Cannabis and endocannabinoid modulators: Therapeutic promises and challenges
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Keywords:
Anandamide
Cannabinoid Receptor Agonists
Synthetic cannabinoids
Anandamide
GPR18
Palmitoylethanolamide
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Anandamide
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Many aspects of the physiology and pharmacology of anandamide (arachidonoyl ethanolamide), the first endogenous cannabinoid ligand (“endocannabinoid”) isolated from pig brain, have been studied since its discovery in 1992. Ethanolamides from other fatty acids have also been identified as endocannabinoids with similar in vivo and in vitro pharmacological properties. 2-Arachidonoyl glycerol and noladin ether (2-arachidonyl glyceryl ether), isolated in 1995 and 2001, respectively, thus far display pharmacological properties in the central nervous system similar to those of anandamide. The endocanabinoids are widely distributed in brain, they are synthesized and released upon neuronal stimulation, and undergo reuptake and are hydrolyzed intracellularly by fatty acid amide hydrolase (FAAH). Pharmacological effects of the endocannabinoids are very similar, yet not identical, to those of the plant-derived and synthetic cannabinoid receptor ligands. In addition to pharmacokinetic explanations, direct or indirect interactions with other receptors have been considered to explain some of these differences, including activities at serotonin and γ-aminobutyric acid (GABA) receptors. Binding affinities for additional receptors such as the vanilloid receptor have to be taken into account in order to fully understand endocannabinoid physiology. Moreover, possible interactions with receptors for the lysophosphatidic acids deserve attention in future studies. Endocannabinoids have been implicated in a variety of physiological functions. These areas of central activity include pain reduction, motor regulation, learning/ memory, and reward. Neuroprotective effects of anandamide and 2-arachidonoyl glycerol have also been reported. Finally, the role of the endocannabinoid system in appetite stimulation in the adult organism, and perhaps more important, its critical involvement in milk ingestion and survival of the newborn, may further our understanding of the physiology of food intake and growth.
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The endocannabinoid system comprises the CB1 and CB2 receptors (the targets of the Cannabis sativa compound delta-9-tetrahydrocannabinol), the endogenous ligands (endocannabinoids) arachidonoyl ethanolamide (anandamide) and 2-arachidonoyl glycerol, their synthesizing machinery and membrane transport system, and the hydrolyzing enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), respectively. The endocannabinoids may act on demand to confer protection against aversive stimuli, which suggests that increasing their brain levels may represent an approach for treatment of anxiety-related disorders. Thus, this article reviews the profile of endocannabinoid reuptake and hydrolysis inhibitors in experimental tests predictive of anxiolytic activity. The FAAH inhibitors and the blockers of anandamide transport, in contrast to direct CB1 receptor agonists, induce anxiolytic effects at doses that do not interfere with motor activity. MAGL inhibitors also reduce anxiety-like behavior, although they are more likely to impair motor activity. Regarding their mechanisms, increasing anandamide levels induce responses mediated by the CB1 receptor and occluded by the transient receptor potential vanilloid type-1 channels, whereas the effects of increasing 2-arachidonoyl glycerol depend on both CB1 and CB2 receptors. Their neuroanatomical targets include various structures related to anxiety and fear responses. Understanding the pharmacological properties of FAAH and MAGL inhibitors may contribute toward the development of new anxiolytic interventions based on the endocannabinoid system.
