; Wotjak, C. T. (March 2009). "Endocannabinoids mediate acute fear adaptation via glutamatergic neurons independently of corticotropin-releasing hormone signaling" (in en). Genes, Brain and Behavior 8 (2): 203–211. doi:10.1111/j.1601-183X.2008.00463.x. PMID 19077175. 
  47. ↑ Masneuf, Sophie; Lowery-Gionta, Emily; Colacicco, Giovanni; Pleil, Kristen E.; Li, Chia; Crowley, Nicole; Flynn, Shaun; Holmes, Andrew et al. (October 2014). "Glutamatergic mechanisms associated with stress-induced amygdala excitability and anxiety-related behavior" (in en). Neuropharmacology 85: 190–197. doi:10.1016/j.neuropharm.2014.04.015. PMID 24796255. 
  48. ↑ Gruden, G; Barutta, F; Kunos, G; Pacher, P (April 2016). "Role of the endocannabinoid system in diabetes and diabetic complications: Role of endocannabinoid system in diabetes" (in en). British Journal of Pharmacology 173 (7): 1116–1127. doi:10.1111/bph.13226. PMID 26076890. 
  49. ↑ Kimberly, W. Taylor; O'Sullivan, John F.; Nath, Anjali K.; Keyes, Michelle; Shi, Xu; Larson, Martin G.; Yang, Qiong; Long, Michelle T. et al. (2017-05-04). "Metabolite profiling identifies anandamide as a biomarker of nonalcoholic steatohepatitis" (in en). JCI Insight 2 (9): e92989. doi:10.1172/jci.insight.92989. ISSN 2379-3708. PMID 28469090. PMC 5414569. https://insight.jci.org/articles/view/92989. 
  50. ↑ "Microdeletion in a FAAH pseudogene identified in a patient with high anandamide concentrations and pain insensitivity". British Journal of Anaesthesia 123 (2): e249–e253. August 2019. doi:10.1016/j.bja.2019.02.019. PMID 30929760. 
  51. ↑ "At 71, She's Never Felt Pain or Anxiety. Now Scientists Know Why.". The New York Times. 28 March 2019. https://www.nytimes.com/2019/03/28/health/woman-pain-anxiety.html. 
  52. ↑ "Scientists find genetic mutation that makes woman feel no pain". The Guardian. 28 March 2019. https://www.theguardian.com/science/2019/mar/28/scientists-find-genetic-mutation-that-makes-woman-feel-no-pain. 
  53. ↑ Police, Anitha; Shankar, Vijay Kumar; Pandey, Pankaj; Rangappa, Srinath; Doerksen, Robert J.; Narasimha Murthy, S. (2023). "Novel topical anandamide formulation for alleviating peripheral neuropathic pain". International Journal of Pharmaceutics 641: 123085. doi:10.1016/j.ijpharm.2023.123085. PMID 37245739. https://www.sciencedirect.com/science/article/abs/pii/S0378517323005057. 
  54. ↑ "AAD ePosters". https://eposters.aad.org/abstracts/43357. 
  55. ↑ "A New Treatment in a New Package for Cutaneous Lupus Erythematosus". 19 March 2023. https://www.managedhealthcareexecutive.com/view/a-new-treatment-in-a-new-package-for-cutaneous-lupus-erythematosus. 

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