Abstract
Despite the explosion of interest in the genetic underpinnings of individual differences in pain sensitivity, conflicting findings have emerged for most of the identified “pain genes”. Perhaps the prime example of this inconsistency is represented by catechol-O-methyltransferase (COMT), as its substantial association to pain sensitivity has been reported in various studies, but rejected in several others. In line with findings from behavioral studies, we hypothesized that the effect of COMT on pain processing would become apparent only when the pain system was adequately challenged (i.e., after repeated pain stimulation). In the present study, we used functional Magnetic Resonance Imaging (fMRI) to investigate the brain response to heat pain stimuli in 54 subjects genotyped for the common COMT val158met polymorphism (val/val = n 22, val/met = n 20, met/met = n 12). Met/met subjects exhibited stronger pain-related fMRI signals than val/val in several brain structures, including the periaqueductal gray matter, lingual gyrus, cerebellum, hippocampal formation and precuneus. These effects were observed only for high intensity pain stimuli after repeated administration. In spite of our relatively small sample size, our results suggest that COMT appears to affect pain processing. Our data demonstrate that the effect of COMT on pain processing can be detected in presence of 1) a sufficiently robust challenge to the pain system to detect a genotype effect, and/or 2) the recruitment of pain-dampening compensatory mechanisms by the putatively more pain sensitive met homozygotes. These findings may help explain the inconsistencies in reported findings of the impact of COMT in pain regulation.
Highlights
Sensitivity to pain varies greatly across humans and growing evidence suggests that genetic factors might explain part of this variability [1,2,3,4,5,6,7,8]
We evaluated the fMRI responses to experimental pain stimuli in subjects genotyped for the COMT val158met polymorphism
Our results demonstrate that individuals with the met/met genotype exhibit stronger pain-evoked BOLD signals in a number of cortical and subcortical structures (PAG, hippocampal formation, lingual gyrus, calcarine cortex, precuneus, cuneus, superior and middle occipital gyri and cerebellum), in spite of identical pain ratings between genotype groups
Summary
Sensitivity to pain varies greatly across humans and growing evidence suggests that genetic factors might explain part of this variability [1,2,3,4,5,6,7,8]. The first direct evidence that this polymorphism affects neural processing of pain came from Zubieta and colleagues [8], who showed that 158met homozygotes were characterized by higher pain sensitivity, diminished regional muopioid system responses to pain, as well as a higher mu-opioid receptor binding potential, compared with heterozygotes (and vice versa for the subjects 158val homozygotes). Despite these intriguing results, the existence of an effect of COMT variation on pain sensitivity is still strongly debated, as some subsequent behavioral studies using larger sample size have failed to show a substantial association It is possible that the inconsistency in the literature on the effects of COMT is attributable to the delayed onset of this effect, which some studies might have failed to capture
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