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Research Paper

Ethnic disparities in pain processing among healthy adults: μ-opioid receptor binding potential as a putative mechanism

Letzen, Janelle E.a,*; Mun, Chung Junga; Kuwabara, Hirotob; Burton, Emily F.a; Boring, Brandon L.c; Walls, Taylord; Speed, Traci J.a; Wong, Dean F.a,b,e,f,g; Campbell, Claudia M.a

Author Information
doi: 10.1097/j.pain.0000000000001759

1. Introduction

Copious evidence demonstrates systematic pain disparities between black/African American and non-Hispanic white (NHW) individuals.22 Specifically, black/African American adults tend to report greater clinical pain intensity,8,39 greater pain-related disability,26,66 and higher rates of acute pain30,60 compared with demographically similar NHW peers. Experimental findings support these data–namely black/African American participants report greater pain sensitivity across a variety of static quantitative sensory testing (QST) measures (ie, lower pain threshold and tolerance), and show less-adaptive dynamic QST responses (eg, greater temporal summation).11,15,16,18,22,41,49,57,62 However, limited research has examined factors contributing to ethnic differences in pain, which might help reduce pain management disparities.

The experience of pain arises from a complex interaction of biological, psychological, and sociocultural processes,27 suggesting several biopsychosocial determinants likely contribute to individual differences in pain outcomes.43 For instance, numerous studies have identified psychosocial factors associated with ethnic pain disparities, such as pain coping15,30,33,38,40,65 and perceived discrimination.21,29,48 Potential biological factors further underlying disparate pain responses are less understood34; however, combined experimental and clinical findings suggest that black/African American individuals exhibit overall poorer endogenous pain modulation compared with NHW peers.13,14,49

One key biological factor that might contribute to ethnic disparities in pain processing is function of neurotransmitter and hormone systems that interact during pain modulation.3,6 Among these systems, µ-opioid receptors (MORs) are a potentially important research target because they have been robustly linked with pain modulation in both endogenous and exogenous forms.17,53,68,69 µ-opioid receptors are located throughout the brain with higher concentrations in the ventral striatum (VS), amygdala, thalamus, periaqueductal gray (PAG), insula, anterior cingulate cortex (ACC), and prefrontal cortex.5,52 Previous work has shown an association between µ-opioid system function and pain sensitivity/modulation in individuals with and without chronic pain.31,32,45,55,68 However, it is unclear whether µ-opioid system function contributes to ethnic pain disparities.

This study compared non-Hispanic black (NHB) and demographically similar NHW healthy adults on µ-opioid imaging outcomes gathered from high-resolution research tomograph positron emission tomography (PET) scanning. First, we aimed to replicate previous findings showing higher pain sensitivity among NHB than NHW participants by pain responses to a tonic, noxious stimulus (ie, capsaicin cream). We hypothesized that NHB individuals would evidence greater pain sensitivity than NHW peers beyond the influence of relevant psychosocial factors. Second, we tested for ethnic differences in [11C]-Carfentanil (a MOR-selective agonist) binding potential (BPND), a PET measure that approximates the availability of MORs, during both non-noxious and tonic, noxious stimulation. Higher [11C]-Carfentanil BPND can be interpreted as a higher number of unoccupied receptors.64 We hypothesized that NHB individuals would have disparate MOR BPND from NHW counterparts during the experience of pain. Third, we conducted an exploratory analysis to examine the association between [11C]-Carfentanil BPND and pain sensitivity.

2. Methods and materials

2.1. Recruitment strategy

Non-Hispanic black and NHW individuals who were similar in age, sex, education, and income were recruited from posted flyers in the community and online (n = 697). Groups were recruited simultaneously using stratified random sampling, and best efforts were made to match groups demographically. Given that not all participants who were enrolled were included in the final sample due to data quality issues, the final groups are demographically similar but not identically matched. Figure 1 provides a diagram of study recruitment, participation, and final sample numbers. Ultimately, a total of 54 participants (NHB n = 27) were included in the present analyses. Ethnicity was determined by participants' subjective reports. Table 1 lists inclusion criteria. All procedures were approved by the Johns Hopkins University Institutional Review Board and enrolled individuals provided verbal and written consent to participate in study procedures. Participants were compensated with $50 for screening visits and $100 for each of the PET scan sessions.

Figure 1.
Figure 1.:
Consort flow diagram for study recruitment and final participant pool.
Table 1
Table 1:
List of inclusion and exclusion criteria.

2.2. Procedures

Participants with interest in the study underwent telephone screening. Eligible participants were scheduled for an initial screening visit and subsequent magnetic resonance imaging (MRI) screening visit. Detailed information on these screening visits is provided below. Participants who passed screening were scheduled for two counterbalanced PET imaging sessions. In one session, topical 10% capsaicin cream was applied to the skin on the dorsal right hand before scanning. In the other session, a control (pain-free) hand cream was applied to the same location. There was no conditioning or manipulation conducted to induce a nocebo effect from the control cream. [11C]-Carfentanil—a selective MOR agonist—was used to assess MOR BPND.

2.2.1. Screening procedures Initial in-person screening

After providing verbal and written consent, participants completed a urine test to confirm the absence of substance use (eg, marijuana, opioids, and illicit drugs) and pregnancy. Participants subsequently completed self-report measures regarding demographics, health history, and psychosocial factors. Demographic information and scores from the Perceived Ethnic Discrimination Questionnaire–Community Version (PEDQ-CV10) were analyzed in this study.

After questionnaires, participants underwent a QST protocol followed by 30 minutes of capsaicin procedures to ensure eligibility. Quantitative sensory testing methods are not discussed further because we only focused on pain ratings collected during PET imaging in this study. Participants were excluded if they reported no pain or negligible levels of capsaicin-induced pain (ie, a score less than 30) and/or very high levels of capsaicin-induced pain (ie, a score of 100) on a 0 to 100 VAS (0 being “no pain at all” and 100 being “the most intense pain imaginable”). This criterion was set to avoid floor and ceiling effects of the pain induction during PET imaging. Eligible participants were scheduled for the subsequent MRI screening and 2 PET scanning sessions. Positron emission tomography scanning conditions counterbalanced the use of a control cream or capsaicin cream and were scheduled at least 1 week apart. Magnetic resonance imaging screening

Participants completed an MRI screening form to determine the presence of ferromagnetic contraindications. Magnetic resonance imaging screening involved a structural neuroimaging through one high-resolution MPRAGE scan during which participants were instructed to remain still. Structural images were used for coregistration of functional PET images during data processing.

