COMT val(158)met genotype affects mu-opioid neurotransmitter responses to a pain stressor

Department of Psychiatry and Mental Health Research Institute, University of Michigan, Ann Arbor, MI 48109-0720, USA.
Science (Impact Factor: 31.48). 03/2003; 299(5610):1240-3. DOI: 10.1126/science.1078546
Source: PubMed

ABSTRACT Responses to pain and other stressors are regulated by interactions between multiple brain areas and neurochemical systems. We examined the influence of a common functional genetic polymorphism affecting the metabolism of catecholamines on the modulation of responses to sustained pain in humans. Individuals homozygous for the met158 allele of the catechol-O-methyltransferase (COMT) polymorphism (val158met) showed diminished regional mu-opioid system responses to pain compared with heterozygotes. These effects were accompanied by higher sensory and affective ratings of pain and a more negative internal affective state. Opposite effects were observed in val158 homozygotes. The COMT val158met polymorphism thus influences the human experience of pain and may underlie interindividual differences in the adaptation and responses to pain and other stressful stimuli.

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    • "The COMT VAL158MET SNP appears to be pleiotropic. Although COMT 158MET homozygotes appear to exhibit better executive function, they also exhibit poorer emotional regulation and resiliency in the face of stress compared to carriers of the COMT VAL158 allele (Olsson et al., 2005; Olsson et al., 2007; Pooley, Fineberg, & Harrison, 2007) and stronger response to pain (Zubieta et al., 2003). These effects can be seen in patterns of brain activation. "
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    ABSTRACT: We hypothesized that normal variation in genes influencing the bioavailability of dopamine in prefrontal cortex contribute to inter-individual differences in working memory (WM), particularly in healthy old age. To test this, 858 healthy young, middle-aged, and older people were tested on a spatial WM task and genotyped for catechol-O-methyltransferase (COMT VAL158MET) and dopamine betahydroxylase (DBH; C-1021T) single nucleotide polymorphisms (SNPs). Since these genes encode enzymes influencing levels of extracellular dopamine, important for WM, we reasoned that individuals with low activity alleles of each SNP (less efficient degradation of dopamine by COMT and less efficient conversion of dopamine to norepinephrine by DBH) would have higher levels of extracellular dopamine and therefore better WM performance. We predicted the poorest WM performance in people who are both COMT VAL/VAL and DBH C/C homozygotes, encoding enzymes with high activity. That prediction was borne out, but only in the older group under difficult discrimination. This suggests the high activity alleles of these 2 genes combine in reducing ability to manipulate information in WM among the old. Further, we predicted the best performance in people who inherited both low activity alleles. That prediction was not borne out. That we found genetic effects only among older people and not in midlife indicates that brain changes late in life heighten negative effects of chronically lower levels of extracellular dopamine due to normal genetic variation. We found that age increased the combined effect on WM of the COMT and DBH genes encoding enzymes controlling levels of extracellular dopamine. (PsycINFO Database Record (c) 2014 APA, all rights reserved).
    Psychology and Aging 06/2014; 29(2):363-373. DOI:10.1037/a0036109 · 2.73 Impact Factor
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    • "COMT has been implicated in the modulation of pain (Diatchenko et al., 2006). Zubieta et al. (2003) demonstrated that healthy individuals with the COMT Val158Val genotype are pain-resistant. The opposite occurs in people with the Met158Met genotype. "
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    ABSTRACT: Abstract 1. Fibromyalgia syndrome (FMS) is a common chronic widespread pain syndrome mainly affecting women. The aim of this study was to explore the frequency and clinical significance of catechol-O-methyltransferase (COMT) gene Val158Met polymorphism in a large cohort of Turkish patients with FMS. 2. The study included 379 FMS patients and 290 controls. Genomic DNA was isolated and genotyped using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analyses. 3. The genotype frequencies of Val158Met polymorphism showed a small difference between FMS patients and healthy controls (p = 0.047), however, the Met/Met genotype was significantly higher in FMS patients than healthy controls (p = 0.016). No difference was observed for allele frequencies between two groups. Stratification analysis according to clinical features for this disease reveals that weight, FMS Impact Questionnaire score, algometry and Raynaud's syndrome, were detected to have statistically significant associations with Val158Met polymorphism (p = 0.037, p = 0.042, p = 0.039 and p = 0.033, respectively). Pain sensitivity, measured by algometry, was statistically higher in patients with Met/Met genotype than the patients with Val/Val and Val/Met genotypes (p = 0.017). 4. The results of this study suggested that COMT gene Val158Met polymorphism is positively associated with FMS and play a relevant role in the clinical symptoms of the disease.
    Xenobiotica 04/2014; 44(10). DOI:10.3109/00498254.2014.913083 · 2.10 Impact Factor
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    • "Experimentally induced pain has been shown to attenuate sensory and pain-specific affective responses through activation of the opioid system (Zubieta et al., 2001; although see Gilchrist, Allard, & Simone, 1996, regarding cases of secondary hyperalgesia). Disruptions in opioidergic brain activity have also been linked to sadness and depression (Kennedy, Koeppe, Young, & Zubieta, 2006; Prossin et al., 2011; Zubieta et al., 2003), suggesting that physical pain may help regulate emotional pain by activating endogenous opioid release. This is analogous to thrill-seeking behavior (Franken, Zijlstra, & Muris, 2006), which may alleviate emotional numbness through activation of the endogenous opioid system. "
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    ABSTRACT: Pain is mostly thought of as a problem-as debilitating or harmful. Despite its unpleasantness, however, under some conditions pain can be associated with positive consequences. In this review, we explore these positive biological, psychological, and social consequences of pain. We highlight three different domains in which pain may be considered to have positive consequences. First, pain facilitates pleasure by providing an important contrast for pleasurable experiences, increasing sensitivity to sensory input, and facilitating self-rewarding behavior. Second, pain augments self-regulation and enhancement by increasing cognitive control, reducing rumination, and demonstrating virtue. Third, pain promotes affiliation by arousing empathy from others, motivating social connection, and enhancing group formation. Drawing on evidence scattered across a range of academic fields, we provide for reflection on how pain is represented, generate insights into pain-seeking behavior, and draw attention to the role of painful experiences in maximizing positive outcomes.
    Personality and Social Psychology Review 04/2014; 18(3). DOI:10.1177/1088868314527831 · 7.55 Impact Factor
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