title: Conditioned pain modulation is associated with common polymorphisms in the serotonin transporter gene.
abstract: BACKGROUND
  Variation in the serotonin transporter (5-HTT) gene (SLC6A4) has been shown to influence a wide range of affective processes. Low 5-HTT gene-expression has also been suggested to increase the risk of chronic pain. Conditioned pain modulation (CPM)--i.e. 'pain inhibits pain'--is impaired in chronic pain states and, reciprocally, aberrations of CPM may predict the development of chronic pain. Therefore we hypothesized that a common variation in the SLC6A4 is associated with inter-individual variation in CPM. Forty-five healthy subjects recruited on the basis of tri-allelic 5-HTTLPR genotype, with inferred high or low 5-HTT-expression, were included in a double-blind study. A submaximal-effort tourniquet test was used to provide a standardized degree of conditioning ischemic pain. Individualized noxious heat and pressure pain thresholds (PPTs) were used as subjective test-modalities and the nociceptive flexion reflex (NFR) was used to provide an objective neurophysiological window into spinal processing.
  
  
  RESULTS
  The low, as compared to the high, 5-HTT-expressing group exhibited significantly reduced CPM-mediated pain inhibition for PPTs (p = 0.02) and heat-pain (p = 0.02). The CPM-mediated inhibition of the NFR, gauged by increases in NFR-threshold, did not differ significantly between groups (p = 0.75). Inhibition of PPTs and heat-pain were correlated (Spearman's rho = 0.35, p = 0.02), whereas the NFR-threshold increase was not significantly correlated with degree of inhibition of these subjectively reported modalities.
  
  
  CONCLUSIONS
  Our results demonstrate the involvement of the tri-allelic 5-HTTLPR genotype in explaining clinically relevant inter-individual differences in pain perception and regulation. Our results also illustrate that shifts in NFR-thresholds do not necessarily correlate to the modulation of experienced pain. We discuss various possible mechanisms underlying these findings and suggest a role of regulation of 5-HT receptors along the neuraxis as a function of differential 5-HTT-expression.
authors.affiliation: Department of Clinical Neuroscience, Osher Center for Integrative Medicine, Stockholm Brain Institute, Karolinska Institutet, Stockholm, Sweden. fredrik.lindstedt@ki.se
authors.forename: Fredrik
authors.initials: F
authors.lastname: Lindstedt
authors.forename: Jonathan
authors.initials: J
authors.lastname: Berrebi
authors.forename: Erik
authors.initials: E
authors.lastname: Greayer
authors.forename: Tina B
authors.initials: TB
authors.lastname: Lonsdorf
authors.forename: Martin
authors.initials: M
authors.lastname: Schalling
authors.forename: Martin
authors.initials: M
authors.lastname: Ingvar
authors.forename: Eva
authors.initials: E
authors.lastname: Kosek
mesh_terms: D000328:Adult; D000375:Aging / Q000473:pathology; D003213:Conditioning, Psychological; D005260:Female; D005838:Genotype; D006358:Hot Temperature; D006801:Humans; D008297:Male; D008875:Middle Aged; D009619:Nociceptors / Q000378:metabolism; D010146:Pain / Q000235:genetics* / Q000503:physiopathology; D010147:Pain Measurement; D017288:Pain Threshold; D010812:Physical Stimulation; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011312:Pressure; D012018:Reflex / Q000502:physiology; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics*; D011795:Surveys and Questionnaires; D055815:Young Adult
chemical_list: C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins