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Cortisol affects pain sensitivity and pain-related emotional learning in experimental visceral but not somatic pain

a randomized controlled study in healthy men and women

Benson, Svena,*; Siebert, Carstena; Koenen, Laura R.a; Engler, Haralda; Kleine-Borgmann, Julianb; Bingel, Ulrikeb; Icenhour, Adrianea; Elsenbruch, Sigrida

doi: 10.1097/j.pain.0000000000001579
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Despite growing interest in the role of stress mediators in pain chronicity, the effects of the stress hormone cortisol on acute pain remain incompletely understood. In a randomized, double-blind, placebo-controlled study with N = 100 healthy volunteers, we tested the effects of oral hydrocortisone (20 mg) in 2 widely used pain models for the visceral and somatic modality. Salivary cortisol was increased in the hydrocortisone group (time × group: P < 0.001). For the visceral modality, assessed using pressure-controlled rectal distensions, hydrocortisone decreased the pain threshold from before to after treatment (time × group: P = 0.011), an effect primarily driven by women (time × sex: P = 0.027). For the somatic modality, cutaneous heat pain thresholds remained unaffected by hydrocortisone. Hydrocortisone did not alter perceived pain intensity or unpleasantness of either modality. Conditioned pain-related fear in response to predictive cues was only observed for the visceral modality (time × modality: P = 0.026), an effect that was significantly reduced by hydrocortisone compared with placebo (time × group: P = 0.028). This is the first psychopharmacological study to support that acutely increased cortisol enhances pain sensitivity and impairs pain-related emotional learning within the visceral, but not the somatic pain modality. Stress-induced visceral hyperalgesia and deficits in emotional pain-related learning could play a role in the pathophysiology of chronic visceral pain.

Oral cortisone administration enhances pain sensitivity and impairs pain-related emotional learning within the visceral, but not the somatic pain modality.

aInstitute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany

bDepartment of Neurology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany

Corresponding author. Address: Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, Hufelandstrasse 55, D-45122 Essen, Germany. Tel.: +49-201-723-4516; fax: +49-201-723-5948. E-mail address: sven.benson@uk-essen.de (S. Benson).

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Received December 03, 2018

Received in revised form March 02, 2019

Accepted March 04, 2019

Online date: April 6, 2019

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1. Introduction

Stress mediators of the hypothalamic–pituitary–adrenal (HPA) axis, including the stress hormone cortisol, likely play a role in the pathophysiology and persistence of chronic pain. However, even in acute pain, the effects of cortisol remain incompletely understood. The administration of hydrocortisone constitutes an established psychopharmacological approach that allows one to test the effects of cortisol on different facets of the response to acute pain, including sensory, cognitive, and affective components. Thus far, hydrocortisone administration has been used in only very few, comparatively small studies,50,66,78 which were conducted exclusively within the somatic pain modality. In visceral pain, the effects of hydrocortisone have never been tested, despite accumulating evidence that HPA-axis mediators play a crucial role in normal and disturbed brain–gut axis interactions relevant to acute and chronic visceral pain.4,14,15,23

Experimental pain studies in different pain modalities are warranted because the psychophysiological principles and neurobiological mechanisms engaged by visceral vs somatic pain are at least partially distinct.6 Visceral pain is more unpleasant and fear-provoking,12,37,69 and evokes greater engagement of the central salience and emotional-arousal networks,2,13,74 even at matched intensity.37 Moreover, pain-related fear learning is enhanced for visceral compared with somatic pain.38 This likely reflects the unique salience of visceral pain, consistent with the concept of preparedness.52 Pain-related fear plays a role in attentional biases, decision-making, and hypervigilance, and likely modulates pain perception.1,8,39,44,75 Effects of cortisol on pain-related fear have never been tested in any pain modality.

This randomized, double-blind, placebo-controlled psychopharmacological study was designed to test effects of oral hydrocortisone in 2 established pain models for the visceral and somatic modality. In these pain modalities, we assessed effects on pain sensitivity, pain ratings, and pain-related fear learning. The study paradigm was built on our recent work on behavioral and neural responses to painful rectal distensions and cutaneous heat pain.37,38 In a de novo recruited sample of N = 100 healthy men and women, our first goal was to test effects of oral hydrocortisone vs placebo on pain thresholds and to explore sex differences. Our second goal was to elucidate effects of hydrocortisone on the acquisition and extinction of pain-related fear induced by modality-specific visual cues, predicting either visceral or somatic pain stimuli matched to pain intensity.

