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Role of lipids and lipid signaling in the development of cannabinoid tolerance

机译：脂质和脂质信号在大麻素耐受性发展中的作用

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Cannabinoid agonists such as Delta(9)-tetrahydrocannabinol (THC) produce a wide range of pharmacological effects both in the central nervous system and in the periphery. One of the most striking features of cannabinoids such as THC is the magnitude to tolerance that can be produced upon repetitive administration of this substance to animals. Relatively modest dosing regimens are capable of producing significant tolerance, whereas greater than 100-fold tolerance can be obtained with aggressive treatments. While cannabinoid tolerance has been studied quite extensively to establish its relevance to the health consequences of marijuana use, it has also proven to be a valuable strategy in understanding the mechanism of action of cannabinoids. The discovery of the endocannabinoid system that contains two receptor subtypes, CB1 and CB2, associated signaling pathways, endocannabinoids (anandamide and 2-arachidonoylglycerol) and their synthetic and degradative pathways has provided a means of systematically evaluating the mechanism of cannabinoid tolerance. It is well known that the CB1 cannabinoid receptor is down-regulated in states of cannabinoid tolerance along with uncoupling from its second messenger systems. Endocannabinoid levels are also altered in selected brain regions during the development of tolerance. While it is reasonable to speculate that a likely relationship exists between receptor and endocannabinoid levels, at present, little is known regarding the biological signal that leads to alterations in endocannabinoid levels. It is also unknown to what degree synthetic and degradative pathways for the endocannabinoids are altered in states of tolerance. The discovery that the brain is abundant in fatty acid amides and glycerols, raises the question as to what roles these lipids contribute to the endocannabinoid system. Some of these lipids also utilize the endocannabinoid metabolic pathways, produce similar pharmacological effects, and are capable of modulating the actions of anandamide and 2-arachidonoylglycerol. In addition, there are dopamine, glycine, and serotonin conjugates of arachidonic acid that may also contribute to the actions of endocannabinoids. A systematic examination of these lipids in cannabinoid tolerance might shed light on their physiological relevance to the endocannabinoid system. (c) 2005 Elsevier Inc. All rights reserved.
机译：诸如Delta（9）-四氢大麻酚（THC）之类的大麻素激动剂在中枢神经系统和周围区域均产生广泛的药理作用。大麻素（例如四氢大麻酚）最引人注目的特征之一是对动物重复施用这种物质后可产生的耐受量。相对适中的给药方案能够产生显着的耐受性，而积极的治疗可获得大于100倍的耐受性。尽管已经对大麻素耐受性进行了广泛的研究以确立其与使用大麻的健康后果的相关性，但它也被证明是了解大麻素作用机理的有价值的策略。包含两个受体亚型CB1和CB2，相关信号传导途径，内源性大麻素（anandamide和2-arachidonoylglycerol）及其合成和降解途径的内源性大麻素系统的发现提供了系统评估大麻素耐受性机制的手段。众所周知，CB1大麻素受体随着其第二信使系统的解偶联而在大麻素耐受状态下被下调。在耐受性发展过程中，选定大脑区域的内源性大麻素水平也发生了变化。尽管可以合理推测受体和内源性大麻素水平之间存在可能的关系，但目前对导致内源性大麻素水平改变的生物学信号知之甚少。还不清楚在耐受状态下内源性大麻素的合成和降解途径在多大程度上发生了改变。大脑富含脂肪酸酰胺和甘油的发现提出了关于这些脂质在内源性大麻素系统中起什么作用的问题。这些脂质中的一些还利用内源性大麻素代谢途径，产生相似的药理作用，并且能够调节花生四烯酸酰胺和2-花生四烯酰基甘油的作用。此外，还有花生四烯酸的多巴胺，甘氨酸和5-羟色胺共轭物，它们也可能有助于内源性大麻素的作用。对这些脂质对大麻素耐受性的系统检查可能有助于阐明它们与内源性大麻素系统的生理相关性。 （c）2005 Elsevier Inc.保留所有权利。

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