Associations between polymorphisms in dopamine neurotransmitter pathway genes and pain response in healthy humans

Abstract

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.

Subthalamic deep brain stimulation modulates small fiber–dependent sensory thresholds in Parkinson’s disease

“…Experimental studies showed that dopaminergic pathways are implicated in pain integration and modulation to heat noxious stimulation [5,32,40]. Genetic factors also support the association between low dopaminergic activity and high pain sensitivity [35].…”

Diagnosis of Fibromyalgia Syndrome: Potential Biomarkers and Proteomic Approach

“…More recently, Treister et al found an association between the dopamine transporter gene (DAT-1) polymorphism and cold pain tolerance. Their results, together with the known function of the investigated candidate gene polymorphisms, suggest that low dopaminergic activity can be associated with high pain sensitivity (Treister et al, 2009). However, Ablin and co-workers, investigating an association between fibromyalgia and DAT1, found no significant association between fibromyalgia and the genetic marker (Ablin et al, 2009 In conclusion, all these genetic studies support a role for the polymorphism of genes of the serotoninergic, catecholaminergic and dopaminergic systems in the etiopathogenesis of fibromyalgia.…”

ADHD risk alleles associated with opiate addiction: study of addicted parents and their children

“…The studies on dopamine receptors were performed according to methods described by Treister et al (38) and those on serotonin transporter according to methods described by Bachner-Melman et al (39). In brief, they are as follows: DRD4 (38): The DRD4 exon III polymorphism was characterized using the following primers: DRD4 P1 5′-GGC GTT GCC GCT CTG AAT GC-3′ and DRD4 P2 5′-GAG GGA CTG AGC TGG ACA ACC-3′.…”

“…The reaction mixture (20 µl) contained 200 µmol/l dNTPs, 0.5 µmol/l primers, Mg/Cl and dimethyl sulfoxide (DMSO) 5% (10 µl), and 20ng DNA. The amplification procedure included a 5-min prestart at 94 °C (for the hot start) and 35 DRD4 EX 120 (38): Hundred nanograms of genomic DNA were amplified in a total volume of 25 ml with the following primers at 0.2 mmol/l: D4upstrFor2 (58-GTTGTCTGTCTTTTCTCATT GTTTCCATTG-38) and D4upstrRev3 (58-GAAGGAGCAGGCAC CGTGAGC-38) with 0.2 mmol/l dNTPs, 5% DMSO, 0.5 U Taq polymerase in standard polymerase chain reaction (PCR) buffer containing 1.5 mmol/l MgCl. PCR cycling conditions are 5 min at 95 °C followed by 30 cycles of 30 s at 94 °C, 30 s at 58 °C, and 60 s at 72 °C with a final extension for 10 min at 72 °C.…”