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2. Methods

2.1. Recruitment

In total, 108 healthy volunteers were recruited by local advertisement between July 2016 and January 2018 (see CONSORT diagram). The recruitment process included an initial telephone screening followed by a personal interview and medical examination. A priori power analysis with G-Power software (version 3.1.9.2, http://www.gpower.hhu.de/) indicated a minimum of 90 participants to detect small-to-medium effect sizes for time × treatment group interactions (f = 0.20; 1 − β = 0.90; correlation between time points r = 0.30). Thus, we randomized N = 100 volunteers (50 men and 50 women) to allow for exclusion of participants in case of measurement error, etc, after randomization. Eight volunteers had to be excluded before randomization, either during the screening process due to medical conditions or medication intake (n = 5) or on the study day due to initial technical problems (n = 3).

Exclusion criteria were age <18 years or >45 years, body mass index (BMI) <18 or >30, regular smoking (>5 cigarettes/month), any known medical condition based on self-report, any regular medication use (except thyroid medications, over-the-counter allergy treatment, or irregular use of over-the-counter pain medications), and lactose intolerance (lactose was an ingredient of placebo pills). To reduce putative confounding by cyclical fluctuations in sex steroid hormones, we aimed to recruit only women on hormonal contraceptives. However, a small proportion of women were free-cycling, as specified in the “Results” section. To exclude recent gastrointestinal symptoms suggestive of a functional or organic gastrointestinal condition, participants were screened with a standardized questionnaire that quantifies frequency and severity of upper and lower gastrointestinal symptoms.41 The German version of the Hospital Anxiety and Depression Scale was used to screen for anxiety or depression symptoms.29 In addition to the screening questionnaires, participants completed a questionnaire battery including the Trier Inventory for Chronic Stress (screening scale)65 and the trait scale of the State-Trait-Anxiety-Inventory,43,68 which was reported for group characteristics herein. All participants underwent a digital rectal examination to exclude perianal tissue damage (ie, hemorrhoids or fissures), which may interfere with balloon placement or rectal distensions. Pregnancy was excluded with a commercially available urinary pregnancy test on the day of the experiment. Previous participation in any of our group's previous or other ongoing studies involving pain-related conditioning was also exclusionary. The study protocol was approved by the local ethics committee of the University Hospital Essen (protocol number 10-4493) and followed the Declaration of Helsinki. All participants gave informed written consent and were compensated for their participation.

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2.2. Study design and procedures

Each volunteer completed the study protocol on 1 study day with a total duration of approximately 2.5 hours. To minimize possible circadian rhythm effects, all participants were tested between 13:00 and 17:00 hours, when endogenous cortisol levels are relatively low and stable. The timeline is illustrated in Figure 1A. The study was conducted in a medically equipped room within a clinical research unit at the University Hospital Essen. Participants were lying in a hospital bed during the experiment. After placement of the rectal balloon and fixation of the thermal device, baseline pain thresholds (PT1) were initially assessed for each modality in counterbalanced order across participants (see below for experimental procedures). Subsequently, a calibration and matching procedure was accomplished to identify individual stimulus intensities that were matched with respect to perceived pain intensity for implementation during conditioning. Participants then received either 20-mg oral hydrocortisone (2 pills of 10-mg Hydrocortison Jenapharm; mibe Arzneimittel GmbH, Brehna, Germany) or 2 identically looking placebo pills (P-Tabletten 7-mm Weiss; Winthrop Arzneimittel GmbH, Frankfurt, Germany) containing lactose. The pills had to be swallowed in whole with 200 mL of water under direct supervision by the study personnel. Notably, this commonly used dose of hydrocortisone produces plasma cortisol levels that are somewhat higher than those caused by a moderate stressor, such as public speaking,28,36 but still within the physiological range.9 In the few previous hydrocortisone studies in somatic pain models, the dose was either the same66 or higher (40 mg50; 60 mg78).

Figure 1

Figure 1

Randomization to the hydrocortisone or placebo group was accomplished using randomization software (www.randomizer.org, allocation ratio 1:1). To ensure blinding of study personnel directly interacting with participants, drug and placebo pills were provided by an investigator who was not directly interacting with participants (author S.B.) in identically looking drug containers labelled only with a code number on the day of the study. Thirty minutes after pill intake, pain thresholds for each modality were assessed again (PT2) in the same order as during baseline, aiming to test hydrocortisone effects on pain thresholds. Pain-related conditioning consisting of an acquisition (Fig. 1B) and an extinction (Fig. 1C) phase followed. At several time points before (−40 and −1 minutes) and after administration of hydrocortisone or placebo (+30, +60, +90, and +120 minutes) (Fig. 1A), saliva samples were collected to assess salivary cortisol concentrations as a marker of bioavailable free cortisol and manipulation check. To confirm the absence of pharmacological effects of hydrocortisone administration on the sympathetic nervous/central norepinephrine system, we also analyzed salivary alpha-amylase activity. To exclude effects on state anxiety, a validated state anxiety questionnaire (STAI-S)43,68 was also completed at every sampling time point.

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2.3. Pain thresholds, calibration, and matching

For visceral pain, pressure-controlled rectal distensions were performed with a barostat system (modified ISOBAR 3 device; G & J Electronics, Toronto, ON, Canada). For somatic pain, cutaneous heat was applied on the left ventral forearm with a thermal device (PATHWAY model CHEPS; Medoc Ltd, Advanced Medical Systems, Ramat Yishai, Israel). Pain thresholds were assessed with the method of limits,22,48 as previously accomplished.37,38 Based on recommendations in the field of neurogastroenterology,35 for visceral distensions, a double-random staircase distention protocol with random pressure increments ranging between 2 and 10 mm Hg was implemented. Note that maximal rectal distension pressure was limited to 50 mm Hg for safety reasons. For thermal stimulation, the mean pain threshold temperature of 5 consecutive measurements was calculated based on a QST protocol established in the field of somatic pain research.22,58 All pain thresholds were obtained with ramped stimuli (1°C/second) that were terminated when the subject pressed a mouse button. The baseline temperature was 32°C (center of neutral range). For the thermode, a temperature limit was set at 50°C to avoid tissue damage. In a small proportion of participants, the distension pressure limit precluded the accurate determination of the pain threshold for rectal distensions (ie, the threshold was not reached at 50 mm Hg), resulting in exclusion of a total of N = 15 participants (N = 8, hydrocortisone group; N = 7, placebo group) from analyses of visceral pain thresholds. In this group of N = 15 excluded participants, N = 3 also had no reliably determined heat pain thresholds. One additional participant had only missing data for heat pain threshold. Hence, N = 4 participants were excluded from analyses of the heat pain threshold. Note that we also conducted additional analyses with exclusion of all N = 16 participants with any missing threshold data, with no effects on results (data not shown). A post hoc power analysis for N = 84 indicated sufficient statistical power of 1 − β = 0.86 for analyses of pain thresholds. Because calibration and matching was successful in all participants (as specified below), there were no missing data for analyses of conditioning-related outcome variables.

Based on previously established methods in these visceral and somatic pain models,37,38 visceral-somatic calibration and matching was performed after thresholding at PT1. The aim was to identify individual stimulation intensities that were adequately painful and matched to perceived pain intensity (ie, 50-70 mm on a 0- to 100-mm visual analogue scale [VAS]). To this end, distensions (pressure −5 mm Hg below individual rectal pain threshold as an anchor) and cutaneous heat stimuli at pain threshold were presented simultaneously with a duration of 30 seconds each. Heating and cooling times of the thermode were matched to the barostat inflation and deflation times, respectively, for each individual. At the end of each combined stimulation trial, participants were prompted to compare the stimuli on a Likert-type response scale (ie, response options: more painful, equally painful, and less painful) aiming to determine stimulus intensities that were perceived as equally painful. If the rating showed a deviation (more or less painful), the temperature was successively adjusted starting with ±1°C (followed by additional adjustments if necessary of decreasing temperature changes: ±0.5, 0.3, and 0.2°C) until the stimuli were rated as equally painful at least 2 consecutive times. The final temperature and matched distension pressure, respectively, were then used during conditioning (see “Pain-related conditioning” section). Note that the matching and calibration procedure was intentionally not repeated after hydrocortisone or placebo administration. However, in the interest of safety, as a precautionary measure, participants were asked to rate the selected stimulus intensities again immediately before the acquisition. This was performed to allow for adjustment in case of overly painful stimulus ratings after pill intake. Adjustments were, however, not necessary in any case.

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2.4. Pain-related conditioning

Acquisition and extinction phases were built on a previously established protocol.37,38 During acquisition (Fig. 1B), a total of 20 visual cues predicting either visceral (CUEVIS: 10 cues) or somatic (CUESOM: 10 cues) painful stimuli (PAINVIS: 10 rectal distensions and PAINSOM: 10 cutaneous heat stimuli) were presented in pseudorandomized order. For visual cues, geometric symbols (circle or square, counterbalanced across participants) were used, one for visceral and another for somatic stimuli. The duration of cue presentations was jittered between 9 and 11 seconds and overlapped with the beginning of painful stimuli (delay conditioning). The duration of painful stimuli was 30 seconds, including inflation/heating, plateau, and deflation/cooling. Heating and cooling times of the thermode were matched to the barostat inflation and deflation times, respectively, for each individual. Rectal and cutaneous heat stimuli were individually calibrated and matched to perceived pain intensity before pill intake, allowing to test effects of hydrocortisone (vs placebo) on pain ratings and pain-related learning. Immediately after each pain stimulus, perceived pain intensity and unpleasantness were rated on 2 separate digitized VAS in response to the questions the questions “How painful was the distension/heat stimulus?” with ends labeled “not painful at all” (0 mm) and “extremely painful” (100 mm) and “How unpleasant was the distension/heat stimulus?” with ends labeled “not unpleasant at all” (0 mm) and “extremely unpleasant” (100 mm). Each trial was followed by a variable intertrial interval (5-7 seconds).

Regarding the order of CUEVIS–PAINVIS and CUESOM–PAINSOM pairings, participants were randomly assigned to 1 of 4 series to avoid potential sequence effects. The programming of pairings aimed for an essentially pseudorandomized order, but avoided more than 2 successive pairings of 1 modality and ensured that sequences alternatingly started with a somatic or visceral pain stimulus, respectively, and that the proportion of visceral and somatic pain stimuli was balanced throughout the sequence. During the extinction phase, identical cues were presented without any pain stimuli (Fig. 1C). To assess emotional learning, cue valence was assessed before the acquisition (baseline), immediately after the acquisition, and immediately after the extinction phase. Participants rated visceral and somatic pain-predictive cues on a VAS with the endpoints “very pleasant” (+100 mm) to “very unpleasant” (−100 mm), with the word “neutral” marked in the middle of the VAS, as previously conducted in our conditioning work.32,37,38 Contingency awareness after the acquisition phase was confirmed with ratings assessing the probability that the visual cue was followed by a visceral or somatic pain stimulus, respectively, using a VAS with the endpoints “never” (0%) to “always” (100%). Note that we had no missing data for ratings because all conditioning-related variables were collected in a digitized manner (responses were required for stimulus presentations to continue) or administered under direct supervision of study personnel.

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2.5. Salivary cortisol concentration and alpha-amylase activity

Saliva samples for analyses of cortisol concentrations and alpha-amylase activity were collected using commercial collection devices (Salivette; Sarstedt, Nümbrecht, Germany). All saliva samples were centrifuged (1000g, 2 minutes, 4°C) and stored at −20°C until analysis. Salivary cortisol concentrations were measured using a commercially available enzyme-linked immunosorbent assay (ELISA; IBL International, Hamburg, Germany) according to the manufacturer's protocol. Intra-assay and inter-assay variances were 4.8% and 5.9%, respectively. The detection limit was 0.138 nmol/L. Salivary alpha-amylase activity was determined using a commercially available enzymatic assay (Alpha-Amylase Saliva Enzymatic Assay; IBL International). Intra-assay and inter-assay variances were 2.3% and 6.9%, respectively. Cortisol and alpha-amylase could not be determined for a very small number of post-treatment time points (3 samples: 1 hydrocortisone group; 2 placebo group). For statistical analyses, these values were imputed based on estimates derived from regression modelling using existing data.

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2.6. Statistical analyses

Note that unblinding was accomplished only after data entry into a database. All statistical analyses were conducted using SPSS version 22.0 (IBM Corporation, Armonk, NY). The groups were characterized and compared with respect to sociodemographic and psychological characteristics using independent-samples t tests. Rectal and cutaneous heat pain thresholds were analyzed with repeated-measures analysis of covariance (ANCOVA), with time (before and after treatment) as the repeated factor, hydrocortisone vs placebo group as the between-group factor, and body weight as a covariate. For analyses of pain and valence ratings, repeated-measures ANCOVA was used with time and modality (visceral vs somatic) as the repeated factors, hydrocortisone vs placebo group as the between-group factor, and body weight as a covariate, followed by analyses within pain modalities. Body weight was included into all analyses to account for interindividual weight differences between study participants. Additional covariates in selected analyses are specified in the “Results” section. Post hoc comparisons were accomplished with ANCOVA with BMI as a covariate. Exploratory analyses of sex differences were conducted with BMI as covariate to follow up significant time × group effects (to increase readability, results are only reported if significant). The Greenhouse–Geisser correction was applied if the sphericity assumption was violated (based on results of the Mauchly test). Partial correlations (accounting for BMI) were computed as Pearson r. Exact P-values are reported throughout the “Results” section, and all results are reported as mean ± SEM. All authors had access to the study data and approved the final manuscript.

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3. Results

3.1. Participants

The treatment groups did not significantly differ in sociodemographic or psychological variables, including age and BMI (Table 1). Consistent with stringent exclusion criteria, gastrointestinal symptom scores41 were low, and Hospital Anxiety and Depression Scale scores for symptoms of anxiety and depression29 were well-within normal range. Trait anxiety43,68 and chronic stress65 were comparable between groups. The majority of women reported using hormonal contraceptives (N = 20 women in the hydrocortisone group; N = 20 women in the placebo group), but some were free-cycling (N = 5 in the hydrocortisone group; N = 5 in the placebo group). Baseline pain thresholds for rectal distensions and thermal heat pain (Table 2) were comparable between groups and similar to means reported in other groups of healthy volunteers in our earlier studies.37,57 Calibration and matching to perceived pain intensity resulted in mean stimulus intensities of 30.9 ± 1.2 mm Hg for visceral pain (29.8 ± 1.7 mm Hg, hydrocortisone group; 32.1 ± 1.6 mm Hg, placebo group, n.s.) and 44.0 ± 0.9°C for heat pain (44.2 ± 1.3°C, hydrocortisone group; 43.7 ± 1.3°C, placebo group, n.s.), which were used during the acquisition phase.

Table 1

Table 1

Table 2

Table 2

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3.2. Salivary cortisol, alpha-amylase, and state anxiety

Oral administration of 20-mg hydrocortisone led to an increase in bioavailable free cortisol as evidenced by a significant increase in salivary cortisol concentration when compared with placebo (time × group: F = 35.60, P < 0.001,

= 0.28, Fig. 2A). Cortisol concentrations were significantly increased in the hydrocortisone group at all post-treatment time points (for results of post hoc tests, see Fig. 2A), with no evidence of significant sex differences (data not shown). On the other hand, neither salivary alpha-amylase activity nor state anxiety scores were affected by hydrocortisone compared with placebo treatment (time × group interaction for alpha-amylase: F = 0.56, P = 0.67,

< 0.01, Fig. 2B; for state anxiety: F = 0.59, P = 0.65,

< 0.01, Fig. 2C).

Figure 2

Figure 2

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3.3. Pain thresholds

Hydrocortisone significantly reduced rectal pain threshold (time × group interaction: F = 6.81, P = 0.011,

= 0.08), but had no effect on cutaneous heat pain threshold (time × group interaction: F = 2.65, P = 0.11,

= 0.03; for post hoc analyses at specific time points, see Table 2). The change in rectal pain thresholds in the hydrocortisone group was primarily driven by women, as revealed by exploratory comparisons of delta scores between men and women (time × sex interaction: F = 5.27, P = 0.024,

= 0.06, for an illustration, see Fig. 3; for post hoc analyses comparing men and women at specific time points, see Table 2).

Figure 3

Figure 3

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3.4. Pain ratings

Note that pain stimulus intensities (distension pressure and cutaneous heat temperature), determined before pill intake, were not recalibrated after pill intake. Overall, perceptual ratings of repeated rectal distensions were perceived as more unpleasant than heat stimuli despite being matched for intensity (main effect of modality for intensity: F = 3.63, P = 0.060,

= 0.04; for unpleasantness: F = 4.42, P = 0.038,

= 0.04). Hydrocortisone did not affect ratings of pain intensity (Fig. 4A) or unpleasantness (Fig. 4B), within either modality (main effects of group for visceral pain intensity: F = 0.01, P = 0.98,

< 0.001; for visceral pain unpleasantness: F = 0.69, P = 0.72,

= 0.007; for somatic pain intensity: F = 0.95, P = 0.33,

= 0.010; and for somatic pain unpleasantness: F = 0.07, P = 0.79,

= 0.001; there were no significant time effects or interactions of group × time, all P > 0.05, data not shown).

Figure 4

Figure 4

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3.5. Valence ratings of pain-predictive cues during acquisition and extinction

Changes in cue valence ratings in response to modality-specific cue–pain pairings were only observed for the visceral modality, despite a comparable awareness of cue–pain contingencies for both modalities (visceral: 79.7 ± 3.8 mm for the hydrocortisone group, 82.3 ± 3.5 mm for the placebo group, n.s.; somatic: 82.6 ± 3.3 mm for the hydrocortisone group, 88.1 ± 2.7 mm for the placebo group, n.s.). After acquisition, visceral pain-predictive cues were perceived as markedly more unpleasant, indicating conditioned pain-related fear, and this successfully extinguished after the extinction phase (time × modality interaction: F = 4.10, P = 0.026,

= 0.04, Fig. 5). Interestingly, hydrocortisone treatment significantly reduced the acquired valence change for visceral pain-predictive cues, as revealed by analyses conducted within the visceral modality (time × treatment interaction: F = 3.87, P = 0.028,

= 0.04). This effect remained significant when rectal pain thresholds were entered as an additional covariate to account for treatment effects on rectal thresholds (time × treatment interaction: F = 4.08; P = 0.023;

= 0.04). For the somatic modality, there was no indication of valence changes for thermal pain-predictive cues across time points (main effect of time: F = 1.37, P = 0.257,

= 0.01) or treatment effects (time × group interaction: F = 1.06, P = 0.342,

= 0.01, Fig. 5). No evidence suggesting sex differences in the effect of hydrocortisone on visceral or thermal pain predicitive cue valence was observed (data not shown). Finally, exploratory partial correlational analyses revealed that valence ratings of visceral pain-predictive cues after acquisition were positively correlated with mean pain intensity (r = 0.358; P < 0.001) as well as unpleasantness (r = 0.394; P < 0.001).

