الفهرس 
الملخص العربي
The life cycle of endocannabinoidOnly 14 pages are availabe for public view
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Abstract
“Cannabinoid” was originally the collective name given to a set of oxygen-containing C21 aromatic hydrocarbon compounds that occur naturally in the plant Cannabis Sativa. However, this term is now generally also used for all naturally occurring or synthetic compounds that can mimic the actions of plant-derived cannabinoids or that have structures that closely resemble those of plant cannabinoids.
Endocannabinoid compounds share two common structural motifs: a polyunsaturated fatty acid moiety (e.g. arachidonic acid) and a polar head group consisting of ethanol-amine or glycerol. Because of these features, endocannabinoid substances seemingly resemble the eicosanoids. However, the endocannabinoids are clearly distinguished from the eicosanoids by their different biosynthetic routes, which do not involve oxidative metabolism.
The two best characterized endocannabinoids, are anandamide (arachidonoylethanolamide, AEA) and 2-arachidonoylglycerol (2-AG).
An anandmide may be produced via hydrolysis of the phospholipid precursor N-arachidonoyl phosphatidylethanolamine (PE), catalyzed by a phospholipase D (PLD)-type activity. There are two possible routes of 2-AG biosynthesis in neurons: Phospholipase C -mediated hydrolysis of membrane phospholipids may produce diacylglycerol (DAG), which may be subsequently converted to 2-AG by diacylglycerol lipase activity. Alternatively, phospholipase A1 may generate a lysophospholipid, which may be hydrolyzed to 2-AG by a lyso-PLC activity. Anandamide and 2-AG may be generated by and released from neurons through a mechanism that does not require vesicular secretion.
Tissue concentrations of the endocannabinoids AEA and 2-AG are regulated by both synthesis and inactivation. Three inactivation processes were found: fatty acid amide hydrolase, monoacylglycerol lipase, and cellular membrane transport. Catabolism of both AEA and 2-AG occurs via hydrolysis to arachidonic acid and ethanolamine and glycerol, respectively. Hydrolysis of AEA is mediated primarily via fatty acid amide hydrolase (FAAH). 2-AG is also a substrate for FAAH, but monoacylglycerol lipase (MGL) likely plays a more important role in its hydrolysis in vivo. Both of these catabolic enzymes are localized intracellularly.
Endocannabinoids are endogenous compounds that bind to and activate cannabinoid receptor 1 (CB1) and/or cannabinoid receptor 2 (CB2). The cannabinoid receptors are a class of receptors under the G-protein coupled receptor superfamily. Their ligands are known as cannabinoids or endocannabinoids depending on whether they come from external or internal (endogenous) sources, respectively. The existance of additional cannabinoid receptors has long been suspected, due to the actions of compounds such as abnormal cannabidiol which produce cannabinoid-like effects on blood pressure and inflammation, yet do not activate either CB1 or CB2. These receptors are known as non-CB1 non-CB2 receptor. Another type of receptor called vanilloid receptor found on sensory neurons. It is an ion channel, and can cause Ca2+ influx and neurotransmitter release. Anandamide is a full agonist at VR1 receptors.
Endocannabinoids are released upon demand after cellular depolarization or receptor stimulation in a calcium-dependent manner. Once produced, they act on the cannabinoid receptors located in the cells surrounding the site of production.
Presynaptically, endocannabinoid have inhibitory effects on adenlyl cyclase, activate K+ currents and inhibit Ca2+ entry into cells, the net effect of the CB receptor stimulation is a local hyperpolarization that leads to the general inhibitory effects. However, a much more complex picture has appeared in different cell types, implicating other potassium ion channels, calcium channels, protein kinase A and C in mechanism of action of endocannabinoids. Endocannabinoids act also postsynaptically by counteracting the activatory inputs entering the postsynaptic cells. This mechanism has been proposed for postsynaptic interactions with dopaminergic transmission. Presynaptic inhibition of endocannabinoid is more important than postsynaptic inhibition.
Presynaptic inhibition of transmitter release by endocannabinoids may adopt two different forms of short-term synaptic plasticity, depending on the involvement of GABA or glutamate transmission, respectively: depolarization-induced suppression of inhibition (DSI) and depolarization-induced suppression of excitation (DSE).
