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11 décembre 2003
Nature reviews neuroscience
2003;4;11; 873-884
lexique
The molecular logic of endocannabinoïd signalling
Daniele Piomelli
Department of Pharmacology, University of California, Irvine USA

Chat-logomini

The endocannabinoids are a family of lipid messengers that engage the cell surface receptors that are targeted by 9-tetrahydrocannabinol, the active principle in marijuana (Cannabis). They are made on demand through cleavage of membrane precursors and are involved in various short-range signalling processes. In the brain, they combine with CB1 cannabinoid receptors on axon terminals to regulate ion channel activity and neurotransmitter release. Their ability to modulate synaptic efficacy has a wide range of functional consequences and provides unique therapeutic possibilities.
 
 
The Cannabis plant has been used in Europe since antiquity, mostly to make cordage and fabric, but first attracted the attention of European scientists when Napoleon's troops brought back from Egypt intriguing accounts of its psychotropic activity. In 1810, a member of Napoleon's Commission des Sciences et des Arts wrote:
 
"For the Egyptians, hemp is the plant par excellence, not for the uses they make of it in Europe and many other countries, but for its peculiar effects. The hemp cultivated in Egypt is indeed intoxicating and narcotic."
 
Before long, detailed descriptions of the plant's properties began to appear and Cannabis extracts were introduced to the medical community.An 1848 commentary of the British Pharmacopoeia outlined quite accurately the psychotropic effects of Cannabis and pointed out its merit as an analgesic and antispasmodic:
 
"Numerous observers have described the Indian hemp as producing in the natives of the East, who familiarly use it instead of intoxicating spirits, sometimes a heavy, lazy state of agreeable reverie, from which the individual may be easily roused to discharge any simple duty sometimes a cheerful, active state of inebriation causing him to dance, sing and laugh, provoking the venereal appetite, and increasing the desire for food and sometimes a quarrelsome drunkenness, leading to acts of violence.During this condition pain is assuaged and spasm arrested. […] On the whole, it is a remedy which deserves a more extensive inquiry than any hitherto instituted."
cannabidoid.receptor
The inquiry into the active chemical constituents of Cannabis turned out to be more time consuming than expected.Many other plant-derived compounds, such as morphine and atropine, had long been identified when the Cannabis plant finally yielded its active principle, the terpenoid derivative 9-tetrahydrocannabinol THC). The psychoactive properties of THC were recognized immediately, but the drug's unique chemical structure offered no hints as to its mechanism of action.
 
To complicate matters further, the hydrophobic nature of THC delayed experimentation and indicated that the compound might act by influencing membrane fluidity, rather than by combining with a specific receptor. This impasse was resolved by the development of new classes of potent and selective THC analogue,which led eventually to the pharmacological identification of cannabinoid-sensitive sites in the brain. The CB1 cannabinoid receptor was molecularly cloned from rat brain in 1990 and its immunesystem counterpart, the CB2 receptor,was identified by sequence homology three years later.These discoveries not only established the mechanism of action of THC, thereby fuelling the development of subtype-selective agonists and antagonists, but they also initiated a hunt for brain-derived cannabinoid ligands. Surprisingly, the first THC-like factor to be isolated was a lipid, rather than the peptide that had been expected on the basis of the precedent set by morphine and the enkephalins.
 
It was identified as the amide of ARACHIDONIC ACID with ethanolamine, and named anandamide after the Sanskrit word for bliss, ananda. This small lipid molecule resembled no known neurotransmitter, but it did share structural features with the EICOSANOIDS,mediators of inflammation and pain with various functions in neural communication12.
 
Though initially controversial, the signalling roles of anandamide were confirmed by the elucidation of the compound's unique metabolic pathways and the demonstration of its release in the live brain14Ð16.As the search for THC-like compounds continued, other bioactive lipids were extracted from animal tissues. These include 2-arachidonoylglycerol (2-AG) noladin ether, virodhamine and N-arachidonoyldopamine.
 
In this article, I review the synthesis, release and deactivation of the endogenous cannabinoids (also called endocannabinoids). I then outline the properties and distribution of brain CB1 receptors. Last, I describe the function of the endocannabinoids as local modulators of synaptic activity and their contribution to memory, anxiety,movement and pain.
anandamide
 
 eicosamoides
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