Figure 5

Figure 5

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4. Discussion

We herein report on a randomized, double-blind, placebo-controlled psychopharmacological study assessing the effects of cortisol on different facets of acute pain in 2 pain modalities. Our first goal was to test effects of hydrocortisone vs placebo treatment on pain thresholds for pressure-controlled rectal distensions and cutaneous heat pain as 2 widely used models for visceral and somatic pain, respectively. Hydrocortisone successfully increased salivary cortisol concentrations, supporting the efficacy of the treatment. The main finding was that hydrocortisone exerted proalgesic effects for the visceral modality, as evidenced by significantly reduced rectal pain threshold when compared with placebo. On the other hand, no effects were observed for cutaneous heat pain threshold. To the best of our knowledge, this is the first psychopharmacological study implementing hydrocortisone to test effects of elevated cortisol levels on visceral sensitivity in humans. Our data support that acutely elevated levels of cortisol increase visceral pain sensitivity in healthy individuals. These results complement pharmacological studies on the modulation of visceral sensorimotor functions by corticotropin-releasing hormone (CRH),5,34,40,45,60,70,71,79 including recent evidence that CRH increased esophageal sensitivity to mechanical distension5 as well as to electrical stimuli.79 Interestingly, public speaking stress led to increased intestinal permeability by mast-cell dependent mechanism only in participants who showed a significant elevation of cortisol,73 suggesting that cortisol may be crucial to stress-induced changes in peripheral mechanisms that regulate visceral afferent signaling and pain processing. Variations across studies in the presence, magnitude, or duration of HPA-axis effector hormone release may indeed explain some of the heterogeneity in findings gathered from other experimental stress models, such as dichotomous listening or auditory stress,11,19,21 public speaking stress,17,18,57,59 cold water hand immersion,51 or challenging neurocognitive tests.54 Several of these studies reported no effects of acute stress on visceral perception as assessed by ratings in healthy control groups,11,18,19,25,51 lending support to the notion that acute stress–induced hyperalgesia may exclusively exist in patients with chronic visceral pain and hypersensitivity11,51,72; for reviews, see Refs. 4,23. However, most studies in the visceral field did not assess pain thresholds. In this study, pain and unpleasantness ratings were unaffected by hydrocortisone, consistent with earlier negative findings in healthy individuals.11,18,19,25,51 Together, these results suggest that cortisol may primarily affect visceral sensory-discriminatory aspects (ie, pain sensitivity) rather than cognitive-evaluative or affective pain components (ie, ratings of intensity and unpleasantness, respectively) in healthy individuals. Furthermore, with a notable exception,34 sex differences have rarely been assessed. Our exploratory analyses suggested that proalgesic effects of cortisol on visceral sensitivity were primarily driven by women, calling for future studies on the role of sex/gender. Finally, the timing of visceral sensory assessments in relation to the cortisol response may be crucial to the presence and directionality of effects, which has been shown both for visceral sensory measures54 as well as motility measures.31 Together, our findings support a role of cortisol as the major effector hormone of the HPA axis in visceral hyperalgesia in healthy adults. Future work is needed to investigate whether cortisol effects on sensitivity involve local/peripheral mechanisms, afferent signaling pathways, and/or central components of the bidirectional brain–gut axis.

Based on the lack of hydrocortisone effect on cutaneous heat pain thresholds, it is tempting to conclude that cortisol induces hyperalgesia exclusively within the visceral modality. However, this would be premature. In the somatic pain field, hydrocortisone administration has thus far been implemented in only few studies using the same or higher doses,50,66,78 drawing attention to a need for dose–response studies. Consistent with our findings, 2 earlier studies in the same thermal pain model reported negative results,66,78 but sample sizes were comparatively small, raising issues of statistical power in future psychopharmacological work. Other experimental approaches to assess the role of HPA-axis mediators including cortisol on somatic pain sensitivity, such as CRH administration,42,47 induction of psychosocial or mental stress,7,24,26,27 and exposure to or threat of electric shock,56 have provided very heterogeneous results. Whether this is due to the presence and/or magnitude of cortisol increase, putative confounds such as distraction in some mental stress paradigms, or concurrent activation of multiple peripheral and central stress systems with pronociceptive and antinociceptive mechanisms remains unclear. Hopefully, our results will inspire more research with psychopharmacological approaches, in different pain models and pain modalities. Our results for the cutaneous heat pain model may not transfer to other pain models within the somatic modality, as supported by first evidence.7,27 Effects of cortisol on more complex phenomena, such as temporal summation and expectancy effects, are far from understood, and we cannot exclude that such nonpsychophysiological phenomena played a role in our thresholding procedures for visceral and somatic pain sensitivity. Furthermore, future studies should consider a reference condition without pain or addition of nonconditioned control group(s) exposed to unpredictable pain stimuli to assess phenomena such as conditioned hyperalgesia or hypoalgesia.

