ENDOCANNABINOIDS RECEPTORS MEDIATED CENTRAL AND PERIPHERAL EFFECTS (REVIEW).

The present article is devoted to the action of endocannabinoids via stimulation of their corresponding receptors. It is well established the existence of three type of endocannabinoids (ECS) such as anandamide (AA), 2-arachidonoylglycerol (2-AG) and palmitoylethanolamide (PE) providing their effects by activation of CB1 and CB2 ECS receptors. AA is a partial agonist for both receptors, having more affinity for CB1 receptors, while 2-AG reveals an equal agonistic properties to both of them in contrast to PE, which may bind to a unidental "CB2-like" receptors. CB1 receptors are distributed in the central and peripheral nervous system being identified in the greater amounts in the brain cortex, basal ganglia, spinal cord, cerebellum, hippocampus and olfactory areas, owing for the modulatory action of ECS on cognitive function, memory, behaviour, emotion and locomotor activity. Their location in the periaqueductal grey matter and dorsal spinal cord may explain their involvement in pain sensation and modulation. Colocallization of the CB1 receptors with the oroxinergic projection system in the lateral hypothalamus is responsible for their implication in feeding behaviour. CB2 receptors were found in the cells of immune system (spleen, macrophages). It should be noted that ECS may also play a role in the regulation of fertility and pre-and postnatal development. The stimulation of ECS receptors is associated with the activation of MAPK, PI/PKB and MEK/ERK signalling pathways with increased activity of different transcription factors. CB1 receptors are involved in neuronal exitability by decreasing synaptic input, implying retrograde transmission and presynaptic inhibition resulting in reduction of neurotransmitter release. In the article it is also described an ionic mechanisms of release of ECS and the steps of their synthesis as well as participation of a transporter in ECS uptaken process in neurons and astrocytes. Aside from this it is proposed the mechanisms of analgesic action of ECS especially concerning reduction in neuropathic pain in comparison to opioids and possible involvement of α2-adrenoceptors in antinociceptive activity of ECS. Some analgesic properties of ECS is due to their inhibitory action on cyclooxygenase-2 (COX-2). Recent evidences showed that regarding antinociceptive action of ECS along with CB1 receptors most significant receptors are PPAR-alpha and TRPV receptors. There are controversial data concerning the influence of ECS on cognitive function. Knockout mices with the absence of CB1 receptors have showed improved memory and long-term potentiation proofing the significant role of ECS in the disorders of "old memories". Some data suggests that genetic or pharmacological inhibition of COX-2 activity may reduce disorders in hippocampal long-term synaptic plasticity and fear memory, as well as supports improving effects of tetrahydrocannabinoids (THC) on neurodegenerative processes such as Alzheimer's disease, because THC facilitates to marked expression of an important endopeptidase neprilysin for degradation of AB proteins. A number of evidence indicates the possible involvement of ECS in schizophrenia and major depressive disorders. Assumingly such beneficial effect of ECS is associated with M1/M2 microglial polarization process. In conclusion it is suggested that ECS as natural ligand for their corresponding receptors provide wide spectrum of pharmacological effects may become an interesting targets for future therapeutic intervention.