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

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

Conditioned pain modulation scores (CPM-scores).

<p>To control for individual variation with regard to baseline values, the proportion of difference from baseline was used rather than the difference of raw values. This was done to control for individual variation in baseline measures and gives positive CPM-scores for pain inhibition and negative ones for facilitation, as compared to the baseline. To enable a comparison of VAS-ratings with threshold values, we define our CPM-scores as q(b–c)/b where b = baseline value (in kPA, mm or mA) and c =  value during CPM. q = 1 for heat-pain VAS-ratings and q = −1 for thresholds ratings.</p

Interaction between pain-ratings for suprathreshold noxious heat and genotype.

<p>Mean VAS-ratings for suprathreshold noxious heat, applied to the right ventral forearm, are shown for the low 5-HTT-expressing and high 5-HTT-expressing genotype groups, respectively. The interaction between temperature level and genotype on the VAS-rating was significant [F(1.60, 65.51) = 4.10, p = 0.03].</p

Conditioned pain modulation.

<p>The low 5-HTT-expressing group, as compared with the high 5-HTT group, had a significantly diminished conditioned pain modulation with regard to pressure pain thresholds [F(1,41) = 5.99, p = 0.02] and heat at 30 seconds [U = 145.5, z = −2.44, p = 0.02, r = −0.36]. There were no significant differences between groups with regard to tonic pain-mediated increase in the threshold for the nociceptive flexion reflex (NFR), F<1.</p

Participants.

<p>Healthy subjects were recruited based on genotype. Both subjects and experimenters were blinded for genotype. The members of the groups did not differ significantly in age [U = 239.5, z = −0.31, p = 0.76] and women did not differ significantly in their menstrual cycles between groups [χ²(1) = 0.001, p = 0.98].</p

Baseline values for test-pain stimuli.

<p>A. Pressure pain thresholds (PPTs) in kPA, assessed by algometry, at baseline. Genotype did not have a significant effect on the baseline level [U = 247, z = −0.14, p = 0.90]. B. No significant differences were found on the basis of genotype [U = 211, z = −0.95, p = 0.35] between the individualized temperatures used as test-stimuli. C. Average of the two baseline NFR-threshold measurements in mA. No significant differences were found between groups, F<1.</p