Gene-to-gene interactions regulate endogenous pain modulation in fibromyalgia patients and healthy controls-antagonistic effects between opioid and serotonin-related genes

Abstract

Chronic pain is associated with dysfunctional endogenous pain modulation, involving both central opioid and serotonergic (5-HT) signaling. Fibromyalgia (FM) is a chronic pain syndrome, characterized by widespread musculoskeletal pain and reduced exercise-induced hypoalgesia (EIH). In this study, we assessed the effects of 3 functional genetic polymorphisms on EIH in 130 patients with FM and 132 healthy controls. Subjects were genotyped regarding the mu-opioid receptor (OPRM1) gene (rs1799971), the serotonin transporter (5-HTT) gene (5-HTTLPR/rs25531), and the serotonin-1a receptor (5-HT1a) gene (rs6296). The patients with FM had increased pain sensitivity and reduced EIH compared with healthy controls. None of the polymorphisms had an effect on EIH on their own. We found significant gene-to-gene interactions between OPRM1 x 5-HTT and OPRM1 x 5-HT1a regarding activation of EIH, with no statistically significant difference between groups. Better EIH was found in individuals with genetically inferred strong endogenous opioid signaling (OPRM1 G) in combination with weak 5-HT tone (5-HTT low/5-HT1a G), compared with strong 5-HT tone (5-HTT high/5-HT1a CC). Based on the proposed mechanisms of these genetic variants, the findings indicate antagonistic interactions between opioid and serotonergic mechanisms during EIH. Moreover, despite different baseline pain level, similar results were detected in FM and controls, not supporting an altered interaction between opioid and 5-HT mechanisms as the basis for dysfunction of EIH in patients with FM. In summary, our results suggest that, by genetic association, the mu-opioid receptor interacts with 2 major serotonergic structures involved in 5-HT reuptake and release, to modulate EIH.

Figure 1.

Flowchart of the methodology of the assessment. The pressure pain threshold (PPT) was assessed at 8 body sites. After testing for maximum voluntary contraction (MVC) of m. quadriceps, the subjects performed an isometric contraction of the right m. quadriceps corresponding to 30% of their individual MVC. The PPT at m. deltoideus was assessed before and approximately every 20 seconds during the contraction or for 5 minutes or until exhaustion. *10 to 15 minutes.

Figure 2.

Normalized pressure pain thresholds (PPTs) (mean ± SEM) at baseline, start, middle, and end of a standardized isometric contraction of m. quadriceps corresponding to 30% of maximum voluntary contraction (MVC) assessed at the resting m. deltoideus. There was a significant difference between the groups at middle (P = 0.001) and end (P = 0.003) of contraction, implying reduced exercise-induced hypoalgesia in patients with fibromyalgia (FM). The curves were adjusted (by adding a coefficient) so that the baseline value always corresponded to 1. Normalized PPT = PPT during contraction/baseline PPT. Statistically significant differences from controls are indicated **P < 0.01.

Figure 3.

Gene-to-gene interactions between (A) OPRM1 x 5-HTT and (B) OPRM1 x 5-HT1a in fibromyalgia patients and healthy controls grouped together. Assessments were based on the pain modulation score (mean ± SEM), assessing the amount of central pain inhibition during isometric exercise. A significant effect was seen in subjects with OPRM1 G-genotype for both serotonergic genes. Subjects with low-expressing 5-HTT or 5-HT1a G-genotype, respectively, had higher pain modulation scores compared with high-expressing 5-HTT (P = 0.023) or 5-HT1a CC-genotype (P = 0.037). PPT = pressure pain threshold. Pain modulation score = (PPT end − PPT baseline)/PPT baseline. *P < 0.05.

Figure 4.

Gene-to-gene interactions between OPRM1a and 5-HTT in (A) patients with fibromyalgia (FM) and (B) healthy controls when assessing exercise-induced hypoalgesia. A significant interaction was found in patients with FM (P < 0.05)—subjects with OPRM1 G-genotype had a significantly higher pain modulation score if they also were genetically inferred 5-HTT low expressing compared with 5-HTT high expressing (P < 0.01). In accordance, the analysis exhibited a trend in low-expressing 5-HTT carriers where OPRM1 G-genotype conferred a higher pain modulation score than AA-genotype (P = 0.10). No significant interactions were found in the control group. PPT = pressure pain threshold. Pain modulation score = (PPT end − PPT baseline)/PPT baseline.

Figure 5.

Gene-to-gene interactions between OPRM1a and 5-HT1a in (A) patients with fibromyalgia (FM) and (B) healthy controls when assessing exercise-induced hypoalgesia. There was a significant interaction of OPRM1 and 5-HT1a in the healthy control group (P < 0.05). OPRM1 AA-genotypes had a significantly higher pain modulation score if they also were 5-HT1a CC-carriers compared with G-carriers (P < 0.05). A trend supporting the results was exhibited for 5-HT1a CC-genotypes, who had a higher pain modulation score if they were OPRM1 AA-carriers compared with G-carriers (P = 0.059). PPT = pressure pain threshold. Pain modulation score = (PPT end − PPT baseline)/PPT baseline.