Opioid analgesia alters corticospinal coupling along the descending pain system in healthy participants
- Department for Systems Neuroscience, University Medical Center Hamburg-Eppendorf, Germany
- Max Planck School of Cognition, Germany
Figures
Figure 1 with 2 supplements
Behavioral results.
(A) Pooled retrospective pain ratings across stimuli (constant, stepwise) and time points (T1, T2) show a significant pain reduction during opioid treatment but no significant difference between Remi50 and Remi100. (B) The difference between baseline and treatment ratings shows that a majority experienced analgesia during the remifentanil treatment. The labels ‘less pain’ and ‘more pain’ refer to the treatment phase compared to baseline. (C) Online pain ratings show a similar pattern: remifentanil reduced pain ratings for both stimuli while there was no significant difference between the Remi50 and Remi100 groups. Results were considered significant at pcorr<0.05. Error bars/shaded areas represent standard error of the mean.
Figure 1—figure supplement 1
Detailed behavioral results for all rating types.
(A) Constant T1. (B) Constant T2. (C) Stepwise T1. (D) Stepwise T2. (E) Mean constant ratings per session. (F) Online ratings per group and stimulus type.
Figure 1—figure supplement 2
Functional MRI (fMRI)-related plots for all three experimental groups.
Figure 2 with 3 supplements
Brain regions responding to remifentanil treatment.
(A) Brain regions that show a significant reduction in activity during remifentanil treatment comprise the thalamus (Thal), supramarginal gyrus (SMG), superior segment of circular insula (cirIns), and opercular part of the inferior frontal gyrus (opIFG). