Perception of thermal pain and the thermal grill illusion is associated with polymorphisms in the serotonin transporter gene

Abstract

Aim: The main aim of this study was to assess if the perception of thermal pain thresholds is associated with genetically inferred levels of expression of the 5-HT transporter (5-HTT). Additionally, the perception of the so-called thermal grill illusion (TGI) was assessed. Forty-four healthy individuals (27 females, 17 males) were selected a-priori based on their 5-HTTLPR/rs25531 ('tri-allelic 5-HTTLPR') genotype, with inferred high or low 5-HTT expression. Thresholds for heat- and cold-pain were determined along with the sensory and affective dimensions of the TGI.

Results: Thresholds to heat- and cold-pain correlated strongly (rho = -0.58, p<0.001). Individuals in the low 5-HTT-expressing group were significantly less sensitive to heat-pain (p = 0.02) and cold-pain (p = 0.03), compared to the high-expressing group. A significant gender-by-genotype interaction also emerged for cold-pain perception (p = 0.02); low 5-HTT-expressing females were less sensitive. The TGI was rated as significantly more unpleasant (affective-motivational dimension) than painful (sensory-discriminatory dimension), (p<0.001). Females in the low 5-HTT expressing group rated the TGI as significantly less unpleasant than high 5-HTT expressing females (p<0.05), with no such differences among men.

Conclusion/significance: We demonstrate an association between inferred low 5-HTT expression and elevated thresholds to thermal pain in healthy non-depressed individuals. Despite the fact that reduced 5-HTT expression is a risk factor for chronic pain we found it to be related to hypoalgesia for threshold thermal pain. Low 5-HTT expression is, however, also a risk factor for depression where thermal insensitivity is often seen. Our results may thus contribute to a better understanding of the molecular underpinnings of such paradoxical hypoalgesia. The results point to a differential regulation of thermoafferent-information along the neuraxis on the basis of 5-HTT expression and gender. The TGI, suggested to rely on the central integration of thermoafferent-information, may prove a valuable tool in probing the affective-motivational dimension of these putative mechanisms.

Figure 1. The thermal grill.

The thermal grill consisted of 8 individual silver plates housed in a PVC unit. The subjects placed their ventral forearm against the grill's surface, orthogonally to the long axis of the silver plates. Temperatures of odd and even numbered plates were set to 41.0°C–42.0°C and/or 15.0°C–16.0°C.

Figure 2. Thermal pain thresholds.

A) Heat-pain thresholds. The difference between average heat-pain threshold for the high- versus the low 5-HTT-expressing groups was significant [U = 155.0, z = −2.03, p = 0.02, one-tailed test]. B) Cold-pain thresholds. The difference between average cold-pain threshold for the high versus the low 5-HTT-expressing groups was significant [U = 162.0, z = −1.91, p = 0.03, one-tailed test].

Figure 3. Validation of the thermal grill illusion for affective and sensory dimensions, all subjects.

The thermal grill illusion was tested along with its constituent temperatures, in a randomized and counterbalanced order. Subjects provided VAS-ratings of both the affective-motivational (i.e. unpleasantness, see panel A) and sensory-discriminatory (i.e. pain, see panel B) dimensions for each condition. Validation of the thermal grill illusion, for all subjects: ***  =  significant at p<0.001, **  =  significant at p<0.01, ns  =  not significant.

Figure 4. Thermal grill illusion on the basis of tri-allelic 5-HTTLPR genotype and gender.

Based on our expectations of gender differences, the genotype groups were further divided into females (panel A) and males (panel B). Females differed significantly in ratings of unpleasantness for the thermal grill, *  =  significant at p<0.05.