Genetic influence on variability in human acute experimental pain sensitivity associated with gender, ethnicity and psychological temperament

&NA; While a variety of cultural, psychological and physiological factors contribute to variability in both clinical and experimental contexts, the role of genetic factors in human pain sensitivity is increasingly recognized as an important element. This study was performed to evaluate genetic influences on variability in human pain sensitivity associated with gender, ethnicity and temperament. Pain sensitivity in response to experimental painful thermal and cold stimuli was measured with visual analogue scale ratings and temperament dimensions of personality were evaluated. Loci in the vanilloid receptor subtype 1 gene (TRPV1), &dgr; opioid receptor subtype 1 gene (OPRD1) and catechol O‐methyltransferase gene (COMT) were genotyped using 5′ nuclease assays. A total of 500 normal participants (306 females and 194 males) were evaluated. The sample composition was 62.0% European American, 17.4% African American, 9.0% Asian American, and 8.6% Hispanic, and 3.0% individuals with mixed racial parentage. Female European Americans with the TRPV1 Val585 Val allele and males with low harm avoidance showed longer cold withdrawal times based on the classification and regression tree (CART) analysis. CART identified gender, an OPRD1 polymorphism and temperament dimensions of personality as the primary determinants of heat pain sensitivity at 49 °C. Our observations demonstrate that gender, ethnicity and temperament contribute to individual variation in thermal and cold pain sensitivity by interactions with TRPV1 and OPRD1 single nucleotide polymorphisms.

[1]  Deborah A. Nickerson,et al.  Additional SNPs and linkage-disequilibrium analyses are necessary for whole-genome association studies in humans , 2003, Nature Genetics.

[2]  C. Dennis.  Epigenetics and disease: Altered states , 2003, Nature.

[3]  B. Scheithauer,et al.  A phase III study of radiation therapy plus carmustine with or without recombinant interferon‐α in the treatment of patients with newly diagnosed high‐grade glioma , 2001 .

[4]  G. De’ath,et al.  CLASSIFICATION AND REGRESSION TREES: A POWERFUL YET SIMPLE TECHNIQUE FOR ECOLOGICAL DATA ANALYSIS , 2000 .

[5]  Maurice M Ohayon,et al.  Using chronic pain to predict depressive morbidity in the general population. , 2003, Archives of general psychiatry.

[6]  Elissa J. Chesler,et al.  Influences of laboratory environment on behavior , 2002, Nature Neuroscience.

[7]  C. Woolf,et al.  Can we conquer pain? , 2002, Nature Neuroscience.

[8]  R. Fillingim,et al.  Race, ethnicity and pain , 2001, PAIN.

[9]  R. Fillingim,et al.  Ethnic differences in thermal pain responses. , 1999, Psychosomatic medicine.

[10]  R Schumacher,et al.  Anxiety, Pain Experience, and Pain Report: A Signal-Detection Study , 1984, Perceptual and motor skills.

[11]  A. Krainer,et al.  Listening to silence and understanding nonsense: exonic mutations that affect splicing , 2002, Nature Reviews Genetics.

[12]  A. Korshunov,et al.  Immunohistochemical markers for intracranial ependymoma recurrence An analysis of 88 cases , 2000, Journal of the Neurological Sciences.

[13]  P. Thompson,et al.  Plasma beta-endorphin, pain thresholds and anxiety levels across the human menstrual cycle. , 1984, Physiology & behavior.

[14]  J. Faucett,et al.  Differences in postoperative pain severity among four ethnic groups. , 1994, Journal of pain and symptom management.

[15]  P. Thompson,et al.  Plasma β-endorphin, pain thresholds and anxiety levels across the human menstrual cycle , 1984, Physiology & Behavior.

[16]  J Sunil Rao,et al.  A long-term analysis of 1018 patients with melanoma by classic Cox regression and tree-structured survival analysis at a major referral center: Implications on the future of cancer staging. , 2002, Surgery.

[17]  S. Ho,et al.  G/A1947 polymorphism in catechol‐O‐methyltransferase (COMT) gene in Parkinson's disease , 1997, Movement disorders : official journal of the Movement Disorder Society.

