There is evidence that addiction has a genetic component. The μ opioid receptor, in particular, has been studied in relation to opioid addiction, not
only because it is an opioid drug target but also because opioid neurons have been implicated in other addictions such as alcohol dependence.
Of the coding μ opioid receptor variants, the Asn40Asp, Asn152Asp, His260Arg, His265Arg and Ser268Pro SNPs have been subjected to intensive study both pharmacologically and genetically. For example, while the Asn40Asp and Asn152Asp variants have thus far not been associated with addiction, they have properties that are distinct from the wild-type. These variants encode receptors that bind the natural β-endorphin ligand with four-fold higher affinity and appear to be trafficked to the cell membrane at reduced levels compared with the wild-type. These variants are of pharmacogenetic interest because they may alter the efficacy of some opioid compounds. Through disruption of another pathway, the Ser268Pro variant, but not the His260Arg or His265Arg variants of the μ opioid receptor, results in diminished receptor desensitization. This may result from the loss of a calmodulin kinase II site required to maintain a basal level of receptor signalling. The effect of the Ser268Pro variant may be attributable to elimination of the competition that normally exists between binding of the receptor to calmodulin kinase or the Gi/Go protein. The 268 Pro receptor variant is therefore more frequently found in the active conformation necessary for ligand binding. This may allow it to play a role in predisposition to addiction, since people expressing the receptor variant are predicted to have an altered tolerance for opioid ligands. The low frequency of the variant, even among addicted individuals, however, may limit its genetic significance.
In view of the failure to identify a single variant that is clearly associated with addiction, a pharmacogenomic approach may be the best approach to identify variant genes disrupting portions of opioid signalling. A study of μ opioid receptor genotypes resulted in the identification of a haplotype comprised of two coding SNPs, Ala6Val and Asp40Asn, that may be more frequent among opiate addicts of African-American descent, although this has not yet been replicated.
