DNA hypermethylation of specific CpG sites in the OPRM1 promoter region found in former heroin addicts could be the result of several independent, but by no means exclusive, mechanisms. Increased DNA methylation could be a predisposing factor for vulnerability to develop heroin addiction. Such a methylation state might be inherited through genomic imprinting. Hypermethylation also may be a result of life events occurring prior to trying heroin. Finally, chronic heroin use or long-term methadone pharmacotherapy may modulate DNA methylation. Long-term heroin addiction, with its repeated cycles of on/off effects due to heroin’s short half-life, may down-regulate OPRM1 expression through a negative feedback mechanism involving DNA methylation. Conversely, the relatively constant level of μ-opioid receptor ligand perfusion resulting from long-acting pharmacokinetics of methadone may increase DNA methylation. Studies of heroin addicts at entrance into methadone pharmacotherapy, and when well-stabilized, should resolve this issue.
