A neuroactive steroid, dehydroepiandrosterone sulfate, prevents the development of morphine dependence and tolerance via c-fos expression linked to the extracellular signal-regulated protein kinase
A neuroactive steroid, dehydroepiandrosterone sulfate, prevents the development of morphine dependence and tolerance via c-fos expression linked to the extracellular signal-regulated protein kinase
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DOI：
10.1016/j.bbr.2003.10.013
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发表时间：
2004-07
影响因子：
2.7
通讯作者：
X. Ren;Y. Noda;T. Mamiya;T. Nagai;T. Nabeshima
中科院分区：
文献类型：
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作者：
X. Ren;Y. Noda;T. Mamiya;T. Nagai;T. Nabeshima
本研究探讨了神经甾体硫酸脱氢表雄酮（DHEAS）对小鼠吗啡依赖和耐受的影响。吗啡（10 mg/kg）每日2次连续给药5天，小鼠对吗啡的镇痛作用产生耐受，并出现依赖性，表现为纳洛酮诱导的严重戒断症状。DHEAS（10 mg/kg）与吗啡合用可显著抑制吗啡镇痛耐受和纳洛酮催促戒断反应的发生，但不影响其表达。在纳洛酮催促戒断症状小鼠的额叶皮质和丘脑中观察到c-fos mRNA的表达，而DHEAS与吗啡联合给药显著降低c-fos mRNA的表达。在纳洛酮催促戒断，小鼠表现出显着的升高，环腺苷酸（cAMP）水平在丘脑，而慢性给药的DHEAS与吗啡没有影响cAMP的增加。有趣的是，重复共同管理的DHEAS与吗啡阻止戒断诱导的细胞外信号调节蛋白激酶（ERK）2在额叶皮层的磷酸化。结果表明，DHEAS可抑制吗啡耐受和依赖的形成，其作用机制可能与调节c-fos mRNA表达有关，可能与ERK信号通路的激活有关，而与cAMP信号通路无关。
In the present study, we investigated how the neurosteroid, dehydroepiandrosterone sulfate (DHEAS) affects the development of morphine dependence and tolerance in mice. Mice administered morphine (10mg/kg) twice a day for 5 days developed tolerance to the analgesic effect and dependence as shown by a severe withdrawal syndrome induced by naloxone. Co-administration of DHEAS (10mg/kg) with morphine significantly inhibited the development, but not the expression, of tolerance to morphine-induced analgesia and the naloxone-precipitated withdrawal. The expression of c-fos mRNA was observed in the frontal cortex and thalamus of mice showing signs of naloxone-precipitated withdrawal, while the expression of c-fos mRNA was significantly diminished by co-administration of DHEAS with morphine. On the naloxone-precipitated withdrawal, mice showed a significant elevation of cyclic AMP (cAMP) levels in the thalamus, whereas chronic administration of DHEAS with morphine did not affect the increase in cAMP. Interestingly, repeated co-administration of DHEAS with morphine prevented the withdrawal-induced phosphorylation of extracellular signal-regulated protein kinase (ERK) 2 in the frontal cortex. These results showed that DHEAS prevented the development of morphine tolerance and dependence and suggested that the attenuating effects of DHEAS might result from the regulation of c-fos mRNA expression, which is possibly involved the signaling activation of ERK, but not of cAMP pathway.