SINGLE-NUCLEOTIDE POLYMORPHISM IN THE HUMAN MU-OPIOID RECEPTOR GENE ALTERS BETA-ENDORPHIN BINDING AND ACTIVITY - POSSIBLE IMPLICATIONS FOR OPIATE ADDICTION

Opioid drugs play important roles in the clinical management of pain, as well as in the development and treatment of drug abuse. The mu opio id receptor is the primary site of action for the most commonly used o pioids, including morphine, heroin, fentanyl, and methadone. By sequen cing DNA from 113 former heroin addicts in methadone maintenance and 3 9 individuals with no history of drug or alcohol abuse or dependence, we have identified five different single-nucleotide polymorphisms (SNP s) in the coding region of the mu opioid receptor gene, The most preva lent SNP is a nucleotide substitution at position 118 (A118G), predict ing an amino acid change at a putative N-glycosylation site. This SNP displays an allelic frequency of approximately 10% in our study popula tion, Significant differences in allele distribution were observed amo ng ethnic groups studied. The variant receptor resulting from the A118 G SNP did not show altered binding affinities for most opioid peptides and alkaloids tested. However, the A118G variant receptor binds beta- endorphin, an endogenous opioid that activates the mu opioid receptor, approximately three times more tightly than the most common allelic f orm of the receptor, Furthermore, beta-endorphin is approximately thre e times more potent at the A118G variant receptor than at the most com mon allelic form in agonist-induced activation of G protein-coupled po tassium channels. These results show that SNPs in the mu opioid recept or gene can alter binding and signal transduction in the resulting rec eptor and may have implications for normal physiology, therapeutics, a nd vulnerability to develop or protection from diverse diseases includ ing the addictive diseases.