2.2.2. Capsaicin procedures for positron emission tomography sessions

Participants completed two single-blind, counterbalanced PET imaging sessions. During the “capsaicin” session, a 10% capsaicin cream (Professional Arts Pharmacy, Baltimore, MD) was applied to the skin on the dorsal right hand. During the “control” session, an identical cream that did not contain capsaicin was applied in the same location on the right dorsal hand. These were applied 30 minutes before the scan start time. During scanning, a thermode was placed over the capsaicin site holding a constant temperature of 40°C. Participants were asked to provide a verbal pain rating on the 0 to 100 scale every 5 minutes over the course of each 90-minute scan.

2.2.3. Positron emission tomography data collection procedures

An intravenous catheter was placed in participants' antecubital vein for radioligand injection. Participants were comfortably positioned supine in the PET scanner using a head restraint to minimize head motion during data acquisition. A high-resolution research tomograph (HRRT; CPS Innovations, Inc, Knoxville, TN ∼2.3-mm axial resolution) was used. Before the emission scan, a 6-minute transmission scan was conducted using a 137Cs point source for attenuation correction. A 90-minute dynamic PET acquisition was conducted in a 3D list mode after an intravenous bolus injection of [11C]-Carfentanil (NHB mean and SD: 18.5 ± 0.4 mCi, range = 17.2-19.1 mCi; NHW mean and SD: 18.5 ± 0.4 mCi, range = 17.4-19.0 mCi). There were no significant group differences in the dose of [11C]-Carfentanil (t52 = 0.05, P = 0.96), and the dose was below the threshold for influencing one's pain perception.68

2.3. Positron emission tomography data processing

Using the iterative ordered-subset expectation-maximization algorithm, acquired emission PET scans were reconstructed to correct for attenuation, scatter, and dead-time. Radioactivity was corrected for physical decay to the injection time and re-binned to 25 dynamic PET frames of 256 (left-to-right) × 256 (nasion-to-inion) × 207 (neck-to-cranium) voxels whose dimensions were 1.2-mm cubic, totaling to 30 frames (4 × 15 seconds, 4 × 30 seconds, 3 × 1 minute, 2 × 2-minute, 5 × 4 minutes, and 12 × 8-minute). Post hoc motion correction was applied to all scans. Specifically, an SPM12 code using mutual information theory was applied, so that all frames were coregistered to the frame that had the highest total counts (with decay uncorrected). Processed PET data were used in two types of second-level analyses.

2.3.1. Volume of interest analyses

Volume of interest (VOI) analyses in this study were limited to 15 areas including bilateral DLPFC, amygdala, insula, dorsal ACC (dACC), subgenual ACC (sgACC), thalamus, VS, and PAG. Volumes of interest were generated with the software library tools of the Oxford Center for Functional MRI of the Brain for subcortical regions and with MRICloud for cortical regions and corrected for insufficiencies using a locally developed VOI-editing tool. The PAG VOI was manually defined using a published approach.7 Volume of interest were transferred to PET space by applying parameters of MRI-to-PET coregistration obtained with SPM12's coregistration module and applied to individual PET frames to obtain time–activity curves.

The primary PET outcome was BPND of [11C]-Carfentanil across the 15 VOIs. Estimates of BPND were derived using reference tissue graphical analysis (RTGA;46). The start of asymptote (t*) was set to 20 minutes with the occipital cortex as the receptor-free reference region. The brain-to-blood clearance rate constant of the reference region was set at 0.104 min−1.23,25 BPND estimates obtained through RTGA are highly correlated with those acquired from the arterial input-based kinetic model.23

2.3.2. Whole-brain Voxel-Wise analyses

To corroborate VOI-based findings and assess BPND without predetermined regions, SPM analyses were conducted. BPND images were produced by voxel-wise RTGA and transferred to a standard space using parameters of PET-to-MRI coregistration and MRI-to-MRI spatial normalization obtained by respective modules of SPM12. A Gaussian kernel of 8-mm full-width at half maximum was applied.

2.4. Measures

2.4.1. Perceived racial discrimination

The PEDQ-CV consists of 24 items and measures lifetime perceived racism and discrimination across various ethnic groups. Items are rated on a 5-point Likert-like scale ranging from 1 (“never happened”) to 5 (“happened very often”) and divided into 4 subscale scores. Total scores are computed as the mean of these 4 subscale scores. Greater total score values indicate higher lifetime exposure to racism and discrimination. Previous studies suggest this measure has good validity and test–retest reliability.10,44 In this study, the Cronbach's alpha was 0.96, suggesting excellent internal consistency. We used the total score from this measure as a covariate reflective of perceived discrimination in analyses.

2.4.2. Pain sensitivity

Thirty minutes after the control or capsaicin cream was applied on participants' skin, PET scanning began. Participants were instructed to provide 0 to 100 numerical pain rating every 5 minutes during the 90-minute PET procedure. In total, participants provided 19 individual pain intensity ratings during each condition. We averaged pain ratings for each participant under each condition as an overall measure of pain sensitivity.

2.5. Data processing

We examined data normality for all variables. Upon inspection, most PET BPND data were determined to have significant skew. We applied log-transformations to all skewed BPND values, which substantially improved normality. Outlier analysis identified 1 to 2 outliers per VOI following log transformation. We conducted sensitivity analyses removing these outliers to determine their influence on results for each VOI. Removal of outliers changed the results of two statistical tests to marginal significance. We highlight these 2 tests the Results section for cautious interpretation.

2.6. Data analytic plan

2.6.1. Demographic characteristics

To avoid sociodemographic confounds, groups were compared on the following demographic characteristics: reported sex, age, education history, marital status, annual household income, and tobacco use. Reported sex (male or female), education history (high school as highest education level or above high school as highest education level), marital status (single or other), annual household income (above $50,000 or below $50,000), and tobacco use (no current use or current use) were compared using chi-squared tests. Participant age was compared using independent-samples t-tests.