[18]  D L Massart,et al.  Classification and regression tree analysis for molecular descriptor selection and retention prediction in chromatographic quantitative structure-retention relationship studies. , 2003, Journal of chromatography. A.

[19]  William J. Roberts.  Sex differences in pain: And now for something completely different , 1997, Behavioral and Brain Sciences.

[20]  G. Milligan,et al.  Protein-protein interactions at G-protein-coupled receptors. , 2001, Trends in pharmacological sciences.

[21]  L. Kenner,et al.  Ethnic and Sex Differences in Response to Clinical and Induced Pain in Chronic Spinal Pain Patients , 1984, Spine.

[22]  M. Nöthen,et al.  Human δ‐opioid receptor gene and susceptibility to heroin and alcohol dependence , 1999 .

[23]  D. Julius,et al.  The capsaicin receptor: a heat-activated ion channel in the pain pathway , 1997, Nature.

[24]  H. Loh,et al.  delta-Opioid receptor gene: effect of Sp1 factor on transcriptional regulation in vivo. , 2001, Molecular pharmacology.

[25]  L. Cardon,et al.  Association study designs for complex diseases , 2001, Nature Reviews Genetics.

[26]  D. McKemy,et al.  Mustard oils and cannabinoids excite sensory nerve fibres through the TRP channel ANKTM1 , 2004, Nature.

[27]  Joshua F. Nitsche,et al.  Retention of Supraspinal Delta-like Analgesia and Loss of Morphine Tolerance in δ Opioid Receptor Knockout Mice , 1999, Neuron.

[28]  W. Maixner,et al.  Ischemic but Not Thermal Pain Sensitivity Varies Across the Menstrual Cycle , 1997, Psychosomatic medicine.

[29]  P. Männistö,et al.  Catechol-O-methyltransferase (COMT): biochemistry, molecular biology, pharmacology, and clinical efficacy of the new selective COMT inhibitors. , 1999, Pharmacological reviews.

[30]  N. Martin,et al.  Testing a model for the genetic structure of personality: a comparison of the personality systems of Cloninger and Eysenck. , 1994, Journal of personality and social psychology.

[31]  E. Keogh,et al.  Investigating the effects of anxiety sensitivity and coping on the perception of cold pressor pain in healthy women , 2001, European journal of pain.

[32]  B. Scheithauer,et al.  A phase III study of radiation therapy plus carmustine with or without recombinant interferon-alpha in the treatment of patients with newly diagnosed high-grade glioma. , 2001, Cancer.

[33]  E. Chesler,et al.  Sex differences in thermal nociception and morphine antinociception in rodents depend on genotype , 2000, Neuroscience & Biobehavioral Reviews.

[34]  H. Pearson.  DNA: Beyond the double helix , 2003, Nature.

[35]  D. Goldman,et al.  Relationship of the delta-opioid receptor gene to heroin abuse in a large Chinese case/control sample. , 2002, American journal of medical genetics.

[36]  L. Jan,et al.  Contribution of GIRK2-mediated postsynaptic signaling to opiate and α2-adrenergic analgesia and analgesic sex differences , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[37]  Nada Lavrac,et al.  Selected techniques for data mining in medicine , 1999, Artif. Intell. Medicine.

[38]  D. McKemy,et al.  Identification of a cold receptor reveals a general role for TRP channels in thermosensation , 2002, Nature.

[39]  Elissa J. Chesler,et al.  The melanocortin-1 receptor gene mediates female-specific mechanisms of analgesia in mice and humans , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[40]  P. Sullivan,et al.  Fatigue in a community sample of twins , 2003, Psychological Medicine.

[41]  J W Overstreet,et al.  Sperm morphology, motility, and concentration in fertile and infertile men. , 2001, The New England journal of medicine.

[42]  J. Mogil,et al.  Heritability of nociception. III. Genetic relationships among commonly used assays of nociception and hypersensitivity , 2002, Pain.

