PMC:3780360 / 23736-26984 JSONTXT

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Thus, endocannabinoids are considered as retrograde messengers that neuromodulate diverse physiological processes. AEA and 2-AG are the two most characterized endocannabinoids (135, 136), although other studies have identified of additional endocannabinoids such as 2-arachidonylglyceryl ether (noladin ether) (137), N-arachidonoyl-dopamine (NADA) (128), and O-arachidonoyl-ethanolamine (virodhamine) (138). However, the physiological functions of these endocannabinoids are still being investigated. While 2-AG acts as a full agonist at CB1 and CB2 receptors, AEA behaves as a partial agonist at both receptors subtypes and can also interact with GPR55 and TRVP1 receptors.\nUnlike other neurotransmitters, AEA and 2-AG are not synthesized and stored in the nerve cells. Rather, they are produced on an “as needed” basis by their membrane lipid precursors in a Ca2+ dependent fashion (133, 139). Although additional studies are needed to ascertain the exact role of the N-acylphosphatidylethanolamine phospho-lipase D in the ECBS, it has been proposed that this enzyme might play a significant role in the synthesis of AEA (140). The enzyme responsible for 2-AG synthesis is the diacylglycerol lipase alpha (141). Upon depolarization of post-synaptic neurons, the endocannabinoids released into the synaptic cleft bind to and activate the presynaptic CB1 receptors, which in turn suppress the release of both excitatory and inhibitory different neurotransmitters [see for review (142)]. Then, AEA and 2-AG are rapidly deactivated by cellular reuptake into both neurons and glial cells and metabolized by specific enzymes (143). AEA can be metabolized by either the FAAH (144), or monoacylglycerol lipase (MAGL), which degrades specifically 2-AG (145). In addition to MAGL, recent studies have suggested that the enzymes ABHD6 and ABHD12 could also be involved in 2-AG metabolism (146, 147). FAAH is over-expressed in the CNS and FAAH-positive neurons are localized in proximity to CB1 receptor-containing terminals, underlining the role for this enzyme in endocannabinoids inhibition (148). Thus, selective inhibition of FAAH (149) and MAGL (150) can prolong the effects of endocannabinoids. Pre-clinical studies have demonstrated that pharmacological inhibition of FAHH with URB597 (149) or PF-3845 compounds (151) induced-anxiolytic-like effects (152, 153) and anti-nociceptive properties in mice (152, 154). Inhibition of MAGL with JZL184 inhibitor causes analgesia, hypothermia, and hypomotility (155). However, chronic exposure to JZL184 impairs endocannabinoid-mediated synaptic plasticity in mouse hippocampus and cerebellum via 2-AG upregulation. It also induces tolerance to the analgesic effects, physical dependence, and persistent activation as well as desensitization of brain CB1 receptors (156). Surprisingly, MAGL knockout mice show enhanced learning behavior and have normal locomotor activity, suggesting the possible role of MAGL in cognitive function (157, 158)."}

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and their metabolizing enzymes\nIn the CNS, endocannabinoids mediate forms of short-term synaptic plasticity known as depolarization-induced suppression of inhibition (DSI) (132, 133) and depolarization-induced suppression of excitation (DSE) (134). Thus, endocannabinoids are considered as retrograde messengers that neuromodulate diverse physiological processes. AEA and 2-AG are the two most characterized endocannabinoids (135, 136), although other studies have identified of additional endocannabinoids such as 2-arachidonylglyceryl ether (noladin ether) (137), N-arachidonoyl-dopamine (NADA) (128), and O-arachidonoyl-ethanolamine (virodhamine) (138). However, the physiological functions of these endocannabinoids are still being investigated. While 2-AG acts as a full agonist at CB1 and CB2 receptors, AEA behaves as a partial agonist at both receptors subtypes and can also interact with GPR55 and TRVP1 receptors.\nUnlike other neurotransmitters, AEA and 2-AG are not synthesized and stored in the nerve cells. Rather, they are produced on an “as needed” basis by their membrane lipid precursors in a Ca2+ dependent fashion (133, 139). Although additional studies are needed to ascertain the exact role of the N-acylphosphatidylethanolamine phospho-lipase D in the ECBS, it has been proposed that this enzyme might play a significant role in the synthesis of AEA (140). The enzyme responsible for 2-AG synthesis is the diacylglycerol lipase alpha (141). Upon depolarization of post-synaptic neurons, the endocannabinoids released into the synaptic cleft bind to and activate the presynaptic CB1 receptors, which in turn suppress the release of both excitatory and inhibitory different neurotransmitters [see for review (142)]. Then, AEA and 2-AG are rapidly deactivated by cellular reuptake into both neurons and glial cells and metabolized by specific enzymes (143). AEA can be metabolized by either the FAAH (144), or monoacylglycerol lipase (MAGL), which degrades specifically 2-AG (145). In addition to MAGL, recent studies have suggested that the enzymes ABHD6 and ABHD12 could also be involved in 2-AG metabolism (146, 147). FAAH is over-expressed in the CNS and FAAH-positive neurons are localized in proximity to CB1 receptor-containing terminals, underlining the role for this enzyme in endocannabinoids inhibition (148). Thus, selective inhibition of FAAH (149) and MAGL (150) can prolong the effects of endocannabinoids. Pre-clinical studies have demonstrated that pharmacological inhibition of FAHH with URB597 (149) or PF-3845 compounds (151) induced-anxiolytic-like effects (152, 153) and anti-nociceptive properties in mice (152, 154). Inhibition of MAGL with JZL184 inhibitor causes analgesia, hypothermia, and hypomotility (155). However, chronic exposure to JZL184 impairs endocannabinoid-mediated synaptic plasticity in mouse hippocampus and cerebellum via 2-AG upregulation. It also induces tolerance to the analgesic effects, physical dependence, and persistent activation as well as desensitization of brain CB1 receptors (156). Surprisingly, MAGL knockout mice show enhanced learning behavior and have normal locomotor activity, suggesting the possible role of MAGL in cognitive function (157, 158)."}