Ueda Hiroshi, Inoue Makoto, Mizuno Kiyonobu
Division of Molecular Pharmacology and Neuroscience, Nagasaki University Graduate School of Biomedical Sciences, 1-14 Bunkyo-machi, 852-8521, Nagasaki, Japan.
Life Sci. 2003 Dec 5;74(2-3):313-20. doi: 10.1016/j.lfs.2003.09.018.
Morphine is now believed not to cause tolerance and dependence when it is appropriately used in clinic. However, in terminal cancer pain, patients' analgesic tolerance to morphine is developed due to the use of high doses of morphine for complete blockade of pain. At higher doses, morphine has more opportunity to show serious side effects, which worsens quality of life (QOL), and leads to the use of potent analgesic adjuvants to reduce the morphine dosage. Here we attempt to summarize recent studies of the molecular basis of morphine tolerance and dependence, and to discuss whether these mechanisms could provide new molecular targets as analgesic adjuvants. They include protein kinase C inhibitor, opioid agonist with low RAVE value, and antagonists of antiopioid receptors (GluRepsilon1 or nociceptin/OFQ receptor). In addition, we demonstrate new approaches to find further candidates of such molecular targets. These approaches include the visualization of neuronal networks in the downstream of opioid neurons by use of the WGA transgene technique and the single cell dissection technique to get new genes involved in plasticity during morphine tolerance and dependence.
目前认为，吗啡在临床合理使用时不会导致耐受性和依赖性。然而，在晚期癌症疼痛中，由于使用高剂量吗啡以完全阻断疼痛，患者会对吗啡产生镇痛耐受性。在较高剂量下，吗啡更易出现严重副作用，这会恶化生活质量（QOL），并导致使用强效镇痛佐剂以减少吗啡用量。在此，我们试图总结吗啡耐受性和依赖性分子基础的近期研究，并讨论这些机制是否能提供新的分子靶点作为镇痛佐剂。它们包括蛋白激酶C抑制剂、低RAVE值的阿片类激动剂以及抗阿片受体（GluRepsilon1或孤啡肽/孤啡肽FQ受体）拮抗剂。此外，我们展示了寻找此类分子靶点更多候选物的新方法。这些方法包括利用WGA转基因技术和单细胞解剖技术观察阿片神经元下游神经网络，以获取参与吗啡耐受性和依赖性可塑性过程的新基因。
