Pharmacogenetics of opioid receptors and addiction

It is generally assumed that combinations of polymorphic alleles of different genes contribute to polygenetic disorders. Variants of the opioid receptors are the obvious candidates underlying addiction. Most research has focused on the coding variation A118G of the mu opioid receptor (MOPr), which replaces asparagine at position 40 by aspartate (Asn40Asp). However, to date, no conclusive evidence exists regarding which physiological effects this mutation may cause. Other rare polymorphisms in the MOPr cause marked effects (e.g. impairment of G-protein coupling) but, due to their low frequency, their role in addiction is questionable. A large number of polymorphic sites have been found in the putative promoter region of the mu opioid receptor. These variations may alter the expression level of the receptors in neurones, but the functional relevance of promoter polymorphisms is hard to predict. In the delta opioid receptor, surprisingly few polymorphisms have been detected within the coding region, and a clear association with addiction has not been shown to date. The kappa opioid receptor contains mainly silent polymorphisms. Nevertheless, there are studies reporting positive associations of silent mutations in the three opioid receptors with drug addiction. The underlying mechanism remains unclear, but examples exist indicating that silent mutations affect mRNA stability. Taken together, the coding polymorphisms, which are rather frequent, reveal no convincing association. The vast number of non-coding, intronic or promoter polymorphisms in the opioid receptors may influence addictive behaviour, but these polymorphisms are far less studied, and their physiological significance remains to be demonstrated.