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 personality disorder, a psychiatric condition characterized by reduced pain sensitivity in conjunction with self-injurious behavior, 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) 
. 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 
, 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 system.
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, 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 (). 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 
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 ) 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 experiences in our two samples. However, BPD patients and 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 stimulus intensities.