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

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Abstract

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.

Original languageEnglish
Pages (from-to)243-250
Number of pages8
JournalBehavioural Brain Research
Volume152
Issue number2
DOIs
Publication statusPublished - 09-07-2004
Externally publishedYes

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Morphine Dependence
Dehydroepiandrosterone Sulfate
Extracellular Signal-Regulated MAP Kinases
Protein Kinases
Morphine
Steroids
Naloxone
Cyclic AMP
Frontal Lobe
Thalamus
Messenger RNA
Analgesia
Neurotransmitter Agents
Analgesics
Phosphorylation

All Science Journal Classification (ASJC) codes

  • Behavioral Neuroscience

Cite this

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title = "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",
abstract = "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.",
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AU - Noda, Yukihiro

AU - Mamiya, Takayoshi

AU - Nagai, Taku

AU - Nabeshima, Toshitaka

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