Chronic morphine intoxication reduces binding of HuD to BDNF long 3′-UTR, while morphine withdrawal stimulates BDNF expression in the frontal cortex of male Wistar rats

Abstract

Background Brain-derived neurotrophic factor (BDNF) mediates opiate dependence phenomenon. In the brain of morphine dependent animals BDNF level is controlled transcriptionally, however, post-transcriptional mechanisms of BDNF regulation in this context remain unknown. Regulation of mRNA by binding of specific proteins to the 3'-untranslated region (3′-UTR) is one of such mechanisms. Among RNA-binding proteins neuronal Hu antigen D (HuD) is the best characterized positive regulator of BDNF, however its involvement in opiate dependence remains obscure. We suggested that HuD binding to the BDNF 3′-UTR may be linked to changes in BDNF expression induced by morphine. The aim of this study was to investigate potential association of HuD with BDNF 3′-UTR in relation to BDNF expression (Exon- and 3′-UTR-specific mRNA variants and protein level) in the frontal cortex and midbrain of male Wistar rats after chronic morphine intoxication and spontaneous withdrawal in dependent animals. Results After chronic morphine intoxication but not during morphine withdrawal HuD binding to the long BDNF 3′-UTR in the frontal cortex decreased as compared with the corresponding control group, however after intoxication BDNF expression did not change. The level of BDNF Exon I as well as mature BDNF polypeptide increased in the frontal cortex upon morphine withdrawal, while no changes in HuD binding could be detected. Conclusion Thus, contrary to the assumption, HuD-BDNF 3′-UTR interaction and BDNF expression in the frontal cortex differentially change in a manner dependent on the context of morphine action.