Altered levels of basal cortisol in healthy subjects with a 118G allele in exon 1 of the Mu opioid receptor gene.
ABSTRACT The mu opioid receptor is centrally involved in the development of the addictive diseases. It also modulates the stress responsive hypothalamic-pituitary-adrenal axis. Receptors encoded by the variant 118G polymorphism in exon 1 of the mu opioid receptor gene have a threefold increase in beta-endorphin binding and beta-endorphin is three times more potent in receptor-mediated activation of G protein-coupled inwardly rectifying potassium channels. Humans with this variant have increased stress response following opioid antagonism. Here, we study basal levels of adrenocorticotropic hormone and cortisol in subjects with this variant. In all, 59 healthy adults were genotyped and had morning levels of adrenocorticotropic hormone and cortisol measured following intravenous administration of saline placebo. Subjects with a 118G allele had significantly greater levels of cortisol than subjects with the prototype gene. Groups did not differ in levels of adrenocorticotropic hormone. A planned comparison revealed significantly greater cortisol in females with at least one copy of the 118G allele compared to females with the prototype gene. There was no significant effect of gender alone, nor was there a significant interaction between gender and genotype, on ACTH or cortisol. Subjects with at least one copy of the 118G allele have increased basal levels of cortisol, which may influence the susceptibility to and treatment of the stress responsive dyscrasia.
- SourceAvailable from: Anne Julsrud Haugen[Show abstract] [Hide abstract]
ABSTRACT: Earlier observations show that development of persistent pain may be associated with the genetic variability in the gene encoding for the mu-opioid receptor 1, the OPRM1 A118G (rs1799971). The aim of this study was to investigate the association between OPRM1 genotype and subjective health complaints in patients with radicular pain and disc herniation.BMC Musculoskeletal Disorders 05/2014; 15(1):161. · 1.90 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Fibromyalgia may present with widespread pain and tenderness, fatigue, anxiety, and depression and is associated with a low pain threshold. The etiology of fibromyalgia is yet to be ascertained, although both genetic and environmental factors may play a role in the susceptibility of patients to fibromyalgia. Various genetic variations have been investigated to explain fibromyalgia susceptibility and differences in pain sensitivity, pain threshold, and tolerance. The A118G rs1799971 polymorphism in the opioid receptor μ1 gene (OPRM1) is one of the candidate genes. We hypothesized that the OPRM1 polymorphism may play a role in fibromyalgia susceptibility and impact the pain intensity and pain-related symptoms in fibromyalgia patients. This study comprised of 108 patients with fibromyalgia and 100 healthy controls. Overall, the 118G allele frequency was 16.3 % and was significantly lower in patients with fibromyalgia than in the control group (13.9 and 19 %, respectively). No difference was observed between fibromyalgia patients with and without the A118G allele with regard to the Beck Depression Inventory, widespread pain index, symptom severity, and Fibromyalgia Impact Questionnaire scores. All body parts of patients with fibromyalgia demonstrated lower pressure pain thresholds (PPT) compared to controls. The PPTs were higher in the 118 A/A genotype carrier fibromyalgia patients than in 118*/G carriers; however, the differences were not significant. As the A118G polymorphism frequency was lower in fibromyalgia patients, this polymorphism may exert a protective effect against fibromyalgia in Turkish women. However, the OPRM1 polymorphism does not have a significant effect on pressure pain and fibromyalgia severity.Rheumatology International 03/2014; 34(9). · 1.63 Impact Factor
Article: Genetics of opiate addiction.[Show abstract] [Hide abstract]
