| Recently, drug addiction has become a significant social and healthy problem feazing the human being. Drug addiction is a chronic, repeated brain disease which is by interaction of drug abuse and brain reward system, and has symptoms of compulsive drug use and constantly craving. The encephalic regions related to addiction are prefrontal cortex, hippocampus, nucleus ceruleus, nucleus accumbens, amygdale, striatum, caudate nucleus and so on. Studies showed that redox equilibrium was involved in the happening and developing of opioid addiction. Meanwhile, there are changes of oxidative stress associated protein during the process of opioid addiction by proteomics technology.Thioredoxin(Trx) is an important protein which regulates oxidative stress. It is a low molecular weight protein extensively existed in prokaryote and eukaryote and contains the conservative active site of Cys-Gly-Pro-Cys. As a multiple-effects cytokine, Trx has important biology functions. Promoter sequence analysis of Trx gene shows that it contains antioxidant responsive element, cAMP responsive element and several binding site for SP-1. An important molecular basis of opiate addiction is that it can up-regulate cAMP, activate CREB and cause the changes of expression of some drug addiction associated genes such as BDNF, CDK5, GDNF and t-PA. These properties provide us with the study hypothesis on the mechanisms on drug addiction. More and more researches performed on drug addition have been reported. However, the relationship between Trx and addiction hasn't been reported yet.The effect of morphine on Trx expression was investigated by using human neuroblastoma SH-SY5Y at a cellular level. Our data showed that Trx expression was increased after exposure to morphine at the concentration of 20μM and this effect was in a dose-dependent manner. Trx is also induced by morphine in time-dependent manner. Trx expression was significantly suppressed after 1-3 h then guadually increased from 6-24 h. Trx expression was suppressed by the inhibitor of PI3K, LY294002. The decreased expression of Trx was restored by an inhibitor of GSK3β, lithium chloride. Also the expression of Trx induced by morphine was suppressed by the antagonist of opioid receptor naloxone. Whereas Trx was restored to the normal level compared with the control group after removal of morphine for 1 h,2 h,3 h,4 h.Privious studies indicated that cyclin dependent kinases-5(Cdk5) has an important regulate roles in drug addiction. Therefore, we also detected the expression of CDK5 in our study. Our results showed that CDK5 had the same alterations with Trx changes after morphine treatment. The expression of CDK5 was suppressed by LY294002. The decreased expression of CDK5 was restored by LiCl. Also the expression of CDK5 induced by morphine was suppressed by naloxone. CDK5 was restored to the normal level after removal of morphine for1 h,2 h,3 h,4 h.Taken together, our study suggested that Trx expression induced by morphine in dose and time-dependent manner. We also elucidated a post-receptor signalling pathway by which morphine induced Trx expression. Interestingly, CDK5 had the same alterations with Trx changes after morphine treatment. These results indicated that Trx may be involved in the process of drug addiction. Thus, Trx is a good candidate for the study on the drug addiction.
|
PDF Full Text Request