2.6.2. Aim 1: replicate ethnic differences in pain sensitivity

A repeated-measures analysis of covariance (ethnicity × condition) was conducted in SPSS v25 to determine ethnic differences in pain sensitivity using pain ratings collected during both PET imaging sessions as the outcome measure. Previous work suggests that perceived racial discrimination and individuals' sex are factors that influence pain sensitivity.4,21,24,34 To more conservatively test for ethnic differences in pain sensitivity, we included perceived racial discrimination and participant's reported sex as covariates.

2.6.3. Aim 2: examine ethnic differences in [11C]-Carfentanil BPND [11C]-Carfentanil BPND among a priori volume of interest

BPND values from 15 VOIs were extracted for each individual and entered into SPSS for comparisons. Our primary outcome for this aim was ethnic differences in MOR BPND across the 15 VOIs, which was tested using Bonferroni-corrected repeated-measures analysis of variance. Both p- and the Bonferroni-specific Q-values are reported in the “Ethnic Differences in [11C]-Carfentanil BPND” section below. Sensitivity analysis

To examine ethnic differences in BPND beyond some pertinent biopsychosocial factors that can influence pain sensitivity, we conducted sensitivity analyses using repeated-measures analysis of covariance controlling for participants' reported sex and perceived discrimination, given that both of these factors are associated with pain disparities.4,29,48 Results for these sensitivity analyses were also Bonferroni-corrected to account for multiple comparisons. Whole-brain [11C]-Carfentanil BPND

As supplemental analyses to the VOI approach, we conducted a voxel-wise repeated-measures analysis of variance across the whole brain using a height-level threshold of P < 0.001 uncorrected and a volume threshold of 0.4 mL (k > 50) with SPM12 with planned comparisons to examine main effects of ethnicity and condition, as well as their potential interaction effect. These analyses were not performed as the primary approach for hypothesis testing and were added solely to support VOI analyses.

2.6.4. Aim 3: explore the association between BPND and pain sensitivity

To investigate the associations among [11C]-Carfentanil BPND and pain sensitivity, we first conducted bivariate correlations using BPND values from VOIs showing significant group differences after Bonferroni correction with pain sensitivity ratings. We then examined the associations between BPND values from significant VOIs and pain sensitivity using partial correlations. PEDQ-CV total scores and participants' reported sex were entered as covariates to control for the effects of perceived racial discrimination and sex.

2.6.5. Aim 4: explore the moderating effect of ethnicity on the association between BPND and pain sensitivity

Although we had limited power to detect moderation effects, we aimed to determine whether there were trends for the moderating effect of ethnicity on associations among [11C]-Carfentanil BPND and pain sensitivity. We conducted linear regressions using capsaicin-related pain ratings as the dependent variable. Predictors included ethnicity, VOI BPND values, and their product term.

3. Results

3.1. Participant characteristics

Table 2 details additional descriptive information for NHB and NHW groups. Consistent with our recruitment plan, there were no significant group differences in reported sex, age, education history, marital status, annual household income, or tobacco use (ps >0.38). Although groups did not substantially differ across any of these characteristics, we controlled for sex in PET sensitivity analyses to further reduce potential confounding effects on MOR BPND.70

Table 2
Table 2:
Comparison of demographic characteristics between non-Hispanic black and non-Hispanic white participants.

3.2. Ethnic differences in perceived racial discrimination and pain sensitivity

Non-Hispanic black individuals reported significantly higher perception of discrimination [PEDQ-CV total score: NHB = 2.08 (0.89), NHW = 1.19 (0.2), t52 = 4.9, P < 0.001, d = 1.38] compared with NHW peers. After controlling for PEDQ-CV total scores (P = 0.33) and participants' reported sex (P = 0.75), there was a significant ethnicity × condition interaction effect of pain sensitivity [F1,51 = 6.6, P = 0.013, ηp2 = 0.11]. Non-Hispanic black participants reported greater pain ratings compared with NHW participants during the capsaicin condition only [control mean (SE): NHB = 1.7 (1.4), NHW = 2.9 (1.5); capsaicin mean (SE): NHB = 39.8 (4.8), NHW = 22.23 (4.9); Fig. 2].

Figure 2.
Figure 2.:
Participants underwent 2 counterbalanced PET imaging sessions that used either a capsaicin or control cream. There was a significant ethnicity × condition interaction effect on pain ratings over a 90-minute period, with NHB participants showing a significantly greater increase in pain sensitivity under the than NHW peers. Bars represent mean pain ratings, lines represent individual differences in pain ratings, and error bars represent SD values. NHB, non-Hispanic black; NHW, non-Hispanic white; PET, positron emission tomography.

3.3. Ethnic differences in [11C]-Carfentanil BPND

3.3.1. [11C]-Carfentanil BPND among a priori volume of interest

Seven of the 15 VOIs showed significant main effects of ethnicity in [11C]-Carfentanil BPND after Bonferroni correction. These regions included bilateral DLPFC (left: F1,52 = 17.3, P < 0.001, Q < 0.001, ηp2 = 0.25; right: F1,52 = 14.17, P < 0.001, Q = 0.02, ηp2 = 0.21), bilateral VS (left: F1,52 = 16.38, P < 0.001, Q < 0.001, ηp2 = 0.24; right: F1,52 = 21.76, P < 0.001, Q < 0.001, ηp2 = 0.3), bilateral sgACC (left: F1,52 = 10.48, P = 0.002, Q = 0.03, ηp2 = 0.17; right: F1,52 = 12.91, P = 0.001, Q = 0.015, ηp2 = 0.2), and bilateral insula (left: F1,52 = 9.5, P = 0.003, Q = 0.045, ηp2 = 0.16; right: F1,52 = 11.0, P = 0.002, Q = 0.03, ηp2 = 0.17). However, there were no significant main effects of condition or ethnicity × condition interaction effects across models. Figure 3 demonstrates overall group averages in BPND based on condition, and Table 3 contains estimated marginal means for each VOI. BPND in the additional 8 VOIs tested did not show significant ethnic group differences after Bonferroni correction (Qs > 0.08).

