Anandamide

Anandamide, also known as N-arachidonoylethanolamine or AEA, is an endogenous cannabinoid neurotransmitter. It was isolated and its structure was first described by 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, 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.

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 receptors 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 been shown to be involved in working memory. 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 interfere with 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 also is 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.



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. Anandamide synthesis from NarPE 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.