Anandamide
Encyclopedia
Anandamide, also known as N-arachidonoylethanolamide or AEA, is an endogenous cannabinoid
neurotransmitter
. The name is taken from the Sanskrit
word ananda
, which means "bliss, delight
", and amide
. 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 therapeutic use.
of the Hebrew University in Jerusalem, which included a post doctoral fellow, Dr. William Devane, a visiting Czech analytical chemist Dr. Lumír Hanuš and Dr. Aviva Breuer in 1992. Additional collaborators were Professor Roger Pertwee from Edinburgh and Professor Asher Mandelbaum of the Technion in Haifa.
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 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.
Moreover, anandamide is thought to be an endogenous
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.
Anandamide has shown to impair working memory in rats. 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 Δ9-THC might influence processes during the earliest stages of human pregnancy. 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.
Anandamide is also important in the regulation of feeding behavior, and the neural generation of motivation and pleasure. 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.
A study published in 1998 shows that anandamide inhibits human breast cancer cell proliferation.
In an attempt to find anandamide or anandamide type endocannabinoids, researchers in 1996 found N-oleoylethanolamine and N-linoleoylethanolamine which may act as cannabinoid mimics. Later studies confirmed that anandamide is not found in chocolate and the two compounds reported earlier did not interact with cannabinoid receptors. The neurological basis of chocolate's appeal still remains elusive.
from lecithin
to the free amine of cephalin through an N-acyltransferase enzyme. Anandamide synthesis from NAPE occurs via multiple pathways and includes enzymes such as phospholipase A2
, phospholipase C
and NAPE-PLD.
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. High fat diet feeding in mice increases levels of anandamide in the liver and increases lipogenesis
. 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
. 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.
Cannabinoids
Cannabinoids are a class of chemical compounds that include the phytocannabinoids , and chemical compounds that mimic the actions of phytocannabinoids or have a similar structure...
neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
. The name is taken from the Sanskrit
Sanskrit
Sanskrit , is a historical Indo-Aryan language and the primary liturgical language of Hinduism, Jainism and Buddhism.Buddhism: besides Pali, see Buddhist Hybrid Sanskrit Today, it is listed as one of the 22 scheduled languages of India and is an official language of the state of Uttarakhand...
word ananda
Ananda
Ānanda was one of the principal disciples and a devout attendant of the Buddha. Amongst the Buddha's many disciples, Ānanda had the most retentive memory and most of the suttas in the Sutta Pitaka are attributed to his recollection of the Buddha's teachings during the First Buddhist Council...
, which means "bliss, delight
Delight
Delight means happiness and may refer to someone or something that brings such a state.It may also refer to :-Foods and beverages:*Angel Delight, a British pudding*Bakers Delight, a chain of bakeries in Australia and New Zealand...
", and amide
Amide
In chemistry, an amide is an organic compound that contains the functional group consisting of a carbonyl group linked to a nitrogen atom . The term refers both to a class of compounds and a functional group within those compounds. The term amide also refers to deprotonated form of ammonia or an...
. 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
Ethanolamine
Ethanolamine, also called 2-aminoethanol or monoethanolamine , is an organic chemical compound that is both a primary amine and a primary alcohol . Like other amines, monoethanolamine acts as a weak base...
and arachidonic acid
Arachidonic acid
Arachidonic acid is a polyunsaturated omega-6 fatty acid 20:4.It is the counterpart to the saturated arachidic acid found in peanut oil, Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega-6 fatty acid 20:4(ω-6).It is the counterpart to the saturated arachidic acid found in peanut oil,...
. As such, inhibitors of FAAH lead to elevated anandamide levels and are being pursued for therapeutic use.
History
It was isolated and its structure was deciphered by a research group led by professor Raphael MechoulamRaphael Mechoulam
Raphael Mechoulam is an Israeli professor of Medicinal Chemistry and Natural Products at the Hebrew University of Jerusalem in Israel...
of the Hebrew University in Jerusalem, which included a post doctoral fellow, Dr. William Devane, a visiting Czech analytical chemist Dr. Lumír Hanuš and Dr. Aviva Breuer in 1992. Additional collaborators were Professor Roger Pertwee from Edinburgh and Professor Asher Mandelbaum of the Technion in Haifa.
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 receptorCannabinoid receptor
The cannabinoid receptors are a class of cell membrane receptors under the G protein-coupled receptor superfamily. As is typical of G protein-coupled receptors, the cannabinoid receptors contain seven transmembrane spanning domains...
s in the central nervous system, and CB2 cannabinoid receptors in the periphery. The latter are mainly involved in functions of the immune system
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
. Cannabinoid receptors were originally discovered as being sensitive to Δ9-tetrahydrocannabinol
Tetrahydrocannabinol
Tetrahydrocannabinol , also known as delta-9-tetrahydrocannabinol , Δ1-THC , or dronabinol, is the main chemical psychoactive substance found in the cannabis plant. It was first isolated in 1964. In pure form, it is a glassy solid when cold, and becomes viscous and sticky if warmed...