Figure 3.
Figure 3.:
Fifteen a priori volumes of interest (VOIs) were selected to examine ethnic differences in binding potential (BPND) of a µ-opioid–selective agonist, [11C]-Carfentanil. Repeated-measures ANOVAs demonstrated significantly higher BPND in bilateral dorsolateral prefrontal cortices (DLPFC), right insula (INS), bilateral subgenual anterior cingulate cortex (sgACC), and bilateral ventral stratum (VS) among NHB compared with NHW participants; however, this main effect was not moderated by condition. After controlling for potential confounding factors (ie, perceived racial discrimination and participants' reported sex), all effects remained, and left insula also emerged as a region showing significantly greater BPND among NHB individuals. Error bars represent SD values. Asterisks represent significant main effects of ethnicity (Bonferroni-corrected P < 0.05), and plus signs represent significant main effects of ethnicity in sensitivity analyses (Bonferroni-corrected P < 0.05). AMY, amygdala; dACC, dorsal anterior cingulate cortex; L, left; NHB, non-Hispanic black; NHW, non-Hispanic white; PAG, periaqueductal grey; R, right; THAL, thalamus.
Table 3
Table 3:
Estimated marginal mean values for raw, untransformed binding potential values within 15 a priori volumes of interest (VOIs) based on condition and ethnic group.

3.3.2. Sensitivity analyses

Across VOIs, no covariates were significantly associated with PET data (P > 0.09). After controlling for these factors and multiple comparisons, significant main effects of ethnicity remained in the left DLPFC (F1,50 = 14.6, P < 0.001, Q < 0.001, ηp2 = 0.23), right DLPFC (F1,50 = 12.2, P = 0.001, Q = 0.02, ηp2 = 0.2), left VS (F1,49 = 13.0, P = 0.001, Q = 0.02, ηp2 = 0.21), right VS (F1,50 = 17.39, P < 0.001, Q < 0.001, ηp2 = 0.26), left insula (F1,50 = 10.5, P = 0.002, Q = 0.03, ηp2 = 0.17), right insula (F1,50 = 11.6, P = 0.001, Q = 0.015, ηp2 = 0.19), and right sgACC (F1,50 = 11.98, P = 0.001, Q = 0.03, ηp2 = 0.19). No other significant effects emerged (Qs > 0.06). Notably, sensitivity analyses removing an outlier from the left insula comparison resulted in marginal significance after Bonferroni correction (F1,51 = 8.38, P = 0.006, Q = 0.09, ηp2 = 0.14), indicating a potentially influential value driving ethnic differences in this VOI. Ethnic differences in left insula BPND should be interpreted cautiously.

3.3.3. Whole-brain [11C]-Carfentanil BPND

There was a significant main effect of ethnicity evidenced on voxel-wise analysis across the whole brain. Using a conservative threshold, 6 clusters emerged, coinciding with bilateral DLPFC, left frontal operculum, right supramarginal gyrus, right rostral frontal lobe, and right superior frontal lobe (Fig. 4). Table 4 provides cluster information. Consistent with VOI analyses, there was not an ethnicity x condition interaction effect even with generous criteria (P < 0.001, uncorrected).

Figure 4.
Figure 4.:
Whole-brain, voxel-based analyses were conducted on PET data to support volume of interest (VOI) analyses. Consistent with VOI analyses, there was a significant main effect of ethnicity but not an ethnicity × condition interaction effect. Six clusters were identified (shown in yellow). Blue crosshairs center on each respective cluster. DLPFC, dorsolateral prefrontal cortex; PET, positron emission tomography.
Table 4
Table 4:
Cluster information on 6 regions identified as having a main effect of ethnicity on μ-opioid binding potential from whole-brain voxel-wise analyses.

3.4. Associations between BPND and pain sensitivity

Exploratory analyses revealed significant correlations between pain sensitivity with MOR BPND in bilateral DLPFC (left: r = 0.36, P = 0.008; right: r = 0.35, P = 0.009), bilateral VS (left: r = 0.46, P = 0.001; right: r = 0.35, P = 0.010), bilateral sgACC (left: r = 0.34, P = 0.01; right: r = 0.36, P = 0.008), and bilateral insula (left: r = 0.36, P = 0.009, right: r = 0.36, P = 0.008). Across the participant sample, individuals with higher BPND had higher reported pain ratings during capsaicin administration. Figure 5 demonstrates these correlations.

Figure 5.
Figure 5.:
Pain sensitivity was measured through pain intensity ratings to topical capsaicin averaged over 90 minutes. Binding potential (BPND) in bilateral ventral striatum (VS), dorsolateral prefrontal cortex (DLPFC), left subgenual anterior cingulate cortex (sgACC), and right insula were significantly associated with pain intensity ratings. Additional exploratory analyses showed that ethnicity had marginal moderating effects on this association in the left sgACC and bilateral VS, so that this association was stronger among non-Hispanic black compared with non-Hispanic white individuals. These results suggest that individuals with greater [11C]-Carfentanil BPND in these regions show greater pain sensitivity.

3.4.1. Sensitivity analyses

Significant correlations remained after controlling for perceived discrimination and participants' reported sex (left DLPFC: r = 0.35, P = 0.01; right DLPFC: r = 0.35, P = 0.01; left VS r = 0.43, P = 0.001; right VS r = 0.33, P = 0.02; left sgACC r = 0.32, P = 0.02; right sgACC r = 0.35, P = 0.012; left insula r = 0.36, P = 0.009; right insula r = 0.36, P = 0.008). Notably, however, removal of one outlier from the right sgACC VOI resulted in marginal significance, indicating a potentially influential value driving the association between right sgACC BPND values and capsaicin-related pain ratings. This association should be interpreted cautiously.

3.5. Ethnicity as a moderator for the association between BPND and pain sensitivity

We examined trends for ethnicity as a moderator for the association between BPND and capsaicin-related pain sensitivity among VOIs showing significant ethnic differences. Three VOIs showed trends for moderation effects. Specifically, although NHB individuals had positive associations between left sgACC (R2 = 0.17, β = −0.71, t = −1.76, P = 0.08), left VS (R2 = 0.23, β = −0.18, t = −1.45, P = 0.15), and right VS (R2 = 0.18, β = −0.26, t = −1.9, P = 0.06) BPND and capsaicin-related pain sensitivity, NHW individuals did not show this effect.

