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,
Hydrocortisone significantly reduced rectal pain threshold (time × group interaction: F = 6.81, P = 0.011,
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,
= 0.001; there were no significant time effects or interactions of group × time, all P > 0.05, data not shown).
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). 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,
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.
The authors have no conflict of interest to declare.
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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