Effect of opioids on Ca2+/cAMP responsive element binding protein

Ca2+ /cAMP response element binding protein (CREB) is an important factor l inking the opioid-regulated secondary messenger systems to alterations in g ene expression. Opioids regulate CREB level, its phosphorylation and bindin g to its corresponding response element in the promoters of several genes i mplicated in drug addiction. CREB mediates the action of opioids on the exp ression of several genes in brain regions responsible for drug-seeking beha vior and manifestation of signs of dependence. Moreover, alterations in CRE B level can affect the rewarding properties of morphine and regulate the se lf-administration of cocaine. At the cellular level CREB acts as convergenc e point for different cellular pathways. Opioids affect two different intra cellular mediator systems: inhibitory connected with cAMP, and stimulatory - involving calcium and the PKC pathway. Both can affect CREB but in differ ent phases of opiate action. The presence of this biphasic mechanism can ex plain the phenomenon of the induction of some CRE-controlled genes after bo th acute and chronic morphine administration. Cellular studies also highlig ht the relevance of other ATF/CREB family members which can affect Ca2+/cAM P response element (CRE) controlled transcription as well as other transcri ption factors which make the opioid induction longer lasting.