COMT val158met Polymorphism and Neural Pain
Christian Schmahl1., Petra Luda ¨scher1*., Wolfgang Greffrath2., Anja Kraus1, Gabriele Valerius1,
Thomas G. Schulze3, Jens Treutlein4, Marcella Rietschel4, Michael N. Smolka5, Martin Bohus1
1Department of Psychosomatic Medicine and Psychotherapy, Central Institute of Mental Health, Mannheim, Germany, 2Division of Neurophysiology, Center of
Biomedicine and Medical Technology, Mannheim, Germany, 3Department of Psychiatry and Psychotherapy, University Medical Center, Goettingen, Germany,
4Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Mannheim, Germany, 5Department of Psychiatry and Psychotherapy, Technische
Universita ¨t Dresden, Dresden, Germany
A functional polymorphism (val158met) of the gene coding for Catechol-O-methyltransferase (COM) has been demonstrated
to be related to processing of emotional stimuli. Also, this polymorphism has been found to be associated with pain
regulation in healthy subjects. Therefore, we investigated a possible influence of this polymorphism on pain processing in
healthy persons as well as in subjects with markedly reduced pain sensitivity in the context of Borderline Personality
Disorder (BPD). Fifty females (25 patients with BPD and 25 healthy control participants) were included in this study.
Genotype had a significant – though moderate - effect on pain sensitivity, but only in healthies. The number of val alleles
was correlated with the BOLD response in several pain-processing brain regions, including dorsolateral prefrontal cortex,
posterior parietal cortex, lateral globus pallidus, anterior and posterior insula. Within the subgroup of healthy participants,
the number of val alleles was positively correlated with the BOLD response in posterior parietal, posterior cingulate, and
dorsolateral prefrontal cortex. BPD patients revealed a positive correlation between the number of val alleles and BOLD
signal in anterior and posterior insula. Thus, our data show that the val158met polymorphism in the COMT gene contributes
significantly to inter-individual differences in neural pain processing: in healthy people, this polymorphism was more related
to cognitive aspects of pain processing, whereas BPD patients with reduced pain sensitivity showed an association with
activity in brain regions related to affective pain processing.
Citation: Schmahl C, Luda ¨scher P, Greffrath W, Kraus A, Valerius G, et al. (2012) COMT val158met Polymorphism and Neural Pain Processing. PLoS ONE 7(1):
Editor: Ben J. Harrison, The University of Melbourne, Australia
Received April 4, 2011; Accepted July 22, 2011; Published January 11, 2012
Copyright: ? 2012 Schmahl et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This work was supported by the German Research Foundation [DFG; SFB 636, SCHM 1526/11-1] and the Borderline Personality Disorder Research
Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
* E-mail: Petra.Ludaescher@zi-mannheim.de
. These authors contributed equally to this work.
Neural processing of pain has different components besides
somatosensory processing [1,2], with affective aspects being
processed in anterior insula, anterior cingulate cortex (ACC) and
amygdala and cognitive aspects in posterior parietal and
dorsolateral prefrontal cortex (DLPFC). DLPFC participates in a
pain control network, which regulates cortico-subcortical and
cortico-cortical loops by inhibiting ascending pathways through
the anterior cingulate cortex .
Besides its role in cognitive function, particularly in the
prefrontal cortex , genetic variations in the gene coding for
the enzyme Catechol-O-methyltransferase (COMT) are associated
with the processing of emotional stimuli in limbic and prefrontal
regions [5,6]. A common functional genetic variation in the
COMT gene is the val158met polymorphism with the val variant
showing higher enzyme activity than the met variant .
