Post-opioid receptor adaptations to chronic morphine; Altered functionality and associations of signaling molecules
Post-opioid receptor adaptations to chronic morphine; Altered functionality and associations of signaling molecules
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DOI：
10.1016/j.lfs.2006.02.016
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发表时间：
2006-07-17
期刊：
影响因子：
6.1
通讯作者：
Chakrabarti, Surnita
中科院分区：
文献类型：
--
作者：
Gintzler, Alan R.;Chakrabarti, Surnita
阿片样物质脱敏/耐受机制主要集中于在β-阿片样物质受体（莫尔）本身水平上发生的适应。这些适应包括阿片样物质受体磷酸化和随后的运输事件。然而，最近的研究揭示了阿片受体下游发生的其他适应，其中涉及信号分子的共价修饰和它们之间的改变。这些包括腺苷酸环化酶（AC）的增强亚型特异性合成及其磷酸化以及G（β-γ）亚基的增强磷酸化。这些变化的总体效应是将μ阿片受体偶联的信号传导从主要的G（i α）抑制性转变为（G（i）衍生的）G（β γ）刺激性AC信号传导。最近，慢性吗啡已显示出增强莫尔和G（s）之间的关联（相互作用），这应该为抵消抑制性莫尔信号传导后遗症提供额外的途径。慢性吗啡引起的后遗症的复杂性，需要不断发展的阿片类药物耐受性产生机制的更广泛和更全面的观点。这将有助于理解耐受性的背景下，生理可塑性，是由长期暴露于滥用药物激活。需要更多的研究来整合迄今为止已经阐明的各种产生耐受性的适应性。具体而言，确定的适应性对阿片类药物耐受性的相对贡献仍然是未知的，因为它们在中枢神经系统的不同区域之间的变化程度也是未知的。(c)2006年爱思唯尔公司All rights reserved.
Opioid desensitization/tolerance mechanisms have largely focused on adaptations that occur on the level of the p-opioid receptor (MOR) itself These include opioid receptor phosphorylation and ensuing trafficking events. Recent research, however, has revealed additional adaptations that occur downstream from the opioid receptor, which involve covalent modification of signaling molecules and altered associations among them. These include augmented isoform-specific synthesis of aderylyl cyclase (AC) and their phosphorylation as well as augmented phosphorylation of the G(beta) subunit of G(beta gamma). The aggregate effect of these changes is to shift mu-opioid receptor-coupled signaling from predominantly G(i alpha), inhibitory to (G(i)-derived) G(beta gamma), stimulatory AC signaling. Most recently, chronic morphine has been shown to enhance the association (interaction) between MOR and G(s), which should provide an additional avenue for offsetting inhibitory MOR signaling sequelae. The unfolding complexity of chronic morphine-induced sequelae demands an evolving broader and more encompassing perspective on opioid tolerance-producing mechanisms. This should facilitate understanding tolerance within the context of physiological plasticity that is activated by chronic exposure to drugs of abuse. Additional research is required to integrate the various tolerance-producing adaptations that have been elucidated to date. Specifically, the relative contribution to opioid tolerance of identified adaptations is still unknown as is the extent to which they vary among different regions of the central nervous system. (c) 2006 Elsevier Inc. All rights reserved.