There is moderate evidence for the role of genes related to the dopamine and GABA systems. The primary mechanism of opioid action is direct activation of μ-opioid receptors located on GABAergic interneurons, which inhibits GABA release resulting in disinhibition of mesolimbic dopamine neurons. Thus, opioids increase nucleus accumbens dopamine levels (Johnson & North, 1992). In addition to genes centrally related to dopaminergic signaling that have been previously identified (e.g., ANKK1/DDRD2, DRD1, and DBH) (Clarke et al., 2014; de los Cobos et al., 2007; Garrido et al., 2011; Hoenicka et al., 2010), the specific variant encoding the μ-opioid receptor (OPRM1, rs1799971, A118G) has frequently been associated with opioid dependence. However, a meta-analysis failed to detect a significant association between this OPRM1 marker and opioid dependence (Agrawal et al., 2012). Further, these genes have not been significantly represented in GWAS studies.