In relation to pain, decreased dopamine neurotransmission, as
conferred by increased COMT activity, is related to increased
enkephaline levels and, in turn, a down-regulation of m-opioid
receptors . Variations in the gene coding for COMT explain
approximately 10% of variability in pain sensitivity . The
influence of the val158met polymorphism appears to be particularly
related to the temporal summation of longer lasting pain stimuli
. This polymorphism has been associated with conditions of
increased pain [9–11]. Met/met individuals also showed higher
pain levels following a single opioid dose . Increased enzyme
activity was associated with higher capacity to activate m-opioid
neurotransmission in thalamus, basal ganglia, limbic and para-
limbic areas in response to a sustained pain challenge resulting in
decreased pain perception .
A psychiatric condition characterized by reduced pain sensitiv-
ity is Borderline Personality Disorder (BPD) and the endogenous
opioid system appears to play an important role in this domain
[13–15]. According to the most recent study by Distel et al. ,
genetic aspects explain 35 to 45% of the variance in BPD. Patients
suffering from BPD frequently experience stress-induced states
with reduced pain perception, which are often relieved by self-
injurious behavior . Reduced pain sensitivity in patients with
BPD was found under non-stress as well as under stress conditions
[18–20]. BPD patients also exhibited greater levels of brain
activation in dorsolateral prefrontal cortex and neural deactivation
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in perigenual anterior cingulate gyrus and amygdala suggesting a
modulation of pain circuits, primarily through the downregulation
of the affective components of pain [21,22].
The aim of the current study was to investigate the influence of
the val158met polymorphism on neural pain processing. Therefore
we investigated healthy female subjects as well as patients with
BPD to obtain a large variance in pain sensitivity. Overall we
expected the number of val alleles to be correlated with brain
activity in pain-processing brain regions. Given the above
mentioned differences between both groups in affective and
cognitive pain-evaluation, we expected different activation pat-
terns in brain areas such as anterior insula, anterior cingulate
cortex, and DLPFC.
The study was conducted in accordance with the declaration of
Helsinki and was approved by the Ethics Committee of the
Medical Faculty of Mannheim, Heidelberg University. After full
explanation of the study, written informed consent was obtained
from all participants.
Twenty- five healthy controls [age: 27.967.9] and twenty-five
female patients diagnosed with BPD [age: 27.567.1] according to
DSM-IV-criteria and matched according to age participated in
this study. Pain processing data of 22 patients and 12 controls have
been published previously . All patients were either inpatients
at the Dept. of Psychosomatic Medicine or were recruited via
announcement on different BPD-specific homepages. Axis I and II
diagnoses were assessed in all participants by trained psychologists
using the Structured Clinical Interview for Axis I disorders (SCID)
 and the International Personality Disorder Examination
(IPDE) , respectively. The inter-rater reliability for the IPDE
was k=.77. All participants were free of psychotropic medication
for at least two weeks prior to study. All subjects were right-handed
as measured by the Edinburgh handedness inventory .
Exclusion criteria comprised neurological diseases, retained metal,
history of head trauma, current depression, alcohol or substance
abuse or dependence, lifetime bipolar I disorder, schizophrenia
and pain disorders. Healthy controls were free of any Axis I or II
disorder. After full explanation of the study, written informed
consent was obtained.
The methods used to characterize neural pain processing by
functional magnetic resonance imaging (fMRI) have been
described elsewhere [21,22]. Briefly, heat stimuli were applied
on the back of the right hand using a peltier based thermode
(363 cm) controlled by a PC-based device (Thermal Sensory
Analyzer, Medoc, Israel). Subjective pain intensity was rated by
the participants after each stimulus using a numerical rating scale
(NRS) ranging from 0 to 100 (‘‘no pain’’ to ‘‘most intense pain
imaginable’’). All participants were measured on a 1.5 T scanner
equipped with a Vision gradient system and a CP head coil
(Siemens Medical Solution, Erlangen, Germany). For whole-brain
structural volumes, we used a T1-weighted three-dimensional
magnetization-prepared rapid acquisition gradient echo sequence
with a voxel size of 1 mm3in all subjects. The blood oxygen level-
dependent (BOLD) signal was acquired using gradient-recalled
echo-planar imaging (number of contiguous transversal slices, 25;
position, covering all but the apical 20 mm of the brain; slice
thickness, 5 mm; echo time, 60 ms; flip angle, 60u; matrix, 64664
2206220 mm2, volume acquisition times 2600 ms, silent periods
between scans 1575 ms). The silent periods interspersed between
scans were used to ask the subjects for pain intensity evaluation
after the first post-stimulation scan and to obtain their rating after
the subsequent scan. During the acquisition of the functional data,
ten stimulation blocks lasting 30 s each were applied. Five blocks
consisted of a fixed moderate intense stimulus temperature (43uC,
condition 1) and five blocks consisted of a higher intense stimulus
temperature individually adjusted to correspond with a subjective
pain intensity of 40% (condition 2) as determined in a psychophys-
ical experiment directly before the scanning session (cf. Schmahl et
al 2006, ). All given stimulus temperatures oscillated with an
amplitude of 2uC to avoid adaptation [21,22]. Stimulation blocks
were interrupted by 60 s intervals with neutral temperature
Data were analyzed with Statistical Parametric Mapping
(SPM5, Wellcome Trust Centre for Neuroimaging, University
College London, London, UK). Following pre-processing (spatial
realignment, normalisation to MNI EPI template, smoothing:
kernel width: 86868 mm), the two conditions (painful [individual
or fixed] vs. neutral temperature) were modelled as explanatory
variables within the context of the general linear model. To detect
associations between COMT genotype and fMRI activation, the
contrast images (positive (1) and negative (2) association between
COMT genotype and fMRI activation) of all subjects were
included in a second level regression analysis (statistical threshold:
p#0.001, uncorrected, k.10). To model the assumed gene–dose
effect, COMT genotype was coded as a covariate by the number
of val alleles (0, 1, or 2) In addition, we used SPSS for Windows
15.0 to conduct non-parametric Spearman-Rho correlation
analyses (‘‘ROI analysis’’) between the number of val alleles and
the mean regression coefficients (betas) per voxel for each ROI
(which showed significant correlations between BOLD signal and
the number of val alleles in the regression analysis in one of the two
groups). To compare healthy controls and patients with BPD
regarding pain sensitivity on low and high pain stimuli, we
conducted an ANOVA with post-hoc Scheffe ´ analyses.
volume repetitiontime, 4175 ms,field ofview
Leucocyte genomic DNA from the 50 participants was isolated
from EDTA anti-coagulated venous blood samples with the
QIAamp DNA extraction kit (Qiagen, Chatsworth, CA, USA).
Genotyping of the single nucleotide polymorphism (SNP) rs4680,
was performed using TaqManH, Drug Metabolism Genotyping
Assays (Assay ID C_25746809_50) and protocol (7900HT Fast
Real-Time-PCR-System, Applied Biosystems, Foster City, CA,
USA). For quality reasons 15% of SNPs were typed twice and
genotype replicate consistency was 100%. Hardy-Weinberg
equilibrium (HWE) was assessed using the exact text implemented
in the DeFinetti program (Strom, T.M. & Wienker, T.F. DeFinetti
In the total group of 50 participants, 12 were homozygous for
the met158 allele of the COMT polymorphism, 26 were
heterozygous, and 12 were homozygous for val158. The genotype
distribution of the controls did not deviate from Hardy-Weinberg
Eight patients in the BPD group were homozygous for met158,
15 were heterozygous and two were homozygous for val158. Of
COMT and Pain Processing
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the healthy controls, four subjects were homozygous for the met
allele, eleven were heterozygous and ten homozygous for val
Subjective heat pain sensations
In proper replication of our previous studies [20,22,26],
subjective heat pain perception was significantly lower in patients
as compared to the control group. (Figure 1B). The mean stimulus
temperatures to induce an equal subjective painful sensation was
more than 1uC lower in BPD as compared to healthy controls
(p,0.005). Therefore, during the fMRI-scanning procedure the
lower stimulation with 43uC (condition 1) induced comparable
subjective heat pain sensations in healthy controls as the higher
heat stimuli were applied in BPD in condition 2 (Figure 1B).
Influence of COMT val158met on pain perception
When comparing the heat pain obtained in subjects with respect
to the different genotypes, the equal heat stimuli of lower intensity
given in condition 1 still gave rise to significantly lower ratings in
BPD irrespective of the COMT val158met polymorphism. Differ-
ences in genotype had no influence on heat pain perception
neither in healthy controls nor in BPD patients. (Fig. 2A;
ANOVA: main effect group: F=11,9, df=1, p,0.01; main effect
genotype: F=0,51, df=2, p=0.61; interaction effect: F=0,01,
df=2, p=0.99). Interestingly however, the mean stimulus
temperatures for a subjective pain rating of 40 displayed nominally
an inverse relation with genotype in the healthy participants
(Fig. 2B; healthy r=0.97, p=0.16; BPD r=0.61; p=0.58).
Influence of COMT val158met on neural pain processing
Significant associations between COMT genotype and BOLD
signal were observed for both stimulus conditions, in all 50
participants in dorsolateral prefrontal cortex (DLPFC), posterior
parietal cortex (PPC), lateral globus pallidus (LGP), and posterior
cingulate cortex (PCC). COMT genotype and BOLD signal were
significantly correlated in anterior and posterior insula as well as
claustrum during condition 1, only (Fig. 3, Fig. 4, Fig. 5E,F). In the
subgroup of BPD patients, pain processing in condition 1 was
additionally correlated with the number of val alleles in postcentral
gyrus, left and right precentral gyrus, superior frontal gyrus (BA 6),
and middle occipital gyrus (Fig. 4E, Fig. 5A–D, Table 1). Within
the subgroup of healthy control participants, pain processing in the
higher intense heat stimulation during condition 2 was positively
correlated to the number of val alleles in DLPFC, PPC, LGP, and
PCC (Fig. 3, Fig. 5E, Table 1).
Figure 1. Patients suffering from BPD are less heat pain
sensitive independent of the val158met polymorphism. (A)
Genotype distribution of the val158met polymorphism in healthy
controls (open) and BPD patients (filled bars) do not differ. (B) Heat pain
perception was markedly reduced in BPD. Dose-response function in
the pretest session (circles) and stimulus temperatures applied during
fMRI (squares) did significantly differ between controls and BPD (ns
p.0.4; * p,0.05; ** p,0.01; *** p,0.001, students t-test).
Figure 2. Association between COMT genotype and pain
sensitivity. A: Lower heat pain perception in BPD in response to
43uC does not depend upon the val158met polymorphism.nsp.0.3,
BPD and control, respectively; * p,0.05; ** p,0.01, students t-test. B:
Stimulus temperatures for the induction of a heat pain sensation of NRS
40 decreases with the number of met alleles in healthy volunteers but
not in BPD patients (ns p.0.19; (*) p,0.1; * p,0.05, students t-test).
COMT and Pain Processing
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As mentioned above, stimulation with 43uC (condition 1) induced
comparable subjective heat pain sensations in healthy controls as
significantly higher heat stimuli applied in BPD in condition 2
(Fig. 1). Therefore, we directly compared these subjectively
adjusted conditions and found a significant correlation of the
COMT genotype and fMRI activation in PPC, LGP, and PCC
In this study, we used a combined fMRI and molecular genetic
approach in the assessment of pain processing. To investigate the
association of altered pain sensitivity with the COMT genotype on
a more fine-granulated level, we used fMRI correlates of thermal
pain stimulation. Here, the number of COMT val158 alleles was
correlated with the activity of several pain-processing brain
regions. These included DLPFC, PPC, LGP, PCC, claustrum as
well as anterior and posterior insula. In healthy persons, we found
the number of val alleles to be correlated with cognitive aspects of
pain processing in DLPFC and PPC. In patients with borderline
Figure 3. Association between COMT genotype and fMRI
activation during painful stimulation in frontal brain areas.