4. Discussion

Non-Hispanic black individuals experience greater pain burden than NHW peers,15,18,30,33 and MOR function might be a potential mechanism of this disparity based on its role in endogenous and exogenous antinociception.58 The present work supports previous findings of heightened pain sensitivity among healthy NHB compared with NHW participants and extends our knowledge showing ethnic differences in µ-opioid system function.

First, using ethnic groups that were similar in age, sex, income, and education, we observed significantly higher sensitivity to capsaicin-induced pain among NHB participants, which is consistent with the extant literature.56 Even after controlling for psychosocial factors associated with pain sensitivity,4,12,29 this effect remained, suggesting these ethnic pain differences were not fully attributable to perceived discrimination or participants' sex.

Next, we examined ethnic differences in BPND for the MOR-selective radioligand, [11C]-Carfentanil, among NHB compared with NHW participants during tonic noxious and non-noxious stimuli in bilateral DLPFC, VS, amygdala, insula, sgACC, dACC, thalamus, and PAG. We chose these regions based on previous radioligand studies showing a somewhat greater density of MORs in limbic and sensorimotor regions.52 In a little over half of these a priori VOIs, NHB individuals had significantly greater BPND values compared with NHW participants accounting for both conditions, with a consistent pattern of relatively greater MOR BPND for NHB individuals in all VOIs. Significant differences occurred in bilateral DLPFC, VS, sgACC, and right insula volumes. After controlling for perceived discrimination and patients' reported sex, these effects remained, suggesting that ethnic differences in MOR BPND were not confounded by sex or perceived discrimination.

We expected to find an ethnicity × condition interaction effect on BPND. However, our results showed that BPND was not moderated by condition. Previous work has shown substantial individual variability in BPND values during the experience of pain in healthy individuals,19 especially in the context of participants' reported sex.71 Indeed, some participants in our sample had increased BPND comparing the capsaicin with control condition, whereas others showed decreased BPND values. It is likely that these individual differences contributed to the muddling of mean-based condition effects. However, ethnic groups differed in overall BPND values, suggesting overall greater MOR BPND in NHB individuals regardless of how this system is modulated by pain. To test this speculation in future work, researchers interested in examining ethnic differences in µ-opioid function and pain are encouraged to (1) use an array of stimulus intensities to determine whether magnitude of pain or stimulus intensity is linked with magnitude of change in BPND, (2) use a larger sample size to examine a three-way interaction of ethnicity x sex x condition, and (3) examine whether overall ethnic differences in BPND are associated with other psychosocial factors that contribute to ethnic differences in pain (eg, pain coping).

Given that some radioligands (such as [11C]-Carfentanil) compete for receptor binding with endogenously released ligands, BPND is considered a measure of unoccupied receptor density.64 This study found greater MOR BPND within NHB under a control stimulus and during a challenge to the µ-opioid system (ie, pain secondary to capsaicin); however, the latter condition did not exert a unique influence on MOR BPND comparing ethnic groups. Because NHB participants reported greater pain sensitivity and demonstrated significantly greater MOR BPND values compared with NHW individuals, it is possible that generally greater unoccupied MOR density contributes to heightened pain sensitivity. However, a limitation of PET imaging is that the data cannot differentiate whether this difference occurs because NHB individuals show a greater density of unoccupied MORs due to differences in regional receptor concentration or in binding of endogenously released µ-opioids.

We tested whether generally greater unoccupied MOR density contributes to heightened pain sensitivity using exploratory analyses. We found significant, positive associations between MOR BPND during the capsaicin condition and participants' pain reports. One potential interpretation of this result is that a greater density of unoccupied MORs is related to higher pain sensitivity. Previous work suggests that levels of endogenous opioid binding might predispose some individuals to higher pain sensitivity or chronic pain.9 Our results, then, implicate DLPFC, VS, sgACC, and insula MOR binding as one potential contributory factor for ethnic differences in pain sensitivity. These associations remained after controlling for other psychosocial factors, cautiously suggesting that the observed ethnic differences in DLPFC, VS, and insula MOR BPND might stem from biological factors, rather than or in addition to the compounded impact of psychosocial experiences. Given that perceptions of having low social status and being socially rejected are associated with changes in activity within these regions,36,37,47 future research is needed to fully determine whether psychosocial factors shown to influence pain sensitivity in NHB adults lead to changes in DLPFC, VS, sgACC, and insula function over time.

We then explored trends in moderating effects of ethnicity on this association. Results demonstrated trends for stronger, positive associations between BPND values in the left sgACC and bilateral VS with pain sensitivity comparing NHB with NHW participants. These results suggest that left sgACC and bilateral VS might be particularly key regions contributing to ethnic differences in pain sensitivity. However, future studies with larger sizes are needed to determine the stability of this moderating effect.

Our data align with previous work that demonstrated a significant association between pain sensitivity and MOR BPND in the VS, insula, and sgACC.20,28,31,32,61,69 Somewhat contrary to our findings, however, previous research in chronic pain populations has shown lower VS, insula, and sgACC MOR BPND among chronic pain patients compared with healthy controls or a negative association between MOR BPND and clinical pain severity. Some authors have speculated that this finding represents aberrant occupation of MORs by endogenous ligands in chronic pain patients as individuals attempt to downregulate pain.32 Given that our study used pain-free healthy controls only, we would not necessarily expect this same relationship between MOR BPND and pain sensitivity. Future work is needed to determine how ethnicity influences MOR function among individuals with chronic pain.

Ethnic differences also emerged in DLPFC MOR BPND. Previous work showed significant associations between DLPFC MOR BPND and pain sensitivity in fibromyalgia patients.61 Evidence from previous research also suggests DLPFC MOR function is typically related to the magnitude of reported placebo analgesia68 and expectations for pain relief.54 Other neuroimaging modalities have consistently shown DLPFC activity in the context of top-down descending pain control, such as placebo analgesia.42,50,67 It is possible, then, that MOR BPND differences in DLPFC VOIs might contribute to ethnic differences through top-down pain control. Future work is encouraged to examine potential contributions of DLPFC MOR BPND to ethnic differences in endogenous pain modulation.

