Serotonin-1A receptor polymorphism (rs6295) associated with thermal pain perception

PLoS One. 2012;7(8):e43221. doi: 10.1371/journal.pone.0043221. Epub 2012 Aug 31.


Background: Serotonin (5-HT) is highly involved in pain regulation and serotonin-1A (5-HT1A) receptors are important in determining central 5-HT tone. Accordingly, variation in the 5-HT1A receptor gene (HTR1A) may contribute to inter-individual differences in human pain sensitivity. The minor G-allele of the HTR1A single nucleotide polymorphism (SNP) rs6295 attenuates firing of serotonergic neurons and reduces postsynaptic expression of the receptor. Experiments in rodents suggest that 5-HT1A-agonism modulates pain in opposite directions at mild compared to high noxious intensities. Based upon this and several other similar observations, we hypothesized that G-carriers would exhibit a relative hypoalgesia at mild thermal stimuli but tend towards hyperalgesia at higher noxious intensities.

Methods: Fourty-nine healthy individuals were selectively genotyped for rs6295. Heat- and cold-pain thresholds were assessed along with VAS-ratings of a range of suprathreshold noxious heat intensities (45°C-49°C). Nociceptive-flexion reflex (NFR) thresholds were also assessed.

Results: Volunteers did not deviate significantly from Hardy-Weinberg equilibrium. G-carriers were less sensitive to threshold-level thermal pain. This relative hypoalgesia was abolished at suprathreshold noxious intensities where G-carriers instead increased their ratings of heat-pain significantly more than C-homozygotes. No differences with regard to NFR-thresholds emerged.

Conclusion/significance: To the best of our knowledge this is the first study of human pain perception on the basis of variation in HTR1A. The results illustrate the importance of including a range of stimulus intensities in assessments of pain sensitivity. In speculation, we propose that an attenuated serotonergic tone may be related to a 'hypo- to hyperalgesic' response-pattern. The involved mechanisms could be of clinical interest as variation in pain regulation is known to influence the risk of developing pain pathologies. Further investigations are therefore warranted.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Alleles
  • Female
  • Genotype
  • Hot Temperature
  • Humans
  • Male
  • Models, Genetic
  • Pain / genetics
  • Pain Perception*
  • Pain Threshold / physiology
  • Polymorphism, Genetic*
  • Polymorphism, Single Nucleotide
  • Receptor, Serotonin, 5-HT1A / genetics*
  • Serotonergic Neurons / metabolism
  • Skin Temperature


  • Receptor, Serotonin, 5-HT1A

Grant support

This study was funded by The Karolinska Institute, Swedish Rheumatism Association and Stockholm County Council (EK); The Swedish Research Council (, grant nr 2011-4807 (MS); The Swedish Heart-Lung Foundation (COH); Petrus and Augusta Hedlunds Stiftelse, The Center for Allergy Research, Swedish Heart-Lung Foundation, Swedish Council for Working Life and Social Research, The Swedish Society for Medicine, The National board of Health and Welfare and Stockholm Stress Center (ML). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.