Significant correlations were observed for both stimulus conditions within
the dorsolateral prefrontal cortex (DLPFC; A,B). Furthermore, the posterior
parietal cortex (PPC; C) and the lateral globus pallidus (LGP; D) also
displayed significant correlation during both conditions. Statistics and
regression lines for group means are shown in gray (all 50 subjects), black
(BPD), and dashed (Control), respectively; significant Pearson product
moment correlation * p,0.05, ** p,0.01, *** p,0.001, versus r=0.
Figure 4. Association between COMT genotype and fMRI
activation during painful stimulation in the anterior and
posterior insula. Significant correlations were observed during
condition 1 within the anterior (A,B) and posterior insula (C), claustrum
(D) and postcentral gyrus (D). Labeling as in Fig. 2, * p,0.05, ** p,0.01.
COMT and Pain Processing
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personality disorder, a psychiatric condition characterized by
reduced pain sensitivity in conjunction with self-injurious behav-
ior, the number of val alleles was positively correlated with brain
activation in regions of affective pain processing, such as anterior
insula. In both groups, basal ganglia activity during painful heat
stimulation was also correlated with the number of val alleles.
The association of the val158 allele with activation in DLPFC
and, potentially, in PPC, may be related to a specific role of this
brain region in pain control . The DLPFC participates in a pain
control network, which regulates cortico-subcortical and cortico-
cortical loops by inhibiting ascending pathways through the ACC.
The study by Lorenz et al.  found an inverse correlation
between the subjective unpleasantness and the perceived intensity
of a heat stimulus and the activation of DLPFC. The interaction of
pain control mechanisms and the activity of the endogenous
opioid system, which may be influenced by COMT activity, is of
particular interest and deserves further research.
Previous investigations revealed a disturbance of affective pain
processing in patients with BPD and a related psychiatric
condition, posttraumatic stress disorder (PTSD) [21,22,27]. In
patients with PTSD, elevated pain-related activity in the anterior
insula, a brain region related to affective pain processing, could be
demonstrated . In the current study, activity in the anterior
and posterior insula was related to COMT activity, particularly in
borderline patients. The insula plays an important role in
monitoring internal bodily states , and increased anterior
insula activity was found in patients with BPD as well as in patients
with PTSD during dissociative states, which are characterized by
depersonalisation, derealisation, and reduced pain perception
In both groups, COMT activity as measured by the number of
val alleles was positively correlated with brain activity in several
parts of the basal ganglia. In carfentanil-PET studies [8,31], a
significant influence of the val158met polymorphism on the activity
of the endogenous opioid system in the striato-pallidal circuits
could be shown. Our data of COMT-related activation patterns in
these regions support these previous findings and suggest a role of
the interaction of the dopamine and the endogenous opioid
The association between the activity in DLPFC, PPC and LGP
with COMT did not critically depend upon stimulus intensity
and/or subjective heat pain sensation. In contrast, PCC displayed
significant correlation with COMT polymorphism only at a higher
level of subjectively adjusted heat pain perception. This brain
region was suggested to be involved in orientation toward noxious
somatosensory stimuli and to represent an emotional pre-processor
that might assist in establishing the personal relevance of sensory
information that comes into the cingulate gyrus . Thus,
Figure 5. Association between COMT genotype and fMRI activation during painful stimulation in additional brain areas. (A) Left
precentral gyrus, (B) Superior frontal gyrus, (C) Middle occipital gyrus, (D) Right precentral gyrus, (E) Posterior cingulated cortex, (F) Dorsolateral
prefrontal cortex. Statistics and regression lines for group means are shown in gray (all 50 subjects), black (BPD), and dashed (Control), respectively;
significant Pearson product moment correlation * p,0.05, ** p,0.01, *** p,0.001, versus r=0.