[43]  A. Aloisi,et al.  Sex differences in pain and analgesia: the role of gonadal hormones , 2004, European journal of pain.

[44]  Johanna Smeyers-Verbeke,et al.  Handbook of Chemometrics and Qualimetrics: Part A , 1997 .

[45]  Eric R. Ziegel,et al.  Handbook of Chemometrics and Qualimetrics, Part B , 2000, Technometrics.

[46]  Peter McIntyre,et al.  ANKTM1, a TRP-like Channel Expressed in Nociceptive Neurons, Is Activated by Cold Temperatures , 2003, Cell.

[47]  Robert C. Coghill,et al.  Reproducibility of pain measurement and pain perception , 2002, Pain.

[48]  D. Borsook.  Molecular neurobiology of pain , 1997 .

[49]  Joshua A. Bueller,et al.  COMT val158met Genotype Affects µ-Opioid Neurotransmitter Responses to a Pain Stressor , 2003, Science.

[50]  A I Basbaum,et al.  Impaired nociception and pain sensation in mice lacking the capsaicin receptor. , 2000, Science.

[51]  J. Belknap,et al.  Genetic sensitivity to hot-plate nociception in DBA/2J and C57BL/6J inbred mouse strains: possible sex-specific mediation by δ 2-opioid receptors , 1997, Pain.

[52]  V. Yuferov,et al.  Opioid receptor and peptide gene polymorphisms: potential implications for addictions. , 2000, European journal of pharmacology.

[53]  D. Turk.  Remember the distinction between malignant and benign pain? Well, forget it. , 2002, The Clinical journal of pain.

[54]  O. Andreassen,et al.  Mice Deficient in Cellular Glutathione Peroxidase Show Increased Vulnerability to Malonate, 3-Nitropropionic Acid, and 1-Methyl-4-Phenyl-1,2,5,6-Tetrahydropyridine , 2000, The Journal of Neuroscience.

[55]  S. Topp,et al.  Cloning and functional expression of a human orthologue of rat vanilloid receptor-1 , 2000, Pain.

[56]  R. Weinshilboum,et al.  Human catechol-O-methyltransferase pharmacogenetics: description of a functional polymorphism and its potential application to neuropsychiatric disorders. , 1996, Pharmacogenetics.

[57]  H. Rommelspacher,et al.  Association between a delta opioid receptor gene polymorphism and heroin dependence in man , 1997, Neuroreport.

[58]  Lin Chang,et al.  Sex-related differences in IBS patients: central processing of visceral stimuli. , 2003, Gastroenterology.

[59]  L. Palmer,et al.  Genomewide scans of complex human diseases: true linkage is hard to find. , 2001, American journal of human genetics.

[60]  A. Patapoutian,et al.  Ion channels: Opposite thermosensor in fruitfly and mouse , 2003, Nature.

[61]  E. Augustson,et al.  Sex-specific effects of pain-related anxiety on adjustment to chronic pain. , 2000, The Clinical journal of pain.

[62]  R. Marshall.  The use of classification and regression trees in clinical epidemiology. , 2001, Journal of clinical epidemiology.

[63]  J. Rhudy,et al.  Fear and anxiety: divergent effects on human pain thresholds , 2000, Pain.

[64]  A. Rigby,et al.  Using twin studies to label disease as genetic or environmental is inappropriate , 2002, BMJ : British Medical Journal.

[65]  Ronald N. Jones,et al.  A nationwide, multicenter, case-control study comparing risk factors, treatment, and outcome for vancomycin-resistant and -susceptible enterococcal bacteremia. , 2000, Diagnostic microbiology and infectious disease.

[66]  R. Lewis.  An Introduction to Classification and Regression Tree (CART) Analysis , 2000 .

[67]  J. Gelernter,et al.  Variant detection at the δ opioid receptor (OPRD1) locus and population genetics of a novel variant affecting protein sequence , 2000, Human Genetics.

[68]  Lakshmi A. Devi,et al.  Heterodimerization of μ and δ Opioid Receptors: A Role in Opiate Synergy , 2000, The Journal of Neuroscience.