The mouse experiment that investigated the effects of morphine on the striatal transcriptome (19) identified 661 morphine-responsive genes. Rgma was one of the top 98 genes that were down-regulated with acute morphine treatment. Consistent downregulation of Rgma was observed among 3 mouse strains, including DBA/2J, 129P3/J and SWR/J, but not C57BL/6J. However, Rgma was specifically upregulated in C57BL/6J mice (in contrast to the other 3 mouse strains) following chronic morphine treatment. The different responses of these mouse strains after chronic or acute morphine treatment may reflect genetic differences, as C57BL/6J mice have been reported to have the greatest preference for orally self-administered morphine of the strains studied (19). Further, in the current study, risk rs12442183*T-allele carriers demonstrated a higher expression of one RGMA transcript in frontal cortex. As downregulation of RGMa can result in neuroprotection and enhanced functional recovery (38) and increased RGMa in brain is associated with risk of multiple neurological disorders, including Alzheimer's disease, Parkinson's disease, and multiple sclerosis, downregulation of RGMa may have a protective effect on neurons after acute morphine treatment, while upregulation of RGMa may induce brain vulnerability with chronic morphine treatment.
