Another key finding indicating compromised integrity of MOR signaling in heroin abuse was the dysregulation of the MAPK/ERK pathway, including differential alterations of ERK1 and ERK2. Most studies have normally assumed that measures of ERK1 are indicative of ERK2 alterations since MEK phosphorylates both these kinases. However, ERK1 inhibits ERK2.(80) Thus increased ERK2 levels observed in the heroin abusers would be in line with compensation for the decreased ERK1 expression. Altogether such aberrant signaling activity of MEK1 and ERK1/2 would be expected to contribute to subsequent downstream changes in ELK1 and gene expression that mediate cellular adaptations to repeated heroin exposure. In summary, the current results demonstrate that the striatum of human heroin abusers is characterized by dysregulation of MOR signaling and the MAPK pathway linked to disturbances of the downstream transcription factor, ELK1. The importance of ELK1 impairment is highlighted by the fact that it targeted the promoter of a large proportion of the repressed genes in the NAc of heroin abusers. The significant contribution of heroin intake history and OPRM1 polymorphisms to individual differences in ELK1 expression also