ABSTRACT: Addiction to MOP-r agonists such as heroin (and also addiction to prescription opioids) has reemerged as an epidemic in the twenty first century, causing massive morbidity. Understanding the genetics contributing to susceptibility to this disease is crucial for the identification of novel therapeutic targets, and also for discovery of genetic markers which would indicate relative protection or vulnerability from addiction, and relative responsiveness to pharmacotherapy. This information could thus eventually inform clinical practice. In this review, we focus primarily on association studies of heroin and opiate addiction, and further describe the studies which have been replicated in this field, and are thus more likely to be useful for translational efforts.Current Psychiatry Reports 11/2014; 16(11):504. · 3.05 Impact Factor
Altered Levels of Basal Cortisol in Healthy Subjects with a
118G Allele in Exon 1 of the Mu Opioid Receptor Gene
Gavin Bart1, K Steven LaForge1, Lisa Borg1, Charles Lilly1, Ann Ho1and Mary Jeanne Kreek*,1
1The Laboratory of the Biology of Addictive Diseases, The Rockefeller University, New York, NY, USA
The mu opioid receptor is centrally involved in the development of the addictive diseases. It also modulates the stress responsive
hypothalamic–pituitary–adrenal axis. Receptors encoded by the variant 118G polymorphism in exon 1 of the mu opioid receptor gene
have a threefold increase in beta-endorphin binding and beta-endorphin is three times more potent in receptor-mediated activation of G
protein-coupled inwardly rectifying potassium channels. Humans with this variant have increased stress response following opioid
antagonism. Here, we study basal levels of adrenocorticotropic hormone and cortisol in subjects with this variant. In all, 59 healthy adults
were genotyped and had morning levels of adrenocorticotropic hormone and cortisol measured following intravenous administration of
saline placebo. Subjects with a 118G allele had significantly greater levels of cortisol than subjects with the prototype gene. Groups did
not differ in levels of adrenocorticotropic hormone. A planned comparison revealed significantly greater cortisol in females with at least
one copy of the 118G allele compared to females with the prototype gene. There was no significant effect of gender alone, nor was
there a significant interaction between gender and genotype, on ACTH or cortisol. Subjects with at least one copy of the 118G allele
have increased basal levels of cortisol, which may influence the susceptibility to and treatment of the stress responsive dyscrasia.
Neuropsychopharmacology (2006) 31, 2313–2317. doi:10.1038/sj.npp.1301128; published online 21 June 2006
Keywords: cortisol; adrenocorticotropin; hypothalamic–pituitary–adrenal axis; opioid receptor; genetics; human
The addictive diseases and several other psychiatric
disorders are characterized by alterations in the stress
(Ehlert et al, 2001; Kreek and Koob, 1998). In the case of
the addictive diseases, these alterations are primarily due to
the pharmacological effects of drugs of abuse but are also
influenced by developmental, environmental, and genetic
factors. As an example of the latter, nonalcoholic sons of
alcoholic fathers have altered HPA responsiveness to
alcohol and mu opioid receptor antagonism compared to
sons of nonalcoholic fathers (King et al, 1998; Schuckit et al,
1987; Wand et al, 1998). In fact, up to 50% of inter-
individual differences in basal and stress-induced cortisol
levels in healthy human volunteers may be explained by
genetic factors (Federenko et al, 2004; Linkowski et al,
1993). While this is likely due to the interaction of several
genes, so too are the genetic determinants of drug addiction.
Indeed, several genes have been associated with the
vulnerability to develop an addictive disease (for a review,
Kreek et al, 2005). Of particular interest are the genes of the
endogenous opioid system whose expression and/or protein
products are either directly or indirectly affected by each of
the substances of abuse. Self-administration of opioids,
cocaine, alcohol, and nicotine does not develop or is
reduced in mu opioid receptor gene (OPRM1) knockout
mice (Becker et al, 2000; Berrendero et al, 2002; Hall et al,
2001; Mathon et al, 2005; Roberts et al, 2000). We have
shown that a functional single nucleotide polymorphism in
the first exon of OPRM1 accounts for up to 21% of the
attributable risk for developing heroin addiction and 11% of
the risk for developing alcoholism in cohorts from central
Sweden (Bart et al, 2004, 2005).
