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

Xiuhai Ren, Yukihiro Noda, Takayoshi Mamiya, Taku Nagai, Toshitaka Nabeshima

研究成果: Article

52 引用 (Scopus)


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 (10 mg/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 (10 mg/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.

ジャーナルBehavioural Brain Research
出版物ステータスPublished - 09-07-2004


All Science Journal Classification (ASJC) codes

  • Behavioral Neuroscience