Taken together, the present findings have implications to address ubiquitously documented ethnic disparities in pain management. Examples of such disparities include poorer assessment of pain, longer emergency department waiting times, and more conservative prescriptions for pain medications (eg, fewer days' supply, lower dose, and lower likelihood of receiving any analgesic).1,35,51,59,63 One potential reason for this disparity is incorrect beliefs of race-based biological differences in pain processing among health care providers and laypeople (eg, NHB people have lower pain sensitivity due to thicker skin).35 These incorrect beliefs might contribute to providers' underestimation of pain sensitivity in NHB patients,1 leading to adverse outcomes, such as oligoanalgesia.59 Provider education about potential biological factors contributing to higher pain sensitivity among NHB individuals, such as the potential of lower endogenous opioid binding among NHB adults—which might suggest enhanced pain sensitivity—might positively influence clinical decision-making and narrow the gap in pain management for underserved populations.

Before this work can be fully translated in clinical settings, however, several limitations should be addressed in future research. As previously noted, the data are cross-sectional and cannot be used to determine whether these ethnic differences in MOR BPND are the result of biological differences or aggregative effects of sociocultural factors on neural function over time.2 Second, our sample comprised pain-free adults. Future studies should replicate procedures to compare the relationship between ethnic differences in MOR BPND related to pain sensitivity and opioid use among chronic pain patients. Third, this study included individuals from two ethnic backgrounds; future work is needed to understand how MOR BPND differs and relates to pain sensitivity across other ethnic minority populations, such as individuals who identify as Hispanic, Asian, and multiracial. Finally, future work should importantly determine whether observed ethnic differences in MOR BPND impact the pharmacodynamic effects of analgesics in NHB individuals.

5. Conclusion

The present findings are suggestive of a greater density of unoccupied MORs within the DLPFC, VS, sgACC, and insula among NHB adults compared with NHW peers beyond biopsychosocial factors. Because data demonstrated a significant association between MOR binding within these regions and pain sensitivity when controlling for psychosocial predictors of pain, results have implications for endogenous opioid binding as a biological mechanism of ethnic pain disparities within a biopsychosocial framework. If replicated, findings have the potential to reduce disparities in pain management.

Conflict of interest statement

The authors have no conflicts of interest to declare.

Supplemental video content

Video content associated with this article can be found online at


The present work was funded by grants from the National Institutes of Health to Drs C.M. Campbell (R01MD009063, Blaustein Pain Research Foundation Grant), Janelle Letzen (F32HL143941), and C.J. Mun (T32NS070201 as a postdoctoral fellow and F32DA049393), as well as Shared Instrument Grants to Dr D.F. Wong (S10RR023623 & S10RR017219).


