View source for Anandamide

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{{chembox
| ImageFile = Anandamide_skeletal.svg
| ImageSize = 200px
| IUPACName = (5''Z'',8''Z'',11''Z'',14''Z'')-''N''-(2-hydroxyethyl)icosa-5,8,11,14-tetraenamide
| OtherNames = ''N''-arachidonoylethanolamine<!-- amine is actually correct here, despite pubchem (see talk page) --><br>arachidonoylethanolamide
| Section1 = {{Chembox Identifiers
|   ChemSpiderID = 4445241
| InChI = 1/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-
| InChIKey = LGEQQWMQCRIYKG-DOFZRALJBA
| CASNo = 94421-68-8
|   PubChem = 5281969
| IUPHAR_ligand = 2364
| IUPHAR_ligand = 737
|   SMILES = O=C(NCCO)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC
|   MeSHName = Anandamide
  }}
| Section2 = {{Chembox Properties
|   Formula = C<sub>22</sub>H<sub>37</sub>NO<sub>2</sub>
|   MolarMass = 347.53 g/mol
|   Appearance = 
|   Density = 
|   MeltingPt = 
|   BoilingPt = 
  }}
| Section3 = {{Chembox Hazards
|   Solubility = 
|   MainHazards = 
|   FlashPt = 
|   Autoignition = 
  }}
}}

'''Anandamide''', also known as '''''N''-arachidonoylethanolamine'''  or '''AEA''', is an endogenous [[cannabinoids|cannabinoid]] [[neurotransmitter]] found in animal and human organs, especially in the [[brain]]. It was isolated and its structure was first described by [[Czechs|Czech]] analytical chemist Lumír Ondřej Hanuš and American molecular pharmacologist William Anthony Devane  in the Laboratory of [[Raphael Mechoulam]], at the [[Hebrew University]] in [[Jerusalem]], [[Israel]] in 1992. The name is taken from the [[Sanskrit]] word ''[[ananda]]'', which means "[[Bliss (spirituality)|bliss]], [[delight]]",  and [[amide]].<ref name="pmid1470919">{{cite journal | author = Devane WA, Hanus L, Breuer A, Pertwee RG, Stevenson LA, Griffin G, Gibson D, Mandelbaum A, Etinger A, Mechoulam R | title = Isolation and structure of a brain constituent that binds to the cannabinoid receptor | journal = Science | volume = 258 | issue = 5090 | pages = 1946–9 | year = 1992 | month = December | pmid = 1470919 | doi = 10.1126/science.1470919| url = | issn = }}</ref><ref name="isbn0-12-551460-3">{{cite book | author =  Mechoulam R, Fride E | authorlink = | editor = Pertwee RG | others = | title = Cannabinoid receptors | edition = | language = | publisher = Academic Press | location = Boston | year = 1995 | origyear = | pages = 233–258 | chapter =   The unpaved road to the endogenous brain cannabinoid ligands, the anandamides | quote = | isbn = 0-12-551460-3 | oclc = | doi = | url = | accessdate = }}</ref> It is synthesized from N-arachidonoyl phosphatidylethanolamine by multiple pathways.<ref name=wang2009>{{cite doi|10.1016/j.prostaglandins.2008.12.002}}</ref> 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.<ref>{{cite doi|10.1016/S0074-7742(09)85005-8}}</ref><ref>{{cite doi|10.1016/j.lfs.2009.06.003}}</ref> 

== Physiological functions ==

Anandamide's effects can be either central, in the brain, or peripheral, in other parts of the body. These distinct effects are mediated primarily by CB1 [[cannabinoid receptor]]s in the central nervous system, and CB2 cannabinoid receptors in the periphery. The latter are mainly involved in functions of the [[immune system]]. Cannabinoid receptors were originally discovered as being sensitive to Δ<sup>9</sup>-[[tetrahydrocannabinol]] (Δ<sup>9</sup>-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.

