Ueda Hiroshi, Matsushita Yosuke
Division of Molecular Pharmacology and Neuroscience, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8523.
Masui. 2009 Sep;58(9):1136-42.
Although the opioid analgesics such as morphine represent an important class of agents for the treatment of severe clinical pain, the development of tolerance and dependence often overshadows the therapeutic advantages of morphine and related opioids in individuals undergoing long-term treatments. The mechanisms underlying opioid tolerance are not fully understood, but appear to be comprised of two types of plasticity or counter-adaptation, at the cellular level and through neuronal circuits. Current studies mostly emphasize the cellular adaptation mechanisms, which include altered gene expression and receptor desensitization due to phosphorylation and endocytosis. However, the mechanisms underlying opioid tolerance and dependence are not always explained by cellular adaptation mechanisms alone. This review focuses on the plasticity in neuronal circuits achieved through an enhancement of so-called anti-opioid glutamate/NMDA receptor synaptic activities. There have been also conceptual advances in understanding the changes to supporting systems, which include the altered expression of key molecules regulating the anti-opioid system through neuron-glial networks. We also introduce a new approach using in vivo electroporation to identify the brain loci responsible for morphine tolerance and dependence.
尽管诸如吗啡之类的阿片类镇痛药是治疗严重临床疼痛的一类重要药物，但耐受性和依赖性的发展常常掩盖了吗啡及相关阿片类药物在长期治疗患者中的治疗优势。阿片类药物耐受性的潜在机制尚未完全明确，但似乎包括细胞水平和通过神经回路的两种可塑性或适应性变化。目前的研究大多强调细胞适应性机制，其中包括由于磷酸化和内吞作用导致的基因表达改变和受体脱敏。然而，阿片类药物耐受性和依赖性的潜在机制并不总是仅由细胞适应性机制来解释。本综述重点关注通过增强所谓的抗阿片类谷氨酸/NMDA受体突触活动而在神经回路中实现的可塑性。在理解支持系统的变化方面也有了概念上的进展，其中包括通过神经元-胶质细胞网络调节抗阿片类系统的关键分子的表达改变。我们还介绍了一种使用体内电穿孔来确定负责吗啡耐受性和依赖性的脑区的新方法。