[1]. Anderson KO, Green CR, Payne R. Racial and ethnic disparities in pain: causes and consequences of unequal care. J Pain 2009;10:1187–204.
[2]. Anderson SR, Losin EAR. A sociocultural neuroscience approach to pain. Cult Brain 2017;5:14–35.
[3]. Bannister K, Dickenson AH. What do monoamines do in pain modulation? Curr Opin Support Palliat Care 2016;10:143–8.
[4]. Bartley EJ, Fillingim RB. Sex differences in pain: a brief review of clinical and experimental findings. Br J Anaesth 2013;111:52–8.
[5]. Baumgärtner U, Buchholz HG, Bellosevich A, Magerl W, Siessmeier T, Rolke R, Höhnemann S, Piel M, Rösch F, Wester HJ, Henriksen G, Stoeter P, Bartenstein P, Treede RD, Schreckenberger M. High opiate receptor binding potential in the human lateral pain system. Neuroimage 2006;30:692–9.
[6]. Benarroch EE. Endogenous opioid systems: current concepts and clinical correlations. Neurology 2012;79:807–14.
[7]. Benarroch EE. Periaqueductal gray: an interface for behavioral control. Neurology 2012;78:210–7.
[8]. Boissoneault J, Bunch JR, Robinson M. The roles of ethnicity, sex, and parental pain modeling in rating of experienced and imagined pain events. J Behav Med 2015;38:809–16.
[9]. Borsook D. Opioidergic tone and pain susceptibility: interactions between reward systems and opioid receptors. PAIN 2017;158:185–6.
[10]. Brondolo E, Brady N, Thompson S, Tobin JN, Cassells A, Sweeney M, McFarlane D, Contrada RJ. Perceived racism and negative affect: analyses of trait and state measures of affect in a community sample. J Soc Clin Psychol 2008;27:150–73.
[11]. Bulls HW, Goodin BR, McNew M, Gossett EW, Bradley LA. Minority aging and endogenous pain facilitatory processes. Pain Med 2016;17:1037–48.
[12]. Burgess DJ, Grill J, Noorbaloochi S, Griffin JM, Ricards J, van Ryn M, Partin MR. The effect of perceived racial discrimination on bodily pain among older African American men. Pain Med 2009;10:1341–52.
[13]. Burton EF, Suen SY, Walker JL, Bruehl S, Peterlin BL, Tompkins DA, Buenaver LF, Edwards RR, Campbell CM. Ethnic differences in the effects of naloxone on sustained evoked pain: a preliminary study. Methods 2017;19:22.
[14]. Campbell CM, Edwards RR. Ethnic differences in pain and pain management. Pain Manag 2012;2:219–30.
[15]. Campbell CM, Edwards RR, Fillingim RB. Ethnic differences in responses to multiple experimental pain stimuli. PAIN 2005;113:20–6.
[16]. Campbell CM, France CR, Robinson ME, Logan HL, Geffken GR, Fillingim RB. Ethnic differences in diffuse noxious inhibitory controls. J Pain 2008;9:759–66.
[17]. Corder G, Castro DC, Bruchas MR, Scherrer G. Endogenous and exogenous opioids in pain. Annu Rev Neurosci 2018;41:453–73.
[18]. Cruz-Almeida Y, Sibille KT, Goodin BR, Petrov ME, Bartley EJ, Riley JL III, King CD, Glover TL, Sotolongo A, Herbert MS, Schmidt JK, Fessler BJ, Staud R, Redden D, Bradley LA, Fillingim RB. Racial and ethnic differences in older adults with knee osteoarthritis. Arthritis Rheumatol 2014;66:1800–10.
[19]. DaSilva AF, Zubieta J-K, DosSantos MF. Positron emission tomography imaging of endogenous mu-opioid mechanisms during pain and migraine. Pain Rep 2019;4:e769.
[20]. DosSantos MF, Martikainen IK, Nascimento TD, Love TM, Deboer MD, Maslowski EC, Monteiro AA, Vincent MB, Zubieta JK, DaSilva AF. Reduced basal ganglia mu-opioid receptor availability in trigeminal neuropathic pain: a pilot study. Mol Pain 2012;8:74.
[21]. Edwards RR. The association of perceived discrimination with low back pain. J Behav Med 2008;31:379–89.
[22]. Edwards RR, Doleys DM, Fillingim RB, Lowery D. Ethnic differences in pain tolerance: clinical implications in a chronic pain population. Psychosom Med 2001;63:316–23.
[23]. Endres CJ, Bencherif B, Hilton J, Madar I, Frost JJ. Quantification of brain μ-opioid receptors with [11C] carfentanil: reference-tissue methods. Nucl Med Biol 2003;30:177–86.
[24]. Forsythe LP, Thorn B, Day M, Shelby G. Race and sex differences in primary appraisals, catastrophizing, and experimental pain outcomes. J Pain 2011;12:563–72.
[25]. Frost JJ, Mayberg HS, Sadzot B, Dannals RF, Lever JR, Ravert HT, Wilson AA, Wagner HN Jr, Links JM. Comparison of [11C] diprenorphine and [11C] carfentanil binding to opiate receptors in humans by positron emission tomography. J Cereb Blood Flow Metab 1990;10:484–92.
[26]. Gagnon CM, Matsuura JT, Smith CC, Stanos SP. Ethnicity and interdisciplinary pain treatment. Pain Pract 2014;14:532–40.
[27]. Gatchel RJ, Peng YB, Peters ML, Fuchs PN, Turk DC. The biopsychosocial approach to chronic pain: scientific advances and future directions. Psychol Bull 2007;133:581–624.
[28]. Gear RW, Levine JD. Nucleus accumbens facilitates nociception. Exp Neurol 2011;229:502–6.
[29]. Goodin BR, Pham QT, Glover TL, Sotolongo A, King CD, Sibille KT, Herbert MS, Cruz-Almeida Y, Sanden SH, Staud R, Redden DT, Bradley LA, Fillingim RB. Perceived racial discrimination, but not mistrust of medical researchers, predicts the heat pain tolerance of African Americans with symptomatic knee osteoarthritis. Health Psychol 2013;32:1117–26.
[30]. Green CR, Anderson KO, Baker TA, Campbell LC, Decker S, Fillingim RB, Kalauokalani DA, Kaloukalani DA, Lasch KE, Myers C, Tait RC, Todd KH, Vallerand AH. The unequal burden of pain: confronting racial and ethnic disparities in pain. Pain Med 2003;4:277–94.
[31]. Hagelberg N, Aalto S, Tuominen L, Pesonen U, Någren K, Hietala J, Scheinin H, Pertovaara A, Martikainen IK. Striatal μ-opioid receptor availability predicts cold pressor pain threshold in healthy human subjects. Neurosci Lett 2012;521:11–14.
[32]. Harris RE, Clauw DJ, Scott DJ, McLean SA, Gracely RH, Zubieta JK. Decreased central mu-opioid receptor availability in fibromyalgia. J Neurosci 2007;27:10000–6.
[33]. Hastie BA, Riley JL, Fillingim RB. Ethnic differences and responses to pain in healthy young adults. Pain Med 2005;6:61–71.
[34]. Herbert MS, Goodin BR, Bulls HW, Sotolongo A, Petrov ME, Edberg JC, Bradley LA, Fillingim RB. Ethnicity, cortisol, and experimental pain responses among persons with symptomatic knee osteoarthritis. Clin J Pain 2017;33:820–6.
[35]. Hoffman KM, Trawalter S, Axt JR, Oliver MN. Racial bias in pain assessment and treatment recommendations, and false beliefs about biological differences between blacks and whites. Proc Natl Acad Sci USA 2016;113:4296–301.
[36]. Hsu DT, Sanford BJ, Meyers KK, Love TM, Hazlett KE, Walker SJ, Mickey BJ, Koeppe RA, Langenecker SA, Zubieta JK. It still hurts: altered endogenous opioid activity in the brain during social rejection and acceptance in major depressive disorder. Mol Psychiatry 2015;20:193–200.
[37]. Hsu DT, Sanford BJ, Meyers KK, Love TM, Hazlett KE, Wang H, Ni L, Walker SJ, Mickey BJ, Korycinski ST, Koeppe RA, Crocker JK, Langenecker SA, Zubieta JK. Response of the μ-opioid system to social rejection and acceptance. Mol Psychiatry 2013;18:1211.
