Acute stress contributes to individual differences in pain and pain-related brain activity in healthy and chronic pain patients

Abstract

Individual differences in pain sensitivity and reactivity are well recognized but the underlying mechanisms are likely to be diverse. The phenomenon of stress-induced analgesia is well documented in animal research and individual variability in the stress response in humans may produce corresponding changes in pain. We assessed the magnitude of the acute stress response of 16 chronic back pain (CBP) patients and 18 healthy individuals exposed to noxious thermal stimulations administered in a functional magnetic resonance imaging experiment and tested its possible contribution to individual differences in pain perception. The temperature of the noxious stimulations was determined individually to control for differences in pain sensitivity. The two groups showed similar significant increases in reactive cortisol across the scanning session when compared with their basal levels collected over 7 consecutive days, suggesting normal hypothalamic-pituitary-adrenal axis reactivity to painful stressors in CBP patients. Critically, after controlling for any effect of group and stimulus temperature, individuals with stronger cortisol responses reported less pain unpleasantness and showed reduced blood oxygenation level-dependent activation in nucleus accumbens at the stimulus onset and in the anterior mid-cingulate cortex (aMCC), the primary somatosensory cortex, and the posterior insula. Mediation analyses indicated that pain-related activity in the aMCC mediated the relationship between the reactive cortisol response and the pain unpleasantness. Psychophysiological interaction analysis further revealed that higher stress reactivity was associated with reduced functional connectivity between the aMCC and the brainstem. These findings suggest that acute stress modulates pain in humans and contributes to individual variability in pain affect and pain-related brain activity.

Figure 1.

The time at which basal (A) and reactive (B) cortisol samples were collected.

Figure 2.

The red line indicates the reactive cortisol response to the noxious stimulations administered in an MRI context and the black line indicates the diurnal basal levels of cortisol collected over 7 d. The results indicate that both healthy individuals (A) and CBP patients (B) displayed significant increases in cortisol after the scanning session (p's < 0.03). Error bars represent SEM.

Figure 3.

A, The [Pain_ramp-up] condition elicited a BOLD-signal response in the NAc. B, The [Pain vs Warm] contrast elicited a BOLD-signal response in pain-related brain regions. Note that both analyses controlled for the group and the individual temperature used to elicit strong heat pain (see Materials and Methods). Functional data are shown over the mean structural image of all participants (displayed at p < 0.001 uncorrected) unless otherwise specified.

Figure 4.

The AUCg of the reactive cortisol response negatively correlated with the BOLD signal response in the NAc (x,y,z 16, 6, −10). The scatter plot (green) represents the residual of the mean parameter estimates (a.u.) in the right NAc against the residual AUCg of the reactive cortisol, after controlling for the group and the stimulus temperature (see Materials and Methods). Additional scatter plots represent the mean parameter estimates (a.u.) in the NAc against the AUCg for reactive cortisol in each CBP patient (red) and healthy individuals (blue) separately. Functional data are shown over the mean structural image of all participants (displayed at p < 0.001 uncorrected unless otherwise specified).

Figure 5.

A, The AUCg of the reactive cortisol response negatively correlated with the BOLD signal response in the aMCC, the S1, and the pINS. The scatter plot (green) represents the residual of the mean parameter estimates (a.u.) in the each of these regions against the residual AUCg of the reactive cortisol. Additional scatter plots represent the relation between AUCg and brain activity for the CBP patients (red) and healthy individuals (blue) separately. Functional data are shown over the mean structural image of all participants (displayed at p < 0.001 uncorrected). B, Bootstrap analyses shows that the aMCC, but not S1 or the pINS, mediated the inverse relation between the reactive cortisol and the pain unpleasantness; *p < 0.05.

Figure 6.

The functional connectivity of the aMCC with the midbrain and the RVM increased during pain, but this effect was reduced in individuals showing stronger acute stress response (AUCg). Functional data are shown over the mean structural image of all participants (displayed at p < 0.001 uncorrected unless otherwise specified).