Gintzler Alan R, Chakrabarti Sumita
Department of Biochemistry, State University of New York, Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, NY 11203, USA.
Novartis Found Symp. 2004;261:167-76; discussion 176-80, 191-3.
Most formulations of the consequences of the persistent activation of opioid receptors have centred on the diminution or loss of opioid receptor-coupled signalling mechanisms. Activation of opposing compensatory circuits remains another of the adaptations proposed to underlie the extreme loss of the antinociceptive potency of narcotics following their chronic administration. Recent research has revealed that adaptations to chronic morphine involve not only the impairment of opioid receptor functionality but also the altered consequences of its G protein coupling. Pre-eminent among the biochemical perturbations that underlie the chronic morphine-induced emergence of new signalling strategies are enhanced phosphorylation and altered expression of key signalling molecules. These molecular changes include the up-regulation and augmented phosphorylation of adenylyl cyclase type II isoforms, which underlies the ability of morphine to shift opioid receptor G protein signalling from predominantly Gialpha inhibitory to Gbetagamma stimulatory. Persistent morphine exposure also enhances the concomitant phosphorylation of G protein receptor kinase, beta arrestin and the G protein Gbeta subunit, one consequence of which is to further enhance G protein receptor signalling via the Gbetagamma subunit. This review will focus on our increasing understanding of the importance of qualitative changes among components of opioid receptor-coupled signalling pathways, as opposed to the interruption of such signalling, as the predominant mode of adapting to the presence of opioids.
大多数关于阿片受体持续激活后果的阐述都集中在阿片受体偶联信号传导机制的减弱或丧失上。激活相反的代偿性回路仍然是另一种被认为是麻醉药长期给药后其镇痛效力极度丧失的潜在适应机制。最近的研究表明，对慢性吗啡的适应不仅涉及阿片受体功能的损害，还涉及其G蛋白偶联后果的改变。在慢性吗啡诱导新信号策略出现的生化扰动中，突出的是关键信号分子磷酸化增强和表达改变。这些分子变化包括II型腺苷酸环化酶亚型的上调和磷酸化增加，这是吗啡将阿片受体G蛋白信号从主要的Gαi抑制性转变为Gβγ刺激性的能力的基础。持续的吗啡暴露还会增强G蛋白受体激酶、β抑制蛋白和G蛋白Gβ亚基的伴随磷酸化，其结果之一是通过Gβγ亚基进一步增强G蛋白受体信号传导。本综述将重点关注我们对阿片受体偶联信号通路成分间性质变化重要性的日益理解，这与此类信号传导的中断相反，是适应阿片类药物存在的主要方式。
