Endocannabinoid system

Endocannabinoids, together with their receptors and specific systems of synthesis and degradation, constitute in the organism the so-called "endogenous cannabinoid system" or "endocannabinoid system". This system (or at least part of its components) appears in a highly conserved form in the great majority of animals, at least in all deuterostomes, and its function so far better established is to constitute a mechanism of retrograde neuromodulation in the nervous system central. Thus, when several neurotransmitter receptors are overactivated in the plasma membrane of a postsynaptic neuron, it synthesizes precursors of endocannabinoids and cleaves them to release the functionally active endocannabinoid synaptic cleft. This happens, for example, after the union of some neurotransmitters like glutamate to its ionotropic or metabotropic receptors, with the consequent elevation of the cytoplasmic concentration of Ca2 +. Endocannabinoids act as retrograde chemical messengers, that is, they bind to CB1 receptors of the presynaptic neuron, which induces, for example, that Ca2 + ions are difficult to enter (by the closure of potential-sensitive Ca2 + channels) and The output of K + ions (through the opening of K + sensitive channels to G proteins) is facilitated. This impairs depolarization of the plasma membrane and inhibits exocytosis processes. In this way the release of the corresponding neurotransmitter (such as the glutamate in this example) is blocked.
endocannabinoid system

The neuromodulatory action of the endocannabinoids, like that of many other neurotransmitters and neuromodulators, is terminated by its cellular recapture through a plasma membrane transport system and its subsequent intracellular degradation, which is carried out by a family of lipases between the Fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) are the best characterized for the breakdown of AEA and 2-AG, respectively.

The cannabinoid CB receptor is in general one of the most highly expressed types of receptors in the central nervous system. The cannabinoid CB1 receptor is in general one of the most highly expressed types of receptors in the central nervous system And, in particular, it is the most abundant G protein-coupled presynaptic receptor in the adult brain of the mammals studied so far, being present, as we have mentioned, in practically all the regions of this organ. The presynaptic location of the CB1 receptor was shown for the first time in axonal terminals of hippocampal interneurons, and today there are numerous examples of other GABAergic (eg, cortical and striatal) neurons as well as glutamatergic neurons (eg cortical, hippocampal, Hypothalamic and cerebellar) or ascending subcortical pathways (eg, cholinergic, noradrenergic and serotonergic terminals), which express high amounts of presynaptic CB1 receptors. In addition to this characteristic localization in presynaptic terminals, the existence of CB1 receptors in some postsynaptic neurons has been described, the activation of which inhibits potential-sensitive Ca 2+ channels and N-methyl-D-aspartate ionotropic glutamate receptors. CB1 receptors of the central nervous system are also expressed in astrocytes, where they could control the trophic contribution of these cells to neurons and synaptic communication processes between both cell types, as well as oligodendrocytes and vascular endothelial cells. 

Finally, the cannabinoid CB2 receptor is expressed in microglial cells, the resident macrophages of nerve tissue, where it inhibits the activation of these cells and thus results in a decrease in the release of proinflammatory cytokines and reactive oxygen and nitrogen species, which Entails an attenuation of neuroinflammatory processes. All these effects complement the action of retrograde messengers that exert the endocannabinoids on the synaptic plasticity and the neuronal functionality.

Finally, it is important to mention that the endocannabinoid system is not only expressed in the adult nervous system, but, as our group and other laboratories have demonstrated, it also does so in the developing brain, in which it shows a pattern of distribution " Atypical ", since, for example, during prenatal stages the CB1 receptor abounds in neural progenitor cells and in axonal projections that form areas of white matter. More recent studies suggest that, during brain development, the endocannabinoid system controls essential processes such as neural cell proliferation, migration, differentiation and survival, as well as elongation and fasciculation of axons and the formation of synaptic connections during the establishment of Morphogenetic patterns of the nervous system.
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