COMT and Pain Processing
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inactivating PCC - which is active during emotion and non-
emotion conditions - may especially reduce perception of noxious
stimulation and suffering from pain as suggested by Vogt .
Regarding pain sensitivity, we found a correlation with the
number of met alleles for the induction of a constant pain sensation
in healthy subjects (Fig. 2B). Here, the stimulus intensity necessary
to induce a painful sensation of NRS 40 decreased with the
number of met alleles. This observation resembles the findings of
Zubieta  who found that the infused volume necessary for the
induction of a constant sustained pain perception decreased with
the number of met alleles. Furthermore we found that the well-
known hypoalgesia in borderline personality disorder for thermal
pain [20,22,26] is not simply explained by the COMT val158met
polymorphism. The impact of diagnosis as opposed to genotype
also becomes apparent when comparing subgroups with the same
genotype: The large subgroups of heterozygote patients and
controls (middle columns in Fig. 2A) still showed markedly
reduced pain sensitivity.
As a limitation of our study it should be mentioned, that we only
focussed on one COMT polymorphism. Several SNPs have been
described in COMT and three COMT haplotypes comprising the
val158met polymorphism were found to account for more than
10% of the variance in pain sensitivity in healthy human subjects
. However, a recently conducted model comparison based on
the Akaike Information Criterion and the Bayesian Information
Criterion reveals that the simplest model, comprising only the
val158met polymorphism, to be the most informative one .
In summary, inter-individual differences in neural pain
processing in healthy people as well as in patients with a disorder
associated with reduced pain sensitivity are significantly influenced
by genetic variations in the COMT gene. Differential modulation
of brain areas by the COMT polymorphism led to similar painful
Table 1. Group-specific regression analyses.
Region Hemisphere Brodmann Areaz-score k (cluster level)
No suprathreshold clusters
Posterior Parietal CortexL 40 4.29139
Lateral Globus PallidusR- 3.60 35
DLPFCL 464.00 33
Posterior Cingulate CortexL 23 3.4314
436C (condition 1)
Claustrum/Lentiform NucleusR- 3.70 72
Precentral gyrusR- 3.86 26
Postcentral gyrusR- 3.42 26
Middle occipital gyrusR 18/193.87 21
Posterior insulaR- 3.7619
Precentral gyrusL- 3.70 15
Anterior insulaR- 3.69 11
Superior frontal gyrusR6 4.05 11
No suprathreshold clusters
Figure 6. Brain areas activated in response to subjectively adjusted heat pain correlate with COMT val158met polymorphism.
During subjectively similar intense heat pain perception (individual temperature in BPD 43uC in healthy controls), posterior parietal cortex (A), lateral
globus pallidus (LGP; B) and the posterior cingulate cortex (PPC; C) displayed significant correlation with COMT-polymorphism. Labelling as in Fig. 2,
COMT and Pain Processing
PLoS ONE | www.plosone.org6 January 2012 | Volume 7 | Issue 1 | e23658
experiences in our two samples. However, BPD patients and Download full-text
healthy control participants differed regarding those modulatory
mechanisms. In healthy participants, the frequency of val alleles
was associated with higher activity in regions processing cognitive
aspects of pain, presumably controlling pain, particularly at higher
pain intensities. In contrast, BPD patients revealed an association
of COMT activity with affective evaluation of pain mainly at lower
We thank Matthias Ruf for his helpful assistance in data acquisition.
Conceived and designed the experiments: CS PL WG AK GV MNS MB.
Performed the experiments: CS PL WG AK GV. Analyzed the data: CS
PL WG AK GV. Contributed reagents/materials/analysis tools: CS TGS
JT MR MNS MB. Wrote the paper: CS PL WG MB. Interpretation of
data: CS PL WG TGS JT MR MNS MB. Drafting the article or revising it
critically for important intellectual content: CS PL WG AK GV TGS JT
MR MNS MB.
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PLoS ONE | www.plosone.org7 January 2012 | Volume 7 | Issue 1 | e23658