Conditioned Pain Modulation Is Associated with Common Polymorphisms in the Serotonin Transporter Gene

Abstract

BackgroundVariation 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.ResultsThe 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.ConclusionsOur 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.

Recent Advances in the Understanding of Genetic Susceptibility to Chronic Pain and Somatic Symptoms

“…However, no association between 5HTTLPR and the endophenotype, sensitivity to sensory stimuli, was observed. This is in contrast to another study that found that the S (low expressing) allele was associated with being less sensitive to heat, cold, and pressure pain compared with the L (high expressing allele) [45,46] in healthy individuals. FM patients are reported to be more sensitive to sensory stimuli, however, and the S allele was associated with an increased risk of FM in earlier studies [19].…”

Pain Catastrophizing and Anxiety are Associated With Heat Pain Perception in a Community Sample of Adults With Chronic Pain

“…35 This is relevant to serotonergic transmission because (1) individuals with low serotonin transporter gene expression, which facilitates serotonin reuptake from the synaptic cleft, have a tendency to focus on negative stimuli, and (2) polymorphisms in the serotonin transporter gene have been associated with alterations in pain scores and pain perception, including HP 0.5. 17,36,37 Similar to the PCS, greater PASS-20 scores were associated with lower standardized values of HP 0.5 and HP 5. This is consistent with previous studies where anxiety sensitivity was correlated with pain intensity and fear of pain.…”

Placebo effects in children: a review

“…A similar assumption has been proposed for children and adolescents (35), but the possibility that further mechanisms, such as instrumental learning (36) or learning by imitation (37), exist cannot be excluded. Furthermore, the contribution of genetic factors is likely but has only been shown in a few studies with adults so far (38)(39)(40).…”