This A118G polymorphism (rs1799971) results in an
asparagine to aspartic acid substitution at amino-acid
position 40 and leads to increased receptor-binding affinity
for the endogenous opioid beta-endorphin and increased
potency of ion channel activation following beta-endorphin
binding (Bond et al, 1998). Two other studies, one in
transiently-expressing COS cells (Befort et al, 2001), the
other in stable HEK293 cell lines (Beyer et al, 2004), did not
replicate these findings. In our prior study (Bond et al,
1998), the variant and prototype receptors were stably-
transfected AV-12 cells, which confer N-glycosylation.
These cells were chosen because, in the mu opioid receptor,
amino-acid position 40 is a putative site of glycosylation.
Further, a recent report on human receptors harvested from
Online publication: 22 May 2006 at http://www.acnp.org/citations/
Received 17 October 2005; revised 9 February 2006; accepted 16
*Correspondence: Dr MJ Kreek, The Laboratory of the Biology of
Addictive Diseases, The Rockefeller University, 1230 York Avenue,
New York, NY 10021, USA, Tel: +1 212 327 8490, Fax: +1 212 327
8574, E-mail: email@example.com
Neuropsychopharmacology (2006) 31, 2313–2317
& 2006 Nature Publishing Group All rights reserved 0893-133X/06 $30.00
post-mortem brain tissue has found that some of the
functional effects seen by Bond et al may be related to a
decrease in mu opioid receptor mRNA expression in
subjects with a variant 118G allele (Zhang et al, 2005).
Other studies have also identified reduced receptor expres-
sion in transfected cell lines of receptors encoded by the
118G allele, a finding also noted in our ongoing studies
(Beyer et al, 2004; Kroslak et al, 2003). The mu opioid
receptor system is also involved, through tonic inhibition,
in modulation of the stress responsive HPA axis and normal
volunteers with a 118G allele have an increased HPA
response (measured through levels of plasma cortisol)
following antagonism of this inhibition with the opioid
antagonist medication naloxone (Chong et al, 2006;
Hernandez-Avila et al, 2003; Wand et al, 2002).
In this report, we tested the hypothesis that, while a 118G
allele influences HPA responsivity to stress and pharmaco-
logical probes, it will not affect basal HPA activity measured
as plasma levels of ACTH and cortisol.
PATIENTS AND METHODS
In all, 59 healthy subjects (28 female) with no history of
substance abuse or dependence (including nicotine) were
recruited by newspaper advertisement and by word of
mouth. All subjects provided written informed consent for
participation in ongoing neuroendocrine studies as well as
separate written consent for genetics research. The Rock-
efeller University Institutional Review Board approved the
study protocols and consent forms.
Evaluation for medical and psychiatric inclusion and
exclusion criteria were made by an internist or psychiatrist
using clinical interview, physical exam, and review of
laboratory and corroborative data. Subjects gave informed
consent for HIV testing. Aliquots of urine were tested daily,
both during the screening process and during the inpatient
stay, for the presence of opioids, cocaine, cannabinoids, or
benzodiazepines. Subjects included in the study were free of
significant medical problems, HIV antibody negative, urine
toxicology negative, were not pregnant (urine beta-hCG
confirmation upon admission), and did not meet DSM-IV
criteria for any axis I diagnosis including substance and/or
alcohol abuse or dependence. Female subjects were not on
hormone replacement therapy or using hormonal contra-
ceptives. Subjects were not taking prescription medications,
and were not regularly using over-the-counter medications
or herbal preparations.
Subjects were admitted to the stress-minimized inpatient
unit at least one evening prior to the test date. Subjects
participated in one of six related neuroendocrine protocols
with similar methodology, however, for this report, placebo-
day data were compiled from all six studies to achieve a
large sample size. Subjects fasted at least 9h prior to the
beginning of testing (between 0930 and 1030h) and were
allowed to eat only after the first 2h of testing had elapsed.
Normal saline placebo (10ml) was administered through,
and blood was withdrawn from, an indwelling intravenous
catheter (BD Angiocath Autoguard, Becton, Dickinson,
Franklin Lakes, NJ), inserted at least an hour prior to the
beginning of testing.