(Δ9-THC, commonly called THC), which is the primary psychoactive cannabinoid found in cannabis
Cannabis
Cannabis is a genus of flowering plants that includes three putative species, Cannabis sativa, Cannabis indica, and Cannabis ruderalis. These three taxa are indigenous to Central Asia, and South Asia. Cannabis has long been used for fibre , for seed and seed oils, for medicinal purposes, and as a...
. 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
Endogenous
Endogenous substances are those that originate from within an organism, tissue, or cell. Endogenous retroviruses are caused by ancient infections of germ cells in humans, mammals and other vertebrates...
ligand
Ligand (biochemistry)
In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. In a narrower sense, it is a signal triggering molecule, binding to a site on a target protein.The binding occurs by intermolecular forces, such as ionic bonds, hydrogen...
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.
Anandamide has shown to impair working memory in rats. 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
Embryo
An embryo is a multicellular diploid eukaryote in its earliest stage of development, from the time of first cell division until birth, hatching, or germination...
in its blastocyst
Blastocyst
The blastocyst is a structure formed in the early embryogenesis of mammals, after the formation of the morula. It is a specifically mammalian example of a blastula. It possesses an inner cell mass , or embryoblast, which subsequently forms the embryo, and an outer layer of cells, or trophoblast,...
form into the uterus
Uterus
The uterus or womb is a major female hormone-responsive reproductive sex organ of most mammals including humans. One end, the cervix, opens into the vagina, while the other is connected to one or both fallopian tubes, depending on the species...
. Therefore cannabinoids such as Δ9-THC might influence processes during the earliest stages of human pregnancy. Peak plasma anandamide occurs at ovulation
Ovulation
Ovulation is the process in a female's menstrual cycle by which a mature ovarian follicle ruptures and discharges an ovum . Ovulation also occurs in the estrous cycle of other female mammals, which differs in many fundamental ways from the menstrual cycle...
and positively correlates with peak estradiol
Estradiol
Estradiol is a sex hormone. Estradiol is abbreviated E2 as it has 2 hydroxyl groups in its molecular structure. Estrone has 1 and estriol has 3 . Estradiol is about 10 times as potent as estrone and about 80 times as potent as estriol in its estrogenic effect...
and gonadotrophin levels, suggesting that these may be involved in the regulation of AEA levels.
Anandamide is also important in the regulation of feeding behavior, and the neural generation of motivation and pleasure. In addition, anandamide injected directly into the forebrain reward-related brain structure nucleus accumbens
Nucleus accumbens
The nucleus accumbens , also known as the accumbens nucleus or as the nucleus accumbens septi , is a collection of neurons and forms the main part of the ventral striatum...
enhances the pleasurable responses of rats to a rewarding sucrose taste, and enhances food intake as well.
A study published in 1998 shows that anandamide inhibits human breast cancer cell proliferation.
In an attempt to find anandamide or anandamide type endocannabinoids, researchers in 1996 found N-oleoylethanolamine and N-linoleoylethanolamine which may act as cannabinoid mimics. Later studies confirmed that anandamide is not found in chocolate and the two compounds reported earlier did not interact with cannabinoid receptors. The neurological basis of chocolate's appeal still remains elusive.
Synthesis and degradation
The human body synthesizes anandamide from N-arachidonoyl phosphatidylethanolamine (NAPE), which is itself made by transferring arachidonic acidArachidonic acid
Arachidonic acid is a polyunsaturated omega-6 fatty acid 20:4.It is the counterpart to the saturated arachidic acid found in peanut oil, Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega-6 fatty acid 20:4(ω-6).It is the counterpart to the saturated arachidic acid found in peanut oil,...
from lecithin
Lecithin
Lecithin is a generic term to designate any group of yellow-brownish fatty substances occurring in animal and plant tissues, and in egg yolk, composed of phosphoric acid, choline, fatty acids, glycerol, glycolipids, triglycerides, and phospholipids .The word lecithin was originally coined in 1847 by...
to the free amine of cephalin through an N-acyltransferase enzyme. Anandamide synthesis from NAPE occurs via multiple pathways and includes enzymes such as phospholipase A2
Phospholipase A2
Phospholipases A2 are enzymes that release fatty acids from the second carbon group of glycerol. This particular phospholipase specifically recognizes the sn-2 acyl bond of phospholipids and catalytically hydrolyzes the bond releasing arachidonic acid and lysophospholipids...
