Genetic basis for individual variations in pain perception and the development of a chronic pain condition

Abstract

Pain sensitivity varies substantially among humans. A significant part of the human population develops chronic pain conditions that are characterized by heightened pain sensitivity. We identified three genetic variants (haplotypes) of the gene encoding catecholamine-O-methyltransferase (COMT) that we designated as low pain sensitivity (LPS), average pain sensitivity (APS) and high pain sensitivity (HPS). We show that these haplotypes encompass 96% of the human population, and five combinations of these haplotypes are strongly associated (P=0.0004) with variation in the sensitivity to experimental pain. The presence of even a single LPS haplotype diminishes, by as much as 2.3 times, the risk of developing myogenous temporomandibular joint disorder (TMD), a common musculoskeletal pain condition. The LPS haplotype produces much higher levels of COMT enzymatic activity when compared with the APS or HPS haplotypes. Inhibition of COMT in the rat results in a profound increase in pain sensitivity. Thus, COMT activity substantially influences pain sensitivity, and the three major haplotypes determine COMT activity in humans that inversely correlates with pain sensitivity and the risk of developing TMD.

The association between headache and Val158Met polymorphism in the catechol–O–methyltransferase gene: the HUNT Study

“…To date, no other functional polymorphisms within the COMT gene have been linked to headache. However, two other different genetic haplotypes of the COMT gene have been found to be involved in pain perception in a recent case-control study [19], and these may be relevant for headache prevalence.…”

Widespread Hyperalgesia in Adolescents With Symptoms of Irritable Bowel Syndrome: Results From a Large Population-Based Study

“…A similar procedure has been used by other research groups previously. 15 Due to right censoring of the heat, pressure and cold-pressor pain tolerance data, Cox proportional hazard regression was used to analyze these outcomes. Heat pain tolerance below 50 degrees Celsius, pressure pain tolerance below 1000 kPa and cold-pressor endurance time below 105 seconds were considered an event in each test respectively and individuals reaching the preset test-limits were treated as censored in the Cox regression analyses.…”

Gene–gene effects on central processing of aversive stimuli

“…7,8 While carriers of the Val 158 allele showed a small but significant increase in perseverative errors in an executive function task [9][10][11] and reduced working memory function, 12 recent findings indicate that a compensating advantage of the Val 158 allele may be an increase in emotional resilience against anxiety, affective disorders and sustained pain. [13][14][15][16][17][18] Behavioral genetics has revealed an effect of the COMT Val 158 Met genotype 4 on negative mood states 17,19 and on another intermediate phenotype, executive cognitive function. 9 A functional 20,21 22-23-bp imperfect repeat polymorphism in the regulatory region (5-HTTLPR) of the serotonin transporter gene (SCL6A4) creates a short (S) allele and a long (L) allele (14-and 16-repeat alleles) and alters promoter activity.…”