Plasma adrenocorticotropic hormone (ACTH) and corti-
sol levels were determined in blood samples drawn at
sequential time points. Time points started 10min prior to,
immediately prior to, and then 10, 20, 30, 40, 50, 60, 75,
and 90minfollowing placebo
was drawn into sodium EDTA vacutainers, and immediately
placed on ice. Samples were stored on ice for up to 40min,
and then centrifuged at 41C at 3000?g for 5min.
Plasma was removed, aliquoted and stored at ?401C
until assayed. Plasma ACTH and cortisol levels were
determined in duplicate by radioimmunoassay procedures,
with slight modifications (ACTH: Nichols Institute, San
Juan Capistrano, CA; cortisol: Diagnostic Products, Los
Angeles, CA). ACTH intra- and inter-assay coefficients of
variation were 9.4 and 15.1%, respectively. Cortisol intra-
and inter-assay coefficients of variation were 2.5 and 6.0%,
Genomic DNA was isolated from peripheral blood lympho-
cytes. Approximately 100ng of genomic DNA was amplified
by polymerase chain reaction (PCR) using primers designed
to amplify the entire coding region of exon 1 of OPRM1.
PCR products were electrophoresed on agarose gel to verify
amplification size and were then purified and sequenced at
The Rockefeller University. The amplification and sequen-
cing primers have been described previously (Bart et al,
2004) and we have compared the accuracy of these primers
with a TaqMan-based methodology and found the con-
cordance of genotyping results between the two methods to
be greater than 99% (Proudnikov et al, 2004). Electropher-
ograms were analyzed by two independent readers who
were blind to the neuroendocrine data.
Area under the curve (AUC) from 0 to 90min after placebo
administration was calculated for each hormone (ACTH
and cortisol) in each subject. A two-way analysis of variance
(ANOVA), Condition by Genotype was used to evaluate the
differences between each hormone and any possible effect
of genotype. As there were only two subjects homozygous
for the 118G allele, they were combined in the analyses with
the 118G heterozygotes.
Subject demographics by A118G allele group are shown in
Table 1. Gender distribution was similar for both groups. In
accordance with previously documented differences in 118G
allele frequency among ethnicities, there were more African
Americans in the prototype group. However, there were
more Hispanics in the 118G allele group than expected.
Basal levels of ACTH and cortisol did not differ between
genders (F(1,55)¼1.82, p¼0.1832 and F(1,55)¼1.18,
p¼0.2815, respectively) (Figure 1). Area under the curve
for ACTH did not differ significantly between subjects with
a 118G allele and those without a 118G allele (F(1,55)¼3.19,
Altered basal cortisol in OPRM1 118G subjects
G Bart et al
p¼0.0794) (Figure 2a). However, subjects with a 118G allele
had significantly greater cortisol AUC than subjects without
a 118G allele (F(1,55)¼4.27, po0.05) (Figure 2b). While
there was no significant interaction between gender and
genotype for either ACTH or cortisol (F(1,55)o1.0 and
F(1,55)¼2.84, p¼0.0974, respectively), a planned compar-
ison of females with a 118G allele and those with the
prototype gene showed significantly greater cortisol AUC in
females with a 118G allele (po0.02) (Figure 2c).
In this report, we found a significant increase in basal levels
of plasma cortisol in healthy subjects with a 118G allele in
exon 1 of OPRM1. Previous reports have shown that
subjects with a 118G allele have increased cortisol response
following administration of the opioid antagonist naloxone
(Hernandez-Avila et al, 2003; Wand et al, 2002; Chong et al,
2006) and, possibly, decreased response to a social stressor
(Chong et al, 2006). These reports did not note an effect of
the 118G allele on basal levels of either ACTH or cortisol.
Interestingly, neither our study nor the other reports have
noted an effect of the 118G allele on basal or stimulated
levels of ACTH. While opioid peptide mRNA has been
detected in the adrenal medulla, there is no known adrenal
cortical expression of the mu opioid receptor and, therefore,
it is unkown whether the effect of the 118G variant allele
on cortisol in these studies is centrally or peripherally
A possible effect of gender must also be considered.
