Faculty of Environmental Science and Engineering, Kunming University of Science and Technology, Kunming 650500, China.
Free Radic Biol Med. 2012 Apr 1;52(7):1218-27. doi: 10.1016/j.freeradbiomed.2012.01.004. Epub 2012 Jan 18.
There are few efficacious interventions to combat morphine dependence. Thioredoxin-1 (Trx-1) and heat shock protein 70 (Hsp70) are emerging as important modulators of neuronal function. They have been shown to be involved in cellular protective mechanisms against a variety of toxic stressors. This study was designed to investigate the effects of geranylgeranylacetone (GGA), a pharmacological inducer of Trx-1 and Hsp70, on morphine-induced hyperlocomotion, rewarding effect, and withdrawal syndrome. Trx-1 and Hsp70 expression was increased in the frontal cortex, hippocampus, ventral tegmental area, and nucleus accumbens of mice after GGA treatment. GGA administration reduced morphine-induced motor activity and inhibited conditioned place preference. GGA markedly attenuated the morphine-naloxone-induced withdrawal signs, including jumping, rearing, and forepaw tremor. Furthermore, the activation of cAMP-responsive element-binding protein and the expression of ΔFosB and cyclin-dependent kinase 5 were decreased in the nucleus accumbens by GGA treatment after morphine withdrawal. In the nucleus accumbens, GGA enhanced morphine-induced expression of Trx-1 and Hsp70 after morphine withdrawal. These results suggest that strengthening the expression of Trx-1 and Hsp70 in the brain by using noncytotoxic pharmacological inducers may provide a novel therapeutic strategy for morphine dependence. GGA could be a safe and novel therapeutic agent for morphine dependence.
目前针对吗啡成瘾，并没有有效的治疗干预手段。硫氧还蛋白-1（Trx-1）和热休克蛋白 70（Hsp70）作为神经元功能的重要调节因子，在多种毒性应激反应的细胞保护机制中发挥着重要作用。本研究旨在探讨金诺芬（一种诱导 Trx-1 和 Hsp70 的药理学诱导剂）对吗啡引起的过度活动、奖赏效应和戒断综合征的影响。金诺芬处理后，小鼠的前额叶皮层、海马体、腹侧被盖区和伏隔核中的 Trx-1 和 Hsp70 表达增加。金诺芬可减少吗啡引起的运动活动，并抑制条件性位置偏爱。金诺芬显著减轻了吗啡-纳洛酮引起的戒断症状，包括跳跃、竖起和前爪震颤。此外，吗啡戒断后，GGA 处理还降低了伏隔核中 cAMP 反应元件结合蛋白的激活以及 ΔFosB 和细胞周期蛋白依赖性激酶 5 的表达。在伏隔核中，GGA 增强了吗啡戒断后吗啡诱导的 Trx-1 和 Hsp70 的表达。这些结果表明，使用非细胞毒性药理学诱导剂增强大脑中 Trx-1 和 Hsp70 的表达可能为吗啡成瘾提供一种新的治疗策略。金诺芬可能是一种安全有效的吗啡成瘾治疗药物。
