Association Between Polymorphisms in Serotonin and Dopamine-Related Genes and Endogenous Pain Modulation

Treister, Roi; Pud, Dorit; Ebstein, Richard P.; Laiba, Efrat; Raz, Yael; Gershon, Edith; Haddad, May; Eisenberg, Elon

doi:10.1016/j.jpain.2011.02.348

Cited by 59 publications

(76 citation statements)

References 57 publications

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“…Previous studies showed that healthy individuals with 5-HTT low expression had decreased conditioned pain modulation 28 and decreased sensory modulation. 40 However, conditioned pain modulation and EIH are 2 different paradigms to study pain modulatory processes and they do not seem to be correlated. 14,41 Thus, the genetic associations related to alterations in EIH seem to be only noticeable when considering the interaction of more than 1 polymorphism, stressing the importance of studying joint gene effects on pain modulation.…”

Section: Discussionmentioning

confidence: 99%

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

Tour

Löfgren

Mannerkorpi

et al. 2017

Pain

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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.

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Section: Discussionmentioning

confidence: 99%

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

Tour

Löfgren

Mannerkorpi

et al. 2017

Pain

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“…As noted previously, although one group found an association between SLC6A3 variants and experimental pain in healthy human volunteers, in a subsequent study they were unable to find an association between this transporter and endogenous pain modulation. [11, 51] Another study could not find an association between SLC6A3 SNPs (including rs403636) and acute postoperative pain among individuals undergoing third molar extraction. [52] Our study provides only a weak evidence for an association between SLC6A3 variants and acute clinical pain after MVC trauma.…”

Section: Discussionmentioning

confidence: 99%

Genetic Polymorphisms in the Dopamine Receptor 2 Predict Acute Pain Severity After Motor Vehicle Collision

Qadri

Bortsov

Orrey

et al. 2015

The Clinical Journal of Pain

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Objectives: Dopaminergic signaling is implicated in nociceptive pathways. These effects are mediated largely through dopamine receptors and modulated in part by dopamine transporters. This study tests the hypothesis that genetic variants in the genes encoding dopamine receptor 2 (DRD2) and the dopamine active transporter (SLC6A3) influence acute pain severity after motor vehicle collision (MVC). Methods: European Americans presenting to the emergency department (ED) after MVC were recruited. Overall pain intensity in ED was assessed using a 0-10 numeric rating scale. DNA was extracted from blood samples and genotyping of single nucleotide polymorphisms (SNPs) in the DRD2 and SLC6A3 gene was performed. Results: A total of 948 patients completed evaluation. After correction for multiple comparisons, SNP rs6276 at DRD2 showed significant association with pain scores, with individuals with the A/A genotype reporting lower mean pain scores (5.3, 95% CI 5.1 to 5.5) than those with A/G (5.9, 95% CI 5.6 to 6.1) or G/G (5.7, 95%CI 5.2 to 6.2) genotypes (p=0.0027). Secondary analyses revealed an interaction between sex and DRD2 SNPs rs4586205 and rs4648318 on pain scores: females with two minor alleles had increased pain intensity, whereas males with two minor alleles had less pain than individuals with a major allele (interaction p=0.0019). Discussion: Genetic variants in DRD2 are associated with acute pain after a traumatic stressful event. These results suggest that dopaminergic agents may be useful for the treatment of individuals with acute post-traumatic pain as part of a multimodal opioid-sparing analgesic regimen.

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“…However, other genetic loci that contribute to catecholamine synthesis and transmission have been implicated in a number of pain phenotypes. Most recently, an association has been revealed between polymorphisms of the serotonin transporter gene ( SLC6A4 ) and experimental thermal pain thresholds76 as well as the conditioned75 81 and emotional82 modulation of experimental pain. Moreover, carriers of the s-allele in the serotonin transporter linked promoter region (5-HTTLPR) within SLC6A4 show decreased 5-HTT function83 and an increased risk for the CWP condition fibromyalgia 84…”

Section: Genetic Correlates Of Pain: Recent Progressmentioning

confidence: 99%

Genetic basis of pain variability: recent advances

2011

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An estimated 15–50% of the population experiences pain at any given time, at great personal and societal cost. Pain is the most common reason patients seek medical attention, and there is a high degree of individual variability in reporting the incidence and severity of symptoms. Research suggests that pain sensitivity and risk for chronic pain are complex heritable traits of polygenic origin. Animal studies and candidate gene testing in humans have provided some progress in understanding the heritability of pain, but the application of the genome-wide association methodology offers a new tool for further elucidating the genetic contributions to normal pain responding and pain in clinical populations. Although the determination of the genetics of pain is still in its infancy, it is clear that a number of genes play a critical role in determining pain sensitivity or susceptibility to chronic pain. In the present review, the authors provide an update of the most recent findings that associate genetic variation with variability in pain and an overview of the candidate genes with the highest translational potential.

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Association Between Polymorphisms in Serotonin and Dopamine-Related Genes and Endogenous Pain Modulation

Cited by 59 publications

References 57 publications

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

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

Genetic Polymorphisms in the Dopamine Receptor 2 Predict Acute Pain Severity After Motor Vehicle Collision

Genetic basis of pain variability: recent advances

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