Discipline of Pharmacology, School of Medical Science, University of Adelaide, South Australia, Australia, 5005.
Pharmacol Rev. 2011 Sep;63(3):772-810. doi: 10.1124/pr.110.004135. Epub 2011 Jul 13.
Vastly stimulated by the discovery of opioid receptors in the early 1970s, preclinical and clinical research was directed at the study of stereoselective neuronal actions of opioids, especially those played in their crucial analgesic role. However, during the past decade, a new appreciation of the non-neuronal actions of opioids has emerged from preclinical research, with specific appreciation for the nonclassic and nonstereoselective sites of action. Opioid activity at Toll-like receptors, newly recognized innate immune pattern recognition receptors, adds substantially to this unfolding story. It is now apparent from molecular and rodent data that these newly identified signaling events significantly modify the pharmacodynamics of opioids by eliciting proinflammatory reactivity from glia, the immunocompetent cells of the central nervous system. These central immune signaling events, including the release of cytokines and chemokines and the associated disruption of glutamate homeostasis, cause elevated neuronal excitability, which subsequently decreases opioid analgesic efficacy and leads to heightened pain states. This review will examine the current preclinical literature of opioid-induced central immune signaling mediated by classic and nonclassic opioid receptors. A unification of the preclinical pharmacology, neuroscience, and immunology of opioids now provides new insights into common mechanisms of chronic pain, naive tolerance, analgesic tolerance, opioid-induced hyperalgesia, and allodynia. Novel pharmacological targets for future drug development are discussed in the hope that disease-modifying chronic pain treatments arising from the appreciation of opioid-induced central immune signaling may become practical.
上世纪 70 年代早期发现阿片受体后，人们受到了极大的启发，于是开始进行临床前和临床研究，旨在研究阿片类药物的立体选择性神经元作用，尤其是在其关键的镇痛作用中所发挥的作用。然而，在过去的十年中，临床前研究产生了对阿片类药物的非神经元作用的新认识，特别是对非经典和非立体选择性作用部位有了新的认识。新发现的先天免疫模式识别受体 Toll 样受体上的阿片类活性极大地丰富了这个不断发展的故事。目前从分子和啮齿动物数据中明显看出，这些新确定的信号事件通过引发胶质细胞（中枢神经系统的免疫细胞）的促炎反应，极大地改变了阿片类药物的药效动力学。这些中枢免疫信号事件包括细胞因子和趋化因子的释放以及谷氨酸稳态的相关破坏，导致神经元兴奋性升高，随后降低阿片类药物的镇痛效果，并导致疼痛状态加剧。这篇综述将检查经典和非经典阿片受体介导的阿片类药物引起的中枢免疫信号的当前临床前文献。阿片类药物的临床前药理学、神经科学和免疫学的统一现在为慢性疼痛、原始耐受、镇痛耐受、阿片类药物引起的痛觉过敏和感觉异常的共同机制提供了新的见解。讨论了新的药理学靶点，以期从阿片类药物引起的中枢免疫信号的认识中产生出可改变疾病的慢性疼痛治疗方法。
