A Polymorphism of the ?-Opioid Receptor Gene
(OPRM1) and Sensitivity to the Effects of Alcohol in
Lara A. Ray and Kent E. Hutchison
Background: Recent research has implicated the endogenous opioid system in the development of
alcohol use disorders. The A118G polymorphism of the OPRM1 gene has been shown to confer functional
the A variant. The goal of this study was to test whether the A118G polymorphism is associated with
sensitivity to the effects of alcohol.
Methods: Participants who were either homozygous for the A allele (n ? 23) or heterozygous (n ? 15)
received intravenous doses of alcohol designed to reach three target levels of breath alcohol concentration:
0.02, 0.04, and 0.06. The testing procedure consisted of measures of subjective intoxication, stimulation,
sedation, and mood states at baseline and at each of the three target breath alcohol concentrations.
Results: The results suggested that individuals with the G allele reported higher subjective feelings of
intoxication, stimulation, sedation, and happiness across trials as compared with participants with the A
allele. Furthermore, participants with the G allele were almost three times more likely to report a positive
family history of alcohol use disorders than participants with the A allele.
Conclusions: These findings may help to explain previous research suggesting that naltrexone is more
effective among individuals with the G allele. A medication that reduces feelings of euphoria after alcohol
consumption may be more successful among individuals with a genetic predisposition to greater feelings of
euphoria after consuming alcohol.
Key Words: Alcohol, Sensitivity, Gene, Phenotype, OPRM1.
mately half of the variability in risk (Heath and Phil, 1995).
Over the past several years, considerable research efforts
have focused on identifying genetic markers for alcohol
abuse and dependence. The search for the genetic under-
pinnings of alcoholism has to a great extent relied on a
candidate gene approach to examine genes of putative
etiological relevance. The endogenous opioid system has
been associated with the pathophysiology of substance de-
pendence, including alcohol addiction (for review, see Bod-
nar and Hadjimarkou, 2003; Gianoulakis, 2001). Evidence
to support this association comes from both the animal (De
Waele et al., 1995) and human (Herz, 1997) literature.
Hence, the gene coding for the ?-opioid receptor (OPRM1)
LCOHOLISM IS A complex disorder with a strong
genetic component that may account for approxi-
has received increased attention as a candidate gene for the
development of alcohol use disorders.
The ?-opioid receptor, which is encoded by the OPRM1
gene, is the primary site of action for opiates with high
abuse potential, such as morphine, heroin, and methadone
(Pasternack, 1993). In addition, research findings have sug-
gested that nonopioid drugs, such as cocaine and alcohol,
may exert some of their effects through the activation of
?-opioid receptors (Herz, 1997; Kreek, 1996). Specifically,
the opioidergic system is thought to mediate drug-induced
feelings of euphoria, analgesia, and withdrawal (Bond et
al., 1998; Gianoulakis, 2001), thus playing an important
role in the rewarding properties of several substances, in-
cluding alcohol. The reinforcing properties that result from
the activation of ?-receptors are thought to be related to
their interaction with the mesolimbic dopamine system, a
pathway theorized to be associated with the rewarding
effects of drugs (Gianoulakis, 2001). Furthermore, indirect
support for the role of opioid receptors in the development
and maintenance of alcohol dependence stems from phar-
macological trials demonstrating the efficacy of naltrexone,
an opioid antagonist, for the treatment of alcohol depen-
dence (Anton et al., 1999; Balldin et al., 2003; Kiefer et al.,
2003; Monti et al., 2001; O’Malley et al., 1992; Volpicelli et
From the University of Colorado at Boulder.
Received for publication May 12, 2004; accepted August 28, 2004.
This research was supported by NIAAA Grants F31 AA14847 (LAR) and
R01 AA12238 (KEH) and by Grant M01 RR00051 from the General Clinical
Research Center Program of the National Center for Research Resources,
National Institutes of Health.
Reprint requests: Kent E. Hutchison, PhD, University of Colorado, Depart-
CO 80309-0345; Fax: 303-492-2967; E-mail: firstname.lastname@example.org.
Copyright © 2004 by the Research Society on Alcoholism.
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OPRM1 AND SENSITIVITY TO ALCOHOL