**3.4 Epigenetics of OPRM1 gene and its impact on cell function**

Human genome has about 45,000-C-phosphate-G-(CpG) islands, many in the promoter regions of genes. The CpG islands are located upstream of the transcription start site to within the first exon [57]. Nielsen et al*.* [58] and Chorbov et al*.* [59] reported that in DNA obtained from peripheral lymphocytes, two of 16 CpG sites in a region of *OPRM1* gene promoter had significantly higher methylation in former heroin addicts than in controls. These two CpG sites are located in binding sites for the potential Sp1 transcription factor. Oertel et al*.* [60] showed that substitution of an A with a G at gene position +118 introduces a new CpG-methylation site at position +117, which leads to enhanced methylation of *OPRM1* gene resulting in decreased expression. Using m-fold software, Johnson et al*.* [61] showed that 118G variant demonstrated an altered folding that could affect mRNA stability. The epigenetic mechanism reported by Oertel et al*.* [60] impedes μ-OR upregulation in brain tissue, and they concluded that while in wild-type subjects, a reduced signaling efficiency associated with chronic heroin exposure was compensated for by an increased receptor density; this upregulation was absent in carriers of the 118G receptor variant due to diminished *OPRM1* mRNA transcription. The *OPRM1* 118A > G SNP variant not only reduces μ-OR signaling efficiency, but by a genetic-epigenetic interaction, also reduces OR expression and therefore, depletes the opioid system of a compensatory reaction to chronic exposure, providing evidence that a change in the genotype can cause a change in the epigenotype with major functional consequences.
