Associations between polymorphisms in dopamine neurotransmitter pathway genes and pain response in healthy humans.
Although evidence shows that several dopamine neurotransmission pathway genes are associated with specific clinical pain syndromes, such as fibromyalgia, chronic headache, and postoperative pain, the exact role of dopamine in pain processing is not fully understood. The aim of this study was to explore the relationship between functional polymorphisms in dopaminergic candidate genes and sensitivity to pain in healthy subjects. Healthy subjects (n=192; 105 F, 87 M) were exposed to experimental tonic cold pain (1 degrees C) and phasic heat pain (47 degrees C) stimuli. DNA samples were obtained from both participants and their parents. The relationships between pain response (intensity in response to heat and cold; threshold and tolerance in response to cold only) and the functional Variable Number of Tandem Repeat (VNTR) polymorphisms of three dopamine-related genes were investigated using a Transmission Disequilibrium Test (TDT). Specifically, 30-bp repeat in the promoter region of the monoamine oxidase-A gene (MAO-A), 40-bp repeat in the 3'-untranslated region of the dopamine transporter gene (DAT-1), and 48-bp repeat in the exon 3 of the dopamine receptor 4 gene (DRD4) were examined. Significant associations between cold pain tolerance and DAT-1 (p=0.008) and MAO-A (p=0.024) polymorphisms were found. Specifically, tolerance was shorter for carriers of allele 10 and the rarer allele 11, as compared to homozygous for allele 9, and for carriers of allele 4 as compared to homozygous for allele 3, respectively. These results, together with the known function of the investigated candidate gene polymorphisms, suggest that low dopaminergic activity can be associated with high pain sensitivity and vice versa.
The Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel.
Roi
R
Treister
Dorit
D
Pud
Richard P
RP
Ebstein
Efrat
E
Laiba
Edith
E
Gershon
May
M
Haddad
Elon
E
Eisenberg
D000293:Adolescent; D000328:Adult; D016009:Chi-Square Distribution; D003080:Cold Temperature / Q000009:adverse effects; D004298:Dopamine / Q000235:genetics / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D006930:Hyperalgesia / Q000209:etiology / Q000235:genetics*; D007585:Jews / Q000235:genetics; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D018598:Minisatellite Repeats / Q000235:genetics; D008995:Monoamine Oxidase / Q000235:genetics*; D010147:Pain Measurement; D017288:Pain Threshold / Q000502:physiology; D011110:Polymorphism, Genetic / Q000235:genetics*; D050638:Receptors, Dopamine D4 / Q000235:genetics*; D055815:Young Adult
C493599:DRD4 protein, human; D050483:Dopamine Plasma Membrane Transport Proteins; C493214:SLC6A3 protein, human; D050638:Receptors, Dopamine D4; D008995:Monoamine Oxidase; D004298:Dopamine