Cannabinoid antinociception is observed in behavioral studies employing different modalities of noxious stimulation including thermal, mechanical and chemical. The potency and efficacy of cannabinoid antinociception rivals that of morphine.The cannabinoids could produce analgesia by an action in the brain via descending modulation, by a direct spinal action, and/or by an action on the peripheral nerve. The consensus from studies conducted in a number of different laboratories is that cannabinoids exert effects at all three locations.
Endocannabinoid have emerged as a regulatory system of the brain supporting appropriate emotional responses. In typical tests of anxiety, inhibition of CB1 receptor function by genetic or pharmacological means leads to an increase in anxiety.
Preclinical data suggest that CB1 receptor stimulation in the CNS facilitate feeding. Current studies suggest that the endocannabinoids may also play an important role in the treatment of nausea and emesis.
Preclinical data demonstrate that the endocannabinoids regulates both energy balance and peripheral metabolism. The endocannabinoids has effects in a variety of peripheral tissues including adipose tissue, liver, and skeletal muscle. Stimulation of CB1 receptors in fat cells reduces adiponectin expression and stimulates lipogenesis.
The hypothalamus is generally considered as the main site of cannabinoid action on neuroendocrine functions. This view is elegantly supported by a publication showing that endocannabinoids act as retrograde messengers activating CB1 receptors expressed at presynaptic glutamatergic terminals in the hypothalamus.
The subsequent activation of the CB1 receptor signaling cascade leads to the inhibition of the release of the excitatory neurotransmitter glutamate onto the neuroendocrine cells of the paraventricular nucleus and the supraoptic nucleus. This leads to a general suppressive effect on neuroendocrine cells and a final inhibitory effect on neuroendocrine function. As a general conclusion, the endocannabinoid system appears to play a very important regulatory role in the secretion of hormones related to reproductive functions and to stress responses.
D-9-THC and synthetic cannabinoids were shown to inhibit GH secretion in rodents. The inhibitory action of D-9-THC on GH secretion could be mediated by somatostatinergic activation. Cannabinoids inhibit thyroid hormone secretion by direct action on thyroid gland. There is a general agreement that cannabinoid activation of the tuberoinfundibolar dopaminergic neurons controlling PRL secretion is the main mechanism responsible for the inhibition of this pituitary hormone. When D-9-THC was chronically administered to ovariectomized or hypophysectomized female rats or to dispersed pituitary cells in culture, no effect was seen on PRL release, suggesting that the inhibitory cannabinoid effect targets the CNS directly.
While FSH secretion seems to be unaffected by administration of exogenous or endogenous cannabinoids, several evidences attribute cannabinoids with a strong ability to down-regulate blood LH levels. Some authors speculate that endocannabinoids may influence hormonal secretion and sexual behavior by directly targeting the CB1 receptor. Although there is still no general consensus, chronic cannabinoid use in several species seems to decrease testosterone production and secretion, to suppress spermatogenesis, and to reduce the weight of testes and accessory reproductive organs.
Evidence indicates that the endocannabinoids influences other physiological systems through interactions with their receptors, intracellular signaling pathways, hormones, and neurotransmitters.
The CB1 receptor appears to be involved in modulating the orexigenic effect of the gastric hormone ghrelin. Reduced endocannabinoid activity may mediate the induction of satiety by cholecystokinin (CCK).
Preclinical data demonstrate that melanocortins inhibit food intake. It has been suggested that CB1 receptor signaling may prevent the melanocortin system from altering food intake.
Some evidence indicates that the endocannabinoids may play an important role in the brain reward process by interacting with the mesolimbic dopaminergic system. Stimulation of nucleus accumbens CB1 receptors may suppress glutaminergic activity, with consequent inhibition of GABAergic neurons that normally inhibit ventral tegmental area dopamine neurons.
An interaction between the endocannabinoids and the opioid system is supported by studies showing that the opioid receptor antagonist and the CB1 receptor antagonist synergistically depress food intake at doses at which neither agent affects food intake when administered alone. Opioid receptors and CB1 receptors are co-expressed in the same subcellular compartments and are coupled to similar intracellular signaling pathways. Both opioid and CB1 receptors inhibit adenylyl cyclase activity through the activation of G proteins. AEA inhibit N-methyl-D-aspartate (NMDA)-induced Ca2+ influx in a CB1 receptor manner.
Further detailed studies are essential for a thorough elucidation of the different types of the endocannabinoid receptors and bioactions of the endocannabinoid in diverse mammalian tissues. Such studies would provide insight into the physiological significance of the endocannabinoid system and may open up new therapeutic approaches to various diseases.