COMT val158met genotype affects mu-opioid neurotransmitter responses to a pain stressor. Science (New York, NY)

Department of Psychiatry and Mental Health Research Institute, University of Michigan, Ann Arbor, MI 48109-0720, USA.
Science (Impact Factor: 33.61). 03/2003; 299(5610):1240-3. DOI: 10.1126/science.1078546
Source: PubMed


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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    • "nt to early - life adversity ( Khashan et al . , 2008 ; Mueller and Bale , 2008 ; Kundakovic et al . , 2013 ; Jacobson - Pick and Richter - Levin , 2010 ; Weathington and Cooke , 2012 ) . Multiple biopsychosocial mechanisms may contribute to these sex differences in pain , including sex hormones , endogenous opioid function , and genetic factors ( Zubieta et al . , 2003 ; Craft , 2007 ; Mogil , 2012 ) ."
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    ABSTRACT: Early stress in the form of repetitive neonatal pain, in infants born very preterm, is associated with long-term dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and with poorer cognitive performance. Brain-derived neurotrophic factor (BDNF) which is important in synaptic plasticity and cognitive functions is reduced by stress. Therefore the BDNF Val66Met variant, which affects secretion of BDNF, may interact with early exposure to pain-related stress in children born very preterm, to differentially affect HPA regulation that in turn may be associated with altered cognitive performance. The aims of this study were to investigate whether in children born very preterm, the BDNF val66met variant modulates the association between neonatal pain-related stress and cortisol levels at age 7 years, and if cortisol levels were related to cognitive function. Furthermore, we examined whether these relationships were sex-specific. Using a longitudinal cohort design, N=90 children born very preterm (24-32 weeks gestation) were followed from birth to age 7 years. Cortisol was assayed from hair as an index of cumulative stress and from saliva to measure reactivity to a cognitive challenge. BDNF Val66Met variant was genotyped at 7 years using real time PCR. Using generalized linear modeling, in boys with the Met allele, greater neonatal pain-related stress (adjusted for clinical risk factors) predicted lower hair cortisol (p=0·006) and higher reactivity salivary cortisol (p=0.002). In both boys and girls with the Met allele, higher salivary cortisol reactivity was correlated with lower IQ (r= - 0.60; p=0.001) and poorer visual-motor integration (r= - 0.48; p=0.008). Our findings show associations between lower BDNF availability (presence of the Met allele) and vulnerability to neonatal pain/stress in boys, but not girls. This exploratory study suggests new directions for research into possible mechanisms underlying how neonatal pain/stress is related to cognitive performance in children born very preterm. Copyright © 2015. Published by Elsevier Ltd.
    Neuroscience 08/2015; DOI:10.1016/j.neuroscience.2015.08.044 · 3.36 Impact Factor
    • "For example, polymorphisms in the gene encoding catechol-O-methyltransferase (COMT), an enzyme that metabolizes catecholamine neurotransmitters, alter activity of the COMT enzyme (Diatchenko et al. 2005; Nackley et al. 2007). Variants of the COMT gene that reduce the enzyme's activity are associated with greater experimental pain sensitivity (Zubieta et al. 2003; Diatchenko et al. 2006), heightened clinical pain ratings (George et al. 2008), and increased incidence of TMD (Diatchenko et al. 2005). COMT genetic variation also mediates responses to stress (Hernaus et al. 2013). "
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    ABSTRACT: When measured once, psychological stress predicts development of painful temporomandibular disorder (TMD). However, a single measurement fails to characterize the dynamic nature of stress over time. Moreover, effects of stress on pain likely vary according to biological susceptibility. We hypothesized that temporal escalation in stress exacerbates risk for TMD, and the effect is amplified by allelic variants in a gene, catechol-O-methyltransferase (COMT), regulating catechol neurotransmitter catabolism. We used data from the Orofacial Pain: Prospective Evaluation and Risk Assessment prospective cohort study of 2,707 community-dwelling adults with no lifetime history of TMD on enrollment. At baseline and quarterly periods thereafter, the Perceived Stress Scale (PSS) measured psychological stress. Genotyped DNA from blood samples determined COMT diplotypes. During follow-up of 0.25 to 5.2 y, 248 adults developed examiner-verified incident TMD. PSS scores at baseline were 20% greater (P < 0.001) in adults who developed incident TMD compared with TMD-free controls. Baseline PSS scores increased by 9% (P = 0.003) during follow-up in cases but remained stable in controls. This stress escalation was limited to incident cases with COMT diplotypes coding for low-activity COMT, signifying impaired catabolism of catecholamines. Cox regression models confirmed significant effects on TMD hazard of both baseline PSS (P < 0.001), modeled as a time-constant covariate, and change in PSS (P < 0.001), modeled as a time-varying covariate. Furthermore, a significant (P = 0.04) interaction of COMT diplotype and time-varying stress showed that a postbaseline increase of 1.0 standard deviation in PSS more than doubled risk of TMD incidence in subjects with low-activity COMT diplotypes (hazard ratio = 2.35; 95% confidence limits: 1.66, 3.32), an effect not found in subjects with high-activity COMT diplotypes (hazard ratio = 1.42; 95% confidence limits: 0.96, 2.09). Findings provide novel insights into dynamic effects of psychological stress on TMD pain, highlighting that effects are most pronounced in individuals whose genetic susceptibility increases responsiveness to catecholamine neurotransmitters. © International & American Associations for Dental Research 2015.
    Journal of dental research 07/2015; 94(9). DOI:10.1177/0022034515595043 · 4.14 Impact Factor
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    • "A possible relationship between a smaller amount of available dopamine in the prefrontal cortex (Val158/Val158 individuals) and a more pronounced nocebo response was also reported in a study with cancer patients, where patients of the Val158/Val158 genotype experienced more pain than the other two genotypes and required higher doses of morphine [43]. Under experimental conditions however, Met158/Met158 individuals reported a higher sensitivity towards experimental pain [49], [50]. "
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    ABSTRACT: A large number of unwanted adverse events and symptoms reported by patients in clinical trials are not caused by the drug provided, since most of adverse events also occur in corresponding placebo groups. These nocebo effects also play a major role in drug discontinuation in clinical practice, negatively affecting treatment efficacy as well as patient adherence and compliance. Experimental and clinical data document a large interindividual variability in nocebo responses, however, data on psychological, biological or genetic predictors of nocebo responses are lacking. Thus, with an established paradigm of behaviorally conditioned immunosuppressive effects we analyzed possible genetic predictors for nocebo responses. We focused on the genetic polymorphisms in the catechol-O-methyltransferase (COMT) gene (Val158Met) and analyzed drug specific and general side effects before and after immunosuppressive medication and subsequent placebo intake in 62 healthy male subjects. Significantly more drug-specific as well as general side effects were reported from homozygous carriers of the Val158 variant during medication as well as placebo treatment compared to the other genotype groups. Val158/Val158 carriers also had significantly higher scores in the somatosensory amplification scale (SSAS) and the BMQ (beliefs about medicine questionnaire). Together these data demonstrate potential genetic and psychological variables predicting nocebo responses after drug and placebo intake, which might be utilized to minimize nocebo effects in clinical trials and medical practice.
    PLoS ONE 09/2014; 9(9):e107665. DOI:10.1371/journal.pone.0107665 · 3.23 Impact Factor
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