[38]. Jordan MS, Lumley MA, Leisen JC. The relationships of cognitive coping and pain control beliefs to pain and adjustment among African-American and Caucasian women with rheumatoid arthritis. Arthritis Care Res 1998;11:80–8.
[39]. Keck ME, Welt T, Müller MB, Erhardt A, Ohl F, Toschi N, Holsboer F, Sillaber I. Repetitive transcranial magnetic stimulation increases the release of dopamine in the mesolimbic and mesostriatal system. Neuropharmacology 2002;43:101–9.
[40]. Kim HJ, Greenspan JD, Ohrbach R, Fillingim RB, Maixner W, Renn CL, Johantgen M, Zhu S, Dorsey SG. Racial/ethnic differences in experimental pain sensitivity and associated factors - cardiovascular responsiveness and psychological status. PLoS One 2019;14:e0215534.
[41]. Kim HJ, Yang GS, Greenspan JD, Downton KD, Griffith KA, Renn CL, Johantgen M, Dorsey SG. Racial and ethnic differences in experimental pain sensitivity: systematic review and meta-analysis. PAIN 2017;158:194–211.
[42]. Krummenacher P, Candia V, Folkers G, Schedlowski M, Schönbächler G. Prefrontal cortex modulates placebo analgesia. PAIN 2010;148:368–74.
[43]. Kvachadze I, Tsagareli MG, Dumbadze Z. An overview of ethnic and gender differences in pain sensation. Georgian Med News 2015:102–8.
[44]. Kwok J, Atencio J, Ullah J, Crupi R, Chen D, Roth AR, Chaplin W, Brondolo E. The perceived ethnic discrimination questionnaire-community version: validation in a multiethnic Asian sample. Cultur Divers Ethnic Minor Psychol 2011;17:271–82.
[45]. Lipman JJ, Miller BE, Mays KS, Miller MN, North WC, Byrne WL. Peak B endorphin concentration in cerebrospinal fluid: reduced in chronic pain patients and increased during the placebo response. Psychopharmacology 1990;102:112–16.
[46]. Logan J, Fowler JS, Volkow ND, Wang GJ, Ding YS, Alexoff DL. Distribution volume ratios without blood sampling from graphical analysis of PET data. J Cereb Blood Flow Metab 1996;16:834–40.
[47]. Ly M, Haynes MR, Barter JW, Weinberger DR, Zink CF. Subjective socioeconomic status predicts human ventral striatal responses to social status information. Curr Biol 2011;21:794–7.
[48]. Mathur VA, Kiley KB, Haywood C, Bediako SM, Lanzkron S, Carroll CP, Buenaver LF, Pejsa M, Edwards RR, Haythornthwaite JA, Campbell CM. Multiple levels of suffering: discrimination in health-care settings is associated with enhanced laboratory pain sensitivity in sickle cell disease. Clin J Pain 2016;32:1076–85.
[49]. Mechlin MB, Maixner W, Light KC, Fisher JM, Girdler SS. African Americans show alterations in endogenous pain regulatory mechanisms and reduced pain tolerance to experimental pain procedures. Psychosom Med 2005;67:948–56.
[50]. van der Meulen M, Kamping S, Anton F. The role of cognitive reappraisal in placebo analgesia: an fMRI study. Soc Cogn Affect Neurosci 2017;12:1128–37.
[51]. Mossey JM. Defining racial and ethnic disparities in pain management. Clin Orthop Relat Res 2011;469:1859–70.
[52]. Oroszi G, Goldman D. Alcoholism: genes and mechanisms. Pharmacogenomics 2004;5:1037–48.
[53]. Peciña M, Love T, Stohler CS, Goldman D, Zubieta JK. Effects of the mu opioid receptor polymorphism (OPRM1 A118G) on pain regulation, placebo effects and associated personality trait measures. Neuropsychopharmacology 2014;40:957.
[54]. Peciña M, Zubieta JK. Molecular mechanisms of placebo responses in humans. Mol Psychiatry 2014;20:416.
[55]. Puig MM, Laorden ML, Miralles FS, Olaso MJ. Endorphin levels in cerebrospinal fluid of patients with postoperative and chronic pain. Anesthesiology 1982;57:1–4.
[56]. Rahim-Williams B, Riley JL III, Williams AKK, Fillingim RB. A quantitative review of ethnic group differences in experimental pain response: do biology, psychology, and culture matter? Pain Med 2012;13:522–40.
[57]. Rahim-Williams FB, Riley JL III, Herrera D, Campbell CM, Hastie BA, Fillingim RB. Ethnic identity predicts experimental pain sensitivity in African Americans and Hispanics. PAIN 2007;129:177–84.
[58]. Ravert HT, Bencherif B, Madar I, Frost JJ. PET imaging of opioid receptors in pain: progress and new directions. Curr Pharm Des 2004;10:759–68.
[59]. Ringwalt C, Roberts AW, Gugelmann H, Skinner AC. Racial disparities across provider specialties in opioid prescriptions dispensed to medicaid beneficiaries with chronic non-cancer pain. Pain Med 2015;16:633–40.
[60]. Riskowski JL. Associations of socioeconomic position and pain prevalence in the United States: findings from the national health and nutrition examination survey. Pain Med 2014;15:1508–21.
[61]. Schrepf A, Harper DE, Harte SE, Wang H, Ichesco E, Hampson JP, Zubieta JK, Clauw DJ, Harris RE. Endogenous opioidergic dysregulation of pain in fibromyalgia: a PET and fMRI study. PAIN 2016;157:2217–25.
[62]. Sheffield D, Biles PL, Orom H, Maixner W, Sheps DS. Race and sex differences in cutaneous pain perception. Psychosom Med 2000;62:517–23.
[63]. Singhal A, Tien YY, Hsia RY. Racial-ethnic disparities in opioid prescriptions at emergency department visits for conditions commonly associated with prescription drug abuse. PLoS One 2016;11:e0159224.
[64]. Sprenger T, Berthele A, Platzer S, Boecker H, Tölle TR. What to learn from in vivo opioidergic brain imaging? Eur J Pain 2005;9:117–21.
[65]. Tan G, Jensen MP, Thornby J, Anderson KO. Ethnicity, control appraisal, coping, and adjustment to chronic pain among black and white Americans. Pain Med 2005;6:18–28.
[66]. Trost Z, Sturgeon J, Guck A, Ziadni M, Nowlin L, Goodin B, Scott W. Examining injustice appraisals in a racially diverse sample of individuals with chronic low back pain. J Pain 2018.
[67]. Wager TD, Rilling JK, Smith EE, Sokolik A, Casey KL, Davidson RJ, Kosslyn SM, Rose RM, Cohen JD. Placebo-induced changes in FMRI in the anticipation and experience of pain. Science 2004;303:1162–7.
[68]. Wager TD, Scott DJ, Zubieta J-K. Placebo effects on human μ-opioid activity during pain. Proc Natl Acad Sci 2007;104:11056–61.
[69]. Zubieta JK, Bueller JA, Jackson LR, Scott DJ, Xu Y, Koeppe RA, Nichols TE, Stohler CS. Placebo effects mediated by endogenous opioid activity on mu-opioid receptors. J Neurosci 2005;25:7754–62.
[70]. Zubieta JK, Dannals RF, Frost JJ. Gender and age influences on human brain mu-opioid receptor binding measured by PET. Am J Psychiatry 1999;156:842–8.
[71]. Zubieta JK, Smith YR, Bueller JA, Xu Y, Kilbourn MR, Jewett DM, Meyer CR, Koeppe RA, Stohler CS. mu-opioid receptor-mediated antinociceptive responses differ in men and women. J Neurosci 2002;22:5100–7.

Ethnic differences; Endogenous pain modulation; Mu-opioid receptors; [11C]-Carfentanil; PET; Neuroreceptor imaging

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