Taylor D A, Fleming W W
Department of Pharmacology and Toxicology, Robert C. Byrd Health Sciences Center, P.O. Box 9223, West Virginia University School of Medicine, Morgantown, WV 26506-9223, USA.
J Pharmacol Exp Ther. 2001 Apr;297(1):11-8.
The cellular basis of tolerance to, and dependence upon, many types of drugs, including opioids, has long defied identification. Tolerance to opioids cannot be explained solely on the basis of modification of opioid receptors or altered metabolism or disposition of the opioid. The development of tolerance following chronic exposure to opioids presents at least three different types of change in cellular responsiveness, each of which has been suggested to represent some type of adaptive modification in cellular responsiveness. These different forms of tolerance are distinguishable on the basis of their time course and whether or not the tolerance is specific for opioid receptor agonists (homologous) or extends to agonists of other systems (heterologous). The adaptive modulation of responsiveness via regulation of cellular proteins has been proposed to be the basis for both longer-term forms of tolerance. The divergent signaling pathways activated by G-protein-coupled receptors like the mu-opioid receptor provide multiple downstream targets for both short- and long-term regulation of cell function that is associated with the development of tolerance and/or dependence. Since the magnitude of receptor activation is an important determinant of the degree to which various signaling pathways are activated, the expressed characteristics of tolerance and/or dependence may be functionally related to which of these diverse pathways are stimulated to the greatest degree. Thus, the possibility that different signaling events are activated either sequentially or concurrently offers the possibility to explain the interaction between these different forms of tolerance and/or dependence.
长期以来，包括阿片类药物在内的许多类型药物的耐受性及依赖性的细胞基础一直难以确定。对阿片类药物的耐受性不能仅通过阿片受体的修饰、阿片类药物代谢或处置的改变来解释。长期接触阿片类药物后耐受性的发展呈现出细胞反应性的至少三种不同类型的变化，每种变化都被认为代表了细胞反应性的某种适应性修饰。这些不同形式的耐受性可根据其时间进程以及耐受性是否对阿片受体激动剂具有特异性（同源性）或是否扩展到其他系统的激动剂（异源性）来区分。通过调节细胞蛋白对反应性进行适应性调节已被认为是两种长期耐受性形式的基础。像μ-阿片受体这样的G蛋白偶联受体激活的不同信号通路为与耐受性和/或依赖性发展相关的细胞功能的短期和长期调节提供了多个下游靶点。由于受体激活的程度是各种信号通路被激活程度的重要决定因素，耐受性和/或依赖性的表现特征可能在功能上与这些不同通路中被最大程度刺激的通路相关。因此，不同信号事件依次或同时被激活的可能性为解释这些不同形式的耐受性和/或依赖性之间的相互作用提供了可能。
