Mechanisms involved in phosphatidylinositol 3-kinase pathway mediated up-regulation of the mu opioid receptor in lymphocytes.

Despite the substantial progress made in understanding initiation expression of the MOR gene in lymphocytes, the signal pathway associated with MOR gene transcription remains to be better defined. As the phosphatidylinositol 3-kinase (PI3K)/AKT pathway can mediate diverse biological responses and is crucial for optimal immune responses and lymphocyte development, this study was undertaken to delineate the role of PI3K/AKT signaling in expression of the MOR gene in CEM x174 cells. The data show that morphine treatment enhanced the level of phosphorylated, rather than un-phosphorylated, PI3K and AKT, which were synchronously recruited to membrane. The levels of PTEN and p53 which are negative regulators of these signal molecules were reduced, and as a result, the interaction between PTEN and p53 was completely interrupted. With morphine treatment, the levels of both cytoplasmic and nuclear E2F1 which is the downstream effecter of AKT were elevated and the interaction of E2F1 with YY1, rather than Sp1, was also increased. Subsequently, E2F1 triggered the transcription of the MOR gene through its enhanced ability to bind the element in promoter region of the MOR gene. All responses to morphine were abolished by naloxone, which is an antagonist of MOR, or by LY294002, an inhibitor of PI3K, implying specific involvement of PI3K/AKT. These results strongly suggest that the PI3K/AKT pathway plays a critical role in the transfer of signal from morphine stimuli to the machinery by which MOR gene transcription is initiated.