Content area
Full text
About the Authors:
Mary R. Lee
* E-mail: [email protected]
Affiliation: National Institute on Drug Abuse, Intramural Research Program, Baltimore, Maryland, United States of America
Courtney L. Gallen
Affiliation: National Institute on Drug Abuse, Intramural Research Program, Baltimore, Maryland, United States of America
Xiaochu Zhang
Affiliation: National Institute on Drug Abuse, Intramural Research Program, Baltimore, Maryland, United States of America
Colin A. Hodgkinson
Affiliation: National Institute on Alcohol Abuse and Alcoholism, Intramural Research Program, Rockville, Maryland, United States of America
David Goldman
Affiliation: National Institute on Alcohol Abuse and Alcoholism, Intramural Research Program, Rockville, Maryland, United States of America
Elliot A. Stein
Affiliation: National Institute on Drug Abuse, Intramural Research Program, Baltimore, Maryland, United States of America
Christina S. Barr
Affiliation: National Institute on Alcohol Abuse and Alcoholism, Intramural Research Program, Rockville, Maryland, United States of America
Introduction
Mu-opioid receptors are located throughout extended brain circuits involved in positive reinforcement and are critical in processing reward, analgesia, and stress responses, reviewed in [1]. Given the important role of this receptor in motivational states, natural reward, and the development of addiction [2], there has been interest in identifying variations in the mu-opioid receptor gene that predict individual differences in reward processes and potentially addiction vulnerability [3].
A commonly occurring non-synonymous SNP (rs1799971; OPRM1 A118G) results in an amino-acid substitution (Asn40Asp or N40D) in the N-terminal region of the mu-opioid receptor. The polymorphism was originally shown to confer a 3-fold increase in affinity for the endogenous ligand, ß-Endorphin [4], although more recent studies have shown the effects of the G allele on affinity for ß-Endorphin to be cell-line dependent, and further, that variant, G-allele, receptors exhibit significantly lower cell-surface receptor binding site availability compared with the prototype 118A receptor [4]–[6]. Further, using a knock-in mouse model of the human A118G SNP, Mague et al. [7] found decreased mRNA expression and receptor protein levels in mice heterozygous for the G allele. Similarly, a human post-mortem study [8] also found decreased mRNA in G118 allele carriers. Taken together, the precise functional consequence of this variant in humans remains unclear.
Although much of the work on the effects of the OPRM1 polymorphism has been in the addiction field, particularly alcohol–induced euphoria, dependence, and treatment response [2], more recent studies suggest that...