COMT val158met Genotype Affects µ-Opioid Neurotransmitter Responses to a Pain Stressor

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 themet158 allele of the catechol-O-methyltransferase (COMT) polymorphism (val158met) showed diminished regional μ-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 COMTval158met polymorphism thus influences the human experience of pain and may underlie interindividual differences in the adaptation and responses to pain and other stressful stimuli.

[1]  Joshua A. Bueller,et al.  μ-Opioid Receptor-Mediated Antinociceptive Responses Differ in Men and Women , 2002, The Journal of Neuroscience.

[2]  E. Nestler,et al.  Psychogenomics: Opportunities for Understanding Addiction , 2001, The Journal of Neuroscience.

[3]  Joshua A. Bueller,et al.  Regional Mu Opioid Receptor Regulation of Sensory and Affective Dimensions of Pain , 2001, Science.

[4]  R. Straub,et al.  Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[5]  M. Fava,et al.  Major Depressive Disorder , 2000, Neuron.

[6]  S. Ho,et al.  Characterization and implications of estrogenic down-regulation of human catechol-O-methyltransferase gene transcription. , 1999, Molecular pharmacology.

[7]  T. Napier,et al.  Opioid Modulation of Ventral Pallidal Inputs , 1999, Annals of the New York Academy of Sciences.

[8]  P. Kalivas,et al.  Involvement of the Pallidal‐thalamocortical Circuit in Adaptive Behavior , 1999, Annals of the New York Academy of Sciences.

[9]  C. Stohler,et al.  Spatial and temporal summation of sensory and affective dimensions of deep somatic pain , 1999, PAIN.

[10]  F. Benedetti,et al.  Neuropharmacological Dissection of Placebo Analgesia: Expectation-Activated Opioid Systems versus Conditioning-Activated Specific Subsystems , 1999, The Journal of Neuroscience.

[11]  C. Gerfen,et al.  Role of dynorphin and enkephalin in the regulation of striatal output pathways and behavior , 1998, Experimental Brain Research.

[12]  J. D. McGaugh,et al.  Norepinephrine release in the amygdala in response to footshock and opioid peptidergic drugs , 1998, Brain Research.

[13]  Karl J. Friston,et al.  A neuromodulatory role for the human amygdala in processing emotional facial expressions. , 1998, Brain : a journal of neurology.

[14]  M. Bushnell,et al.  Pain affect encoded in human anterior cingulate but not somatosensory cortex. , 1997, Science.

[15]  I. T. Miller,et al.  High-activity catechol-O-methyltransferase allele is more prevalent in polysubstance abusers. , 1997, American journal of medical genetics.

[16]  A. Oke,et al.  Three-dimensional mapping of norepinephrine and serotonin in human thalamus , 1997, Brain Research.

[17]  J. Ott,et al.  Genotype determining low catechol-O-methyltransferase activity as a risk factor for obsessive-compulsive disorder. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[18]  T. Napier,et al.  Morphine modulation of GABA- and glutamate-induced changes of ventral pallidal neuronal activity , 1997, Neuroscience.

[19]  B. Vogt,et al.  Localization of Mu and Delta Opioid Receptors to Anterior Cingulate Afferents and Projection Neurons and Input/Output Model of Mu Regulation , 1995, Experimental Neurology.

[20]  P. Bellgowan,et al.  Microinfusion of mu but not delta or kappa opioid agonists into the basolateral amygdala results in inhibition of the tail flick reflex in pentobarbital-anesthetized rats. , 1995, The Journal of pharmacology and experimental therapeutics.

[21]  I. Ulmanen,et al.  Kinetics of human soluble and membrane-bound catechol O-methyltransferase: a revised mechanism and description of the thermolabile variant of the enzyme. , 1995, Biochemistry.

[22]  M. Kreek,et al.  Repeated cocaine administration upregulates kappa and mu, but not delta, opioid receptors. , 1994, Neuroreport.

[23]  J. F. Chen,et al.  Continuous treatment with the D2 dopamine receptor agonist quinpirole decreases D2 dopamine receptors, D2 dopamine receptor messenger RNA and proenkephalin messenger RNA, and increases mu opioid receptors in mouse striatum , 1993, Neuroscience.

[24]  B. Everitt,et al.  Effects of medial dorsal thalamic and ventral pallidal lesions on the acquisition of a conditioned place preference: Further evidence for the involvement of the ventral striatopallidal system in reward-related processes , 1993, Neuroscience.

[25]  H. Fibiger,et al.  Formation and Clearance of Interstitial Metabolites of Dopamine and Serotonin in the Rat Striatum: An In Vivo Microdialysis Study , 1992, Journal of neurochemistry.

[26]  G. Mogenson,et al.  The contribution of basal forebrain to limbic-motor integration and the mediation of motivation to action. , 1991, Advances in experimental medicine and biology.

[27]  D. Watson,et al.  Development and validation of brief measures of positive and negative affect: the PANAS scales. , 1988, Journal of personality and social psychology.

[28]  S. Shelton,et al.  Opiate modulation of separation-induced distress in non-human primates , 1988, Brain Research.

[29]  I. Kopin,et al.  Catecholamine metabolism: basic aspects and clinical significance. , 1985, Pharmacological reviews.

[30]  J. Warsh,et al.  Formation and Clearance of Norepinephrine Glycol Metabolites in Mouse Brain , 1984, Journal of neurochemistry.

[31]  M. E. Lewis,et al.  Endogenous opioids: biology and function. , 1984, Annual review of neuroscience.

[32]  L. Watkins,et al.  Organization of endogenous opiate and nonopiate pain control systems. , 1982, Science.