Wand et al studied only men and Hernandez-Avila et al
included only four women (three A118A and one 118G).
While Chong et al studied a large cohort including at least
30 women (21 A118A and nine A118G), no basal difference
in ACTH or cortisol was noted, although their baseline was
determined using only two time points separated by fifteen
minutes. Given positron-emission tomography (PET) ima-
ging data indicating that mu opioid receptor-binding
potential is higher in women (Zubieta et al, 1999),
replication of our findings will be needed with a larger
sample size and frequent sample measurements in order to
determine if a gene–gender interaction contributes to the
increase in basal levels of cortisol noted in 118G subjects.
Also, given the difference in ethnic distribution between
groups, the possibility of other, more ethnicity-specific
polymorphisms that influence HPA axis function cannot be
ruled out. The direct influence of ethnicity on basal and
stress-induced cortisol levels has been studied with
conflicting results, which indicates that ethnicity alone
may not influence cortisol; however, disparities in socio-
economic factors, which are often along ethnic lines may
explain these conflicting results (eg Bennett et al, 2004; Masi
et al, 2004). This study was not large enough to control for
demographic factors such as socioeconomic status and
In summary, this preliminary report shows that basal
levels of serum cortisol are significantly greater in subjects
with a 118G allele than in subjects with the prototypical
A118A genotype. Further work is needed to address whether
the differences in basal and stress-induced cortisol response
in subjects with a 118G allele are due to altered receptor
function and/or expression, and if these differences con-
tribute to the vulnerability to develop specific addictions
and other psychiatric disorders characterized by altered
HPA axis responsivity. Whether the effectiveness of
treatment agents for these disorders (such as increased
treatment response to naltrexone in alcoholics with a 118G
allele described by Oslin et al, 2003) may be influenced by
the effects of a 118G allele on HPA axis responsiveness
should also be investigated.
Table 1 Demographic Characteristics
1 or 2 copies
Male (n) 20 11
White, non-Hispanic 209
African American 173
Mean age in years (SD)34.1 (10.7)29.1 (4. 5)
Mean body mass index (SD) 25.3 (4.5) 27.1 (7.0)
Values represent absolute numbers or means. Group differences in ethnic
distribution were evaluated with a w2analysis. There was a significant difference
(w2¼10.9; df¼2; po0.01) in the proportion of ethnicities between the
prototype group and the group with a 118G allele.
0 10 20 30 40 50 60 7590
010 20 30 40 50 60 7590
shown for adrenocorticotropic hormone (ACTH, on the left) and cortisol (right). Means and SE are displayed for men and women. There was no significant
difference between genders for each hormone.
Plasma levels of adrenocorticotropic hormone and cortisol by gender. Plasma levels from just before to 90min after injection of placebo are
Altered basal cortisol in OPRM1 118G subjects
G Bart et al
This work was supported by National Institutes of Health
(NIH) grants DA05130, DA12848 and DA00049. The
research was conducted at the Rockefeller University
Hospital General Clinical Research Center (NIH/National
Center for Research Resources M01RR00102). The authors
have no involvement, financial or otherwise, that might
potentially bias their work. The authors would like to
acknowledge Matthew Randesi for expertise in sequencing
and reading electropherograms. Also acknowledged are
Johannes Adomako-Mensah, Julia Allen, Lauren Bence,
Jason Choi, Nicole Dankert, Caitlin Smith, and Matthew
Swift for technical assistance.
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AUC (0-90 min)
AUC (0-90 min)
AUC (0-90 min)
under the curve (AUC) for adrenocorticotropic hormone (ACTH) and (b) cortisol are shown for the genetic prototype group and the group with a 118G
allele. Analysis of variance showed a significant effect of the 118G allele on cortisol (po0.05) but not ACTH. (c) AUC for cortisol by genotype and gender is
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significantly greater cortisol levels than women with the prototype gene (po0.02).
Area under the curve of adrenocorticotropic hormone and cortisol by genotype (prototype vs subjects with a 118G allele). (a) The 90-min area
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Altered basal cortisol in OPRM1 118G subjects
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