, phospholipase C
Phospholipase C
Phosphoinositide phospholipase C is a family of eukaryotic intracellular enzymes that play an important role in signal transduction processes. In general, this enzyme is denoted as Phospholipase C, although three other families of phospholipase C enzymes have been identified in bacteria and in...
and NAPE-PLD.
Endogenous anandamide is present at very low levels and has a very short half-life
Half-life
Half-life, abbreviated t½, is the period of time it takes for the amount of a substance undergoing decay to decrease by half. The name was originally used to describe a characteristic of unstable atoms , but it may apply to any quantity which follows a set-rate decay.The original term, dating to...
due to the action of the enzyme fatty acid amide hydrolase (FAAH), which breaks it down into free arachidonic acid
Arachidonic acid
Arachidonic acid is a polyunsaturated omega-6 fatty acid 20:4.It is the counterpart to the saturated arachidic acid found in peanut oil, Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega-6 fatty acid 20:4(ω-6).It is the counterpart to the saturated arachidic acid found in peanut oil,...
and ethanolamine
Ethanolamine
Ethanolamine, also called 2-aminoethanol or monoethanolamine , is an organic chemical compound that is both a primary amine and a primary alcohol . Like other amines, monoethanolamine acts as a weak base...
. Studies of piglets show that dietary levels of arachidonic acid
Arachidonic acid
Arachidonic acid is a polyunsaturated omega-6 fatty acid 20:4.It is the counterpart to the saturated arachidic acid found in peanut oil, Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega-6 fatty acid 20:4(ω-6).It is the counterpart to the saturated arachidic acid found in peanut oil,...
and other essential fatty acids affect the levels of anandamide and other endocannabinoids in the brain. High fat diet feeding in mice increases levels of anandamide in the liver and increases lipogenesis
Lipogenesis
Lipogenesis is the process by which acetyl-CoA is converted to fats. The former is an intermediate stage in metabolism of simple sugars, such as glucose, a source of energy of living organisms. Through lipogenesis, the energy can be efficiently stored in the form of fats...
. This suggests that anandamide may play a role in the development of obesity, at least in rodents.
Paracetamol
Paracetamol
Paracetamol INN , or acetaminophen USAN , is a widely used over-the-counter analgesic and antipyretic . It is commonly used for the relief of headaches and other minor aches and pains and is a major ingredient in numerous cold and flu remedies...
(or acetaminophen in the U.S.A.) is metabolically combined with arachidonic acid by FAAH to form AM404
AM404
AM404, also known as N-arachidonoylethanolamide, is an active metabolite of paracetamol , responsible for all or part of its analgesic action.-Pharmacology:...
. This metabolite of paracetamol is a potent agonist
Agonist
An agonist is a chemical that binds to a receptor of a cell and triggers a response by that cell. Agonists often mimic the action of a naturally occurring substance...
at the TRPV1
TRPV1
The transient receptor potential cation channel subfamily V member 1 ', also known as the capsaicin receptor and the vanilloid receptor 1, is a protein that, in humans, is encoded by the TRPV1 gene...
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
Analgesic
An analgesic is any member of the group of drugs used to relieve pain . The word analgesic derives from Greek an- and algos ....
effects of paracetamol.
See also
- CannabinoidsCannabinoidsCannabinoids are a class of chemical compounds that include the phytocannabinoids , and chemical compounds that mimic the actions of phytocannabinoids or have a similar structure...
- VirodhamineVirodhamineVirodhamine is an endocannabinoid and a nonclassic eicosanoid, derived from arachidonic acid. O-Arachidonoyl ethanolamine is arachidonic acid and ethanolamine joined by an ester linkage, the opposite of the amide linkage found in anandamide...
- TetrahydrocannabinolTetrahydrocannabinolTetrahydrocannabinol , also known as delta-9-tetrahydrocannabinol , Δ1-THC , or dronabinol, is the main chemical psychoactive substance found in the cannabis plant. It was first isolated in 1964. In pure form, it is a glassy solid when cold, and becomes viscous and sticky if warmed...
(THC) - 2-Arachidonoylglycerol2-Arachidonoylglycerol2-Arachidonoylglycerol is an endocannabinoid, an endogenous agonist of the CB1 receptor. It is an ester formed from the omega-6 fatty acid arachidonic acid and glycerol. It is present at relatively high levels in the central nervous system, with cannabinoid neuromodulatory effects. It has been...
- Fatty acid amide hydrolase
External links
- Could anandamide be the missing link to "runner's high"? Accessed 2008-10-18