Polymorphisms of the μ-opioid receptor gene influence cerebral pain processing in fibromyalgia

Abstract

Background: Dysregulation of the μ-opioid receptor has been reported in fibromyalgia (FM) and was linked to pain severity. Here, we investigated the effect of the functional genetic polymorphism of the μ-opioid receptor gene (OPRM1) (rs1799971) on symptom severity, pain sensitivity and cerebral pain processing in FM subjects and healthy controls (HC).

Methods: Symptom severity and pressure pain sensitivity was assessed in FM subjects (n = 70) and HC (n = 35). Cerebral pain-related activation was assessed by functional magnetic resonance imaging during individually calibrated painful pressure stimuli.

Results: Fibromyalgia subjects were more pain sensitive but no significant differences in pain sensitivity or pain ratings were observed between OPRM1 genotypes. A significant difference was found in cerebral pain processing, with carriers of at least one G-allele showing increased activation in posterior cingulate cortex (PCC) extending to precentral gyrus, compared to AA homozygotes. This effect was significant in FM subjects but not in healthy participants, however, between-group comparisons did not yield significant results. Seed-based functional connectivity analysis was performed with the seed based on differences in PCC/precentral gyrus activation between OPRM1 genotypes during evoked pain across groups. G-allele carriers displayed decreased functional connectivity between PCC/precentral gyrus and prefrontal cortex.

Conclusions: G-allele carriers showed increased activation in PCC/precentral gyrus but decreased functional connectivity with the frontal control network during pressure stimulation, suggesting different pain modulatory processes between OPRM1 genotypes involving altered fronto-parietal network involvement. Furthermore, our results suggest that the overall effects of the OPRM1 G-allele may be driven by FM subjects.

Significance: We show that the functional polymorphism of the μ-opioid receptor gene OPRM1 was associated with alterations in the fronto-parietal network as well as with increased activation of posterior cingulum during evoked pain in FM. Thus, the OPRM1 polymorphism affects cerebral processing in brain regions implicated in salience, attention, and the default mode network. This finding is discussed in the light of pain and the opioid system, providing further evidence for a functional role of OPRM1 in cerebral pain processing.

FIGURE 1

Schematic representation of the experimental paradigm. In the instructed conditioning paradigm participants were presented with a green or red cue (2 s) that was followed by a delay (2–6 s) before pressure stimulation (5 s) of lower or higher intensity, respectively. Each stimulus presentation was followed by a rating period (8 s) using a 0–100 visual analogue scale (VAS). Intensity of pressure stimulations were individually calibrated to represent approximately 10/100 VAS (P10) and 50/100 VAS (P50). Figure adapted from (Sandström et al., 2020)

FIGURE 2

Calibrated pressure input in mmHg for OPRM1 genotypes (*/G vs. AA) to match 10/100 VAS (P10) and 50/100 VAS (P50) pressure intensity. There was a significant difference in input pressure (i) between groups and (ii) between P50 (white boxplot) and P10 (grey boxplot) pressure in mmHg. No difference between OPRM1 genotypes was observed. Whiskers represent the maximum 1.5 interquartile range (IQR). Circles represent data outside the IQR. FM, fibromyalgia; HC, healthy controls; VAS, visual analogue scale

FIGURE 3

Pain ratings for OPRM1 genotype A (n = 88) and OPRM1 G‐carriers (n = 30) during 10/100 VAS (P10) and 50/100 VAS (P50) stimulus pressure intensity. Individual pain ratings were acquired using a VAS ranging from ‘no pain’ (0) to ‘worst pain imaginable’ (100). There was a significant difference between groups (FM/HC) and between stimulus intensities (P10/P50) but no difference between OPRM1 genotypes (AA/*G). (a) Pain ratings are displayed for stimuli of lower intensity (P10) and (b) for stimuli of higher intensity (P50). Error bars represent the standard error of the mean. FM, fibromyalgia; HC, healthy controls; VAS, visual analogue scale

FIGURE 4

Main effect of pressure pain stimulation. A main effect of pressure stimulus was observed in regions associated with pain processing, including insula and somatosensory cortices/parietal operculum. Maps are displayed whole brain family wise error‐corrected at a threshold of p < 0.05 using a one‐sample t test resulting in t‐maps, overlaid on a group‐average structural image

FIGURE 5

Cortical brain activity during processing of painful pressure stimulation for OPRM1 genotype A (n = 77) compared to OPRM1 G‐carriers (n = 28). Carriers of at least one G allele displayed increased activation in a cluster encompassing the posterior cingulate cortex (PCC) and precentral gyrus (peak at [−2 –28 48], Table 6) with an enlarged image of the finding from the region‐of‐interest PCC analysis (peak at [−2 –28 46], Table 5). Results are overlaid on a group‐average structural image (visualization threshold p < 0.001 uncorrected). The bar plot shows group means and standard errors of parameter estimates extracted from the activation cluster of the contrast OPRM1 */G > OPRM1 AA. a.u., arbitrary units; R, right

FIGURE 6

Cortical brain activity in FM subjects (n = 71) during processing of evoked pain for OPRM1 genotype A (n = 50) compared to OPRM1 G‐carriers (n = 21). FM carriers of at least one G allele displayed increased activation in a cluster encompassing the posterior cingulate cortex (PCC) and precentral gyrus (peak at [−2 –28 48], Table 6) with an enlarged image of the finding from the region‐of‐interest PCC analysis (peak at [−2 –28 46], Table 5). Results are overlaid on a group‐average structural image (visualization threshold p < 0.001 uncorrected). The bar plot shows group means and standard errors of parameter estimates extracted from the activation cluster of the contrast OPRM1 */G > OPRM1 AA. a.u., arbitrary units; R, right

FIGURE 7

Psychophysiological interaction analysis. Psychophysiological interaction analysis revealed increased functional coupling in homozygote OPRM1 AA compared to OPRM1 G‐carriers between posterior cingulate cortex/precentral gyrus and middle frontal gyrus/DLPFC (peak at [−34 2 60], Table 7) extending to the precentral gyrus. In addition, increased coupling was observed with the inferior parietal lobe (peak at [−58 –54 30]), that is, angular gyrus extending to the supramarginal gyrus. Results are overlaid on a group‐average structural image (visualization threshold p < 0.001 uncorrected). The bar plots display group means and standard errors of parameter estimates extracted from the respective activation cluster. a.u., arbitrary units; R, right