Moreover, anandamide is thought to be an [[endogenous]] [[ligand (biochemistry)|ligand]] for [[vanilloid receptors]] (which are involved in the transduction of acute and inflammatory pain signals), activating the receptor in a PKC-dependent (protein kinase C-dependent) manner.{{Fact|date=January 2009}}

Anandamide has been shown to be involved in working memory.<ref>{{cite journal | author = allet PE, Beninger RJ| title = The endogenous cannabinoid receptor agonist anandamide impairs memory in rats | url = http://www.behaviouralpharm.com/pt/re/bpharm/abstract.00008877-199605000-00008.htm | year = 1996 | journal = Behavioural Pharmacology | pages = 276–284 | volume = 7 | issue = 3 }}</ref> Studies are under way to explore what role anandamide plays in human behavior, such as eating and sleep patterns, and pain relief.

Anandamide is also important for implantation of the early stage [[embryo]] in its [[blastocyst]] form into the [[uterus]]. Therefore cannabinoids such as Δ<sup>9</sup>-THC might interfere with the earliest stages of human pregnancy.<ref name="pmid14702623">{{cite journal | author = Piomelli D | title = THC: moderation during implantation | journal = Nat. Med. | volume = 10 | issue = 1 | pages = 19–20 | year = 2004 | month = January | pmid = 14702623 | doi = 10.1038/nm0104-19 | url = | issn = }}</ref> 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 AEA levels.<ref>{{cite journal |author=El-Talatini MR, Taylor AH, Konje JC |title=The relationship between plasma levels of the endocannabinoid, anandamide, sex steroids, and gonadotrophins during the menstrual cycle |journal=Fertil. Steril. |volume=93 |issue=6 |pages=1989–96 |year=2010 |month=April |pmid=19200965 |doi=10.1016/j.fertnstert.2008.12.033 |url=}}</ref>

Anandamide also is important in the regulation of feeding behavior, and the neural generation of motivation and pleasure.  Both anandamide and [[exogenous]] [[cannabinoids]] like [[THC]] enhance the drive for food intake in animals and humans, an effect that is commonly known as "the munchies".  In addition, 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.<ref name="pmid17406653">{{cite journal | author = Mahler SV, Smith KS, Berridge KC | title = Endocannabinoid hedonic hotspot for sensory pleasure: anandamide in nucleus accumbens shell enhances 'liking' of a sweet reward | journal = Neuropsychopharmacology | volume = 32 | issue = 11 | pages = 2267–78 | year = 2007 | month = November | pmid = 17406653 | doi = 10.1038/sj.npp.1301376 | url = | issn = }}</ref>

A study published in 1998 shows that anandamide inhibits human breast cancer cell proliferation.<ref name="pmid9653194">{{cite journal | author = De Petrocellis L, Melck D, Palmisano A, Bisogno T, Laezza C, Bifulco M, Di Marzo V | title = The endogenous cannabinoid anandamide inhibits human breast cancer cell proliferation | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 95 | issue = 14 | pages = 8375–80 | year = 1998 | month = July | pmid = 9653194 | pmc = 20983 | doi = 10.1073/pnas.95.14.8375| url = | issn = }}</ref>

[[Image:LumRaf.jpg|thumb|right|[[Raphael Mechoulam]] (right), discoverer of psychoactive compound, (-)-''trans''-delta-9-tetrahydrocannabinol, from ''Cannabis sativa'' L. (1964) and [[Lumír Ondřej Hanuš]] (left), discoverer of endogenous ligand, anandamide, from brain (1992). Both compounds bind to the cannabinoid receptors in the brain.]]

