title: Serotonin transporter polymorphism alters citalopram effects on human pain responses to physical pain.
abstract: Humans exhibit substantial inter-individual differences in pain perception, which contributes to variability in analgesic efficacy. Individual differences in pain sensitivity have been linked with variation in the serotonin transporter gene (5-HTTLPR), and selective serotonin reuptake inhibitors (SSRIs) such as citalopram have been increasingly used as treatments for multiple pain conditions. We combined genotyping, pharmacological challenge, and neuroimaging during painful electrical stimulation to reveal how serotonin genetics and pharmacology interact to influence pain perception and its underlying neurobiological mechanisms. In a double-blind, placebo-controlled procedure, we acutely administrated citalopram (30mgpo) to short/short (s/s) and long/long (l/l) healthy male 5-HTTLPR homozygotes during functional MRI with painful and non-painful electrical stimulation. 5-HTTLPR genotype modulated citalopram effects on pain-related brain responses in the thalamus, cerebellum, anterior insula, midcingulate cortex and inferior frontal cortex. Specifically, citalopram significantly reduced pain-related brain responses in l/l but not in s/s homozygotes. Moreover, the interaction between 5-HTTLPR genotype and pain-related brain activity was a good predictor of the citalopram-induced reductions in pain reports. The genetic modulations of citalopram effects on brain-wide pain processing were paralleled by significant effects on the Neurological Pain Signature, a multivariate brain pattern validated to be sensitive and specific to physical pain. This work provides neurobiological mechanism by which genetic variation shapes brain responses to pain perception and treatment efficacy. These findings have important implications for the types of individuals for whom serotonergic treatments provide effective pain relief, which is critical for advancing personalized pain treatment.
authors.affiliation: Department of Psychology, Peking University, Beijing, China; State Key Laboratory of Cognitive Neuroscience and Learning, Beijing Normal University, Beijing 100875, China; IDG/McGovern Institute for Brain Research, Beijing Normal University, Beijing 100875, China. Electronic address: yma@bnu.edu.cn.
authors.forename: Yina
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Department of Psychology, Peking University, Beijing, China; PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing, China.
authors.forename: Chenbo
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Psychology, Peking University, Beijing, China; PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing, China.
authors.forename: Siyang
authors.initials: S
authors.lastname: Luo
authors.affiliation: PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing, China; Peking-Tsinghua Center for Life Sciences at School of Life Sciences, Peking University, Beijing, China.
authors.forename: Bingfeng
authors.initials: B
authors.lastname: Li
authors.affiliation: Psychology Department, University of Colorado Boulder, Boulder, CO, USA.
authors.forename: Tor D
authors.initials: TD
authors.lastname: Wager
authors.affiliation: PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing, China; Peking-Tsinghua Center for Life Sciences at School of Life Sciences, Peking University, Beijing, China.
authors.forename: Wenxia
authors.initials: W
authors.lastname: Zhang
authors.affiliation: PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing, China; Peking-Tsinghua Center for Life Sciences at School of Life Sciences, Peking University, Beijing, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Rao
authors.affiliation: Department of Psychology, Peking University, Beijing, China; PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing, China; Beijing Key Laboratory of Behavior and Mental Health, Peking University, Beijing, China. Electronic address: shan@pku.edu.cn.
authors.forename: Shihui
authors.initials: S
authors.lastname: Han
mesh_terms: D000700:Analgesics / Q000008:administration & dosage; D015283:Citalopram / Q000008:administration & dosage*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D010147:Pain Measurement / Q000187:drug effects; D058748:Pain Perception / Q000187:drug effects*; D017288:Pain Threshold / Q000187:drug effects*; D000071185:Pharmacogenomic Testing / Q000379:methods; D015990:Placebo Effect; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics*; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000700:Analgesics; D015283:Citalopram; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors
keywords: 5-HTTLPR; Pain perception; Personalized medicine; SSRI; fMRI