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Addiction and rewarding effect is a primary side effect of morphine, which is commonly used to relieve the acute or chronic pain. Several lines of evidence have suggested that inflammation response in the VTA contributes to morphine-induced reward (conditioned place preference, CPP), while the mechanism are poorly understood. The present study showed that repeated morphine conditioning persistently increased the expression of CXCL12 mRNA and protein in VTA. Furthermore, inhibition of CXCL12 prevented the acquisition and maintenance, but not the expression, of morphine-induced CPP in rodent. In addition, molecular analysis revealed that morphine conditioning increased the occupancy of p-STAT3 in the specific binding site (-1667/-1685) of CXCL12 promoter regions, and enhanced the interaction between acetyltransferase p300 and STAT3, and, hence, induced the histone H4 hyperacetylation in the promoter region and facilitated the transcription and expression of CXCL12 in VTA. Collectively, these results, for the first time, provided the evidence that persisted increase of VTA CXCL12 via epigenetic mechanism mediated the acquisition and maintenance, but not the expression, of morphine CPP.Persistently increased CXCL12 expression in the VTA contributed to the acquisition and maintenance of morphine CPP.p-STAT3 bound to special sites in the CXCL12 promoter region and regulated CXCL12 expression.Interaction between p-STAT3 and P300 induced epigenetic upregulation of CXCL12 after morphine conditioning.