The effects of cortisol on more complex phenomena relevant to pain modulation, including pain-related fear, remain essentially unknown. Therefore, our second goal was to test effects of hydrocortisone on emotional pain-related learning and extinction in response to visceral and somatic pain-predictive cues. We herein replicated our earlier finding that—given concurrent application of visceral and somatic pain stimuli—only predictive cues for the visceral modality come to elicit pain-related fear38 as a result of associative learning. These findings support that conditioned emotional responses evoked during the expectation of pain are shaped by pain modality, extending efforts to elucidate modality-specific effects of aversive expectancy and underlying neural correlates.20,67 In line with the concept of preparedness, our data support that pain-related learning is shaped by the salience and hence threat value of unconditioned stimuli. This is consistent with overshadowing phenomena, relevant to learning and nocebo mechanisms.16 On a cautionary note, it remains unclear whether our results are exclusively attributable to the visceral modality and/or this specific pain model of rectal distensions. Different stimulus locations (ie, bodily regions)63 or degree of invasiveness of the stimulus application rather than modality per se likely also shapes salience, although previous studies that implemented somatic and visceral pain stimuli in closer proximity to each other (eg, by stimulating the midline chest,69 proximal vs distal portions of the esophagus2 or anorectal areas13,30,46) have revealed converging findings.

Interestingly, we found that conditioned visceral pain-related fear was significantly reduced in the hydrocortisone group. This finding suggests that elevated cortisol may interfere with pain-related emotional learning. Conditioned fear is best conceptualized as an evolutionary-driven, adaptive response that is essential for behavioral adjustment to salient threat and safety signals, including successful avoidance behavior and behavioral generalization.61 From this perspective, our results of reduced conditioned pain-related fear of visceral pain under conditions of pharmacologically induced cortisol increase are well in line with evidence that stress reduces behavioral flexibility. Stress reportedly disrupts the ability to adaptively adjust learning by attenuating the flexible updating of aversive value.55 Along the same lines, acute stress was found to reduce the ability to modulate pain in a dose-dependent manner26 and to increase nocebo hyperalgesia in a visceral pain model.57 Our previous work provided insight into shared and distinct brain regions engaged during cued pain anticipation and pain across modalities.37,38 Testing the neural correlates underlying the herein observed hydrocortisone effects on emotional pain-related learning is an important next step.62 After all, at least some of the neurobiological responses evoked during cued pain anticipation shape the response to actual painful stimulation,1,8,39,44,75 rendering efforts to elucidate the effects of stress mediators on pain expectation, an important research area in the pain field.

Taken together, our findings of cortisol-induced visceral hyperalgesia and impaired emotional cue–pain learning for the visceral modality extend knowledge regarding the role of acute stress in visceral sensorimotor functions along the brain–gut axis4,15,23 and pave the way towards interconnecting the fields of visceral pain and the affective neurosciences. Patients with chronic visceral pain and visceral hyperalgesia show disturbed HPA-axis regulation in response to stress14 and demonstrate altered pain-related learning and memory processes,32,40 as do patients with other types of chronic pain.3,49,64 If cortisol increases the vulnerability to maladaptive threat responses, as has recently been proposed,55 different stress-related disorders and chronic pain conditions may share trajectories, involving emotional learning and memory processes.76 Both stress and fear contribute to the pathophysiology of chronic pain and are targets for psychological as well as pharmacological treatment approaches.10,33,53,77 Results from our psychopharmacological study in healthy volunteers therefore call for translational work in patients with chronic pain.

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Conflict of interest statement

The authors have no conflict of interest to declare.

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Acknowledgments

The authors thank Mara Beuster and Anna-Theresa Schneider for support during data acquisition and Alexandra Kornowski for laboratory support. This project was funded by the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG) as part of the DFG Research Unit FOR 1581 (grant number: EL 236/9-2) and the CRC1280 “Extinction Learning” (project A10), and by the Ministry of Innovation, Science, and Research of the State of NRW for gender research. The funding agencies had no role in the conception, analysis, or interpretation of the data.

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Keywords:

Visceral pain; Rectal distension; Somatic pain; Cutaneous heat pain; Pain sensitivity; Stress; Cortisol; Emotional learning; Extinction; Pain-related learning

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