Chronic morphine treatment and withdrawal induce up-regulation of c-Jun N-terminal kinase 3 gene expression in rat brain

Chronic opiate applications produce long-term impacts on many functions of the brain and induce tolerance, dependence, and addiction. It has been demonstrated that opioid drugs are capable to induce apoptosis of neuronal cells, but the mechanism is not clear. c-Jun N-terminal kinase 3 (JNK3), specifically expressed in brain, has been proved to mediate neuronal apoptosis and is involved in opiate-induced cell apoptosis in vitro. The present study investigated the effect of opioid administration on expression of JNK3, an important mediator involved in apoptosis of neurons, in rat brain. Our results showed that single or chronic injection of morphine resulted in a 45-50% increase in the level of JNK3 mRNA in frontal cortex, while no significant change was detected in other brain regions such as thalamus, hippocampus and locus coeruleus. Similar to what was observed after the acute or chronic morphine administration, no significant change in JNK3 expression was detected in locus coeruleus following cessation of the chronic morphine administration. However, interestingly, sustained elevation of JNK3 expression peaked on day 14 after cessation of morphine treatment was observed in the brain regions such as hippocampus and thalamus, where acute or chronic morphine treatment did not cause any significant change in JNK3 gene expression. The increased JNK3 mRNA in these brain areas returned to the control levels in 28 days following cessation of chronic morphine treatment. Taken together, these results demonstrated for the first time that the expression of JNK3 gene is regulated by opioids and that chronic opioid administration and withdrawal could induce sustained elevation of JNK3 mRNA in many important brain areas. The changes in JNK3 gene expression in brain induced by chronic opioid treatment may play a role in opioid-induced apoptosis and neurotoxicity.