== Synthesis and degradation ==

The human body synthesizes anandamide from ''N''-arachidonoyl phosphatidylethanolamine (NAPE), which is itself made by transferring [[arachidonic acid]] from [[lecithin]] to the free amine of [[cephalin]] through an [[N-acyltransferase]] enzyme.<ref name="pmid7126608">{{cite journal | author = Natarajan V, Reddy PV, Schmid PC, Schmid HH | title = N-Acylation of ethanolamine phospholipids in canine myocardium | journal = Biochim. Biophys. Acta | volume = 712 | issue = 2 | pages = 342–55 | year = 1982 | month = August | pmid = 7126608 | doi = | url = | issn = }}</ref><ref name="pmid9006968">{{cite journal | author = Cadas H, di Tomaso E, Piomelli D | title = Occurrence and biosynthesis of endogenous cannabinoid precursor, N-arachidonoyl phosphatidylethanolamine, in rat brain | journal = J. Neurosci. | volume = 17 | issue = 4 | pages = 1226–42 | year = 1997 | month = February | pmid = 9006968 | doi = | url = | issn = }}</ref> Anandamide synthesis from NarPE occurs via multiple pathways and includes enzymes such as [[phospholipase A2]], [[phospholipase C]] and [[NAPE-PLD]]. <ref name=wang2009/>
 
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.<ref name="pmid11353819">{{cite journal | author = Berger A, Crozier G, Bisogno T, Cavaliere P, Innis S, Di Marzo V | title = Anandamide and diet: inclusion of dietary arachidonate and docosahexaenoate leads to increased brain levels of the corresponding N-acylethanolamines in piglets | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 98 | issue = 11 | pages = 6402–6 | year = 2001 | month = May | pmid = 11353819 | pmc = 33480 | doi = 10.1073/pnas.101119098 | url = | issn = }}</ref> High fat diet feeding in mice increases levels of anandamide in the liver and increases [[lipogenesis]].<ref name="pmid15864349">{{cite journal | author = Osei-Hyiaman D, DePetrillo M, Pacher P, Liu J, Radaeva S, Bátkai S, Harvey-White J, Mackie K, Offertáler L, Wang L, Kunos G | title = Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity | journal = J. Clin. Invest. | volume = 115 | issue = 5 | pages = 1298–305 | year = 2005 | month = May | pmid = 15864349 | pmc = 1087161 | doi = 10.1172/JCI23057 | url = | issn = }}</ref> This suggests that anandamide may play a role in the development of obesity, at least in rodents.

[[Paracetamol]] (or [[acetaminophen]] in the U.S.A.) is metabolically combined with arachidonic acid by FAAH to form [[AM404]].<ref name=AM404>{{cite doi|10.1074/jbc.M501489200}}</ref> 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.<ref name="pmid17227290">{{cite journal | author = Bertolini A, Ferrari A, Ottani A, Guerzoni S, Tacchi R, Leone S | title = Paracetamol: new vistas of an old drug | journal = CNS Drug Rev | volume = 12 | issue = 3-4 | pages = 250–75 | year = 2006 | pmid = 17227290 | doi = 10.1111/j.1527-3458.2006.00250.x | url = | issn = }}</ref><ref name="pmid19053765">{{cite journal | author = Sinning C, Watzer B, Coste O, Nüsing RM, Ott I, Ligresti A, Di Marzo V, Imming P | title = New analgesics synthetically derived from the paracetamol metabolite N-(4-hydroxyphenyl)-(5Z,8Z,11Z,14Z)-icosatetra-5,8,11,14-enamide | journal = J. Med. Chem. | volume = 51 | issue = 24 | pages = 7800–5 | year = 2008 | month = December | pmid = 19053765 | doi = 10.1021/jm800807k | url = | issn = }}</ref> 

== See also ==
* [[Cannabinoids]]
* [[Tetrahydrocannabinol]] (THC)
* [[2-Arachidonoylglycerol]]
* [[Fatty acid amide hydrolase]]

== References ==
{{Reflist|2}}

== External links ==
* [http://www.runnersworld.com/article/0,7120,s6-243-297--1102-0,00.html Could anandamide be the missing link to "runner's high"?] Accessed 2008-10-18


{{Cannabinoids}}
{{Neurotransmitters}}

[[Category:Cannabinoids]]
[[Category:Neurotransmitters]]
[[Category:Amides]]
[[Category:Biomolecules]]
[[Category:Alcohols]]

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