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2-Arachidonoylglycerol
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The endocannabinoid system consists of cannabinoid CB 1 and CB 2 receptors, of endogenous agonists for these receptors known as ‘endocannabinoids’, and of processes responsible for endocannabinoid biosynthesis, cellular uptake and metabolism. There is strong evidence first, that this system up-regulates in certain disorders as indicated by an increased release of endocannabinoids onto their receptors and/or by increases in the expression levels or coupling efficiency of these receptors, and second, that this up-regulation often appears to reduce or abolish unwanted effects of these disorders or to slow their progression. This discovery has raised the possibility of developing a medicine that enhances up-regulation of the endocannabinoid system associated with these disorders by inhibiting the cellular uptake or intracellular metabolism of an endocannabinoid following its ‘autoprotective’ endogenous release. For inhibition of endocannabinoid metabolism, research has focused particularly on two highly investigated endocannabinoids, anandamide and 2-arachidonoyl glycerol, and hence on inhibitors of the main anandamide-metabolising enzyme, fatty acid amide hydrolase (FAAH), and of the main 2-arachidonoyl glycerol-metabolising enzyme, monoacylglycerol (MAG) lipase. The resulting data have provided strong preclinical evidence that selective FAAH and MAG lipase inhibitors would ameliorate the unwanted effects of several disorders, when administered alone or with a cyclooxygenase inhibitor, and that the benefit-to-risk ratio of a FAAH inhibitor would exceed that of a MAG lipase inhibitor or dual inhibitor of FAAH and MAG lipase. Promising preclinical data have also been obtained with inhibitors of endocannabinoid cellular uptake. There is now an urgent need for clinical research with these enzyme and uptake inhibitors.
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Endocannabinoids are thought to act as retrograde messengers in the central nervous system. By activating presynaptic cannabinoid CB1 receptors they can reduce neurotransmitter release and modulate synaptic plasticity. To date, anandamide and 2-arachidonoylglycerol (2- AG) are the best studied endocannabinoids. The life span of these lipid molecules in the extracellular space is an important factor in the regulation of their cellular responses. In this review we will discuss the metabolic fate of endocannabinoids, i.e. the mechanisms leading to the termination and / or modification of their actions. It is thought that endocannabinoids can be inactivated via a two-step mechanism. First, endocannabinoids are proposed to be translocated into the cell via selective transporter(s). However, the elusive nature of the putative protein responsible for endocannabinoid uptake has initiated a debate on its existence. Evidence in favor and against will be discussed. Once inside the cell, two major metabolic pathways act upon endocannabinoids: hydrolysis and oxygenation. Hydrolysis of the amide or ester function in anandamide and 2-AG, respectively, terminates their activity on cannabinoid receptors. The proteins responsible for their hydrolysis, fatty acid amide hydrolase and monoacylglycerol lipase, have been cloned and studied in detail. Much less is known about the oxygenation pathways. Lipoxygenase- and cycloxygenase-catalyzed oxygenation of endocannabinoids has been shown to generate a new array of possible biologically active compounds, such as the prostamides and the prostaglandin-glycerols, acting upon novel molecular targets. We will discuss the formation and the possible actions of these novel endocannabinoid derivatives. Keywords: anandamide, 2-ag, cannabinoid, cyclooxygenase, fatty acid amide hydrolase, lipoxygenase, mono acyl glycerol lipase, prostamide
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Periaqueductal gray
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During marijuana and alcohol consumption as well as during inflammation the reproductive axis is inhibited, mainly through the inhibition of luteinizing hormone-releasing hormone release. In male rats, this inhibitory effect is mediated, at least in part, by the activation of hypothalamic cannabinoid type 1 receptors (CB1). During inflammation, this activation of the endocannabinoid system seems to be mediated by an increase in TNF-α production followed by anandamide augmentations, similarly the effect of intragastric administration of ethanol (3 g/kg) seems to be due to an increase in anandamide. On the other hand, a number of different actions mediated by the endocannabinoid system in various organs and tissues have been described. Both cannabinoid receptors, CB1 and CB2, are localized in the submandibular gland where they mediate the inhibitory effect of intrasubmandibular injections of the endocannabinoid anandamide (6 × 10<sup>–5</sup><i>M</i>) on salivary secretion. Lipopolysaccharide (5 mg/kg/3 h) injected intraperitoneally and ethanol (3 g/kg/1 h) injected intragastrically inhibited the salivary secretion induced by the sialogogue metacholine; this inhibitory effect was blocked by CB1 and/or CB2 receptor antagonists. Similar to the hypothalamus, these effects seem to be mediated by increased anandamide. In summary, similar mechanisms mediate the inhibitory actions of endocannabinoids and cannabinoids in both hypothalamus and submandibular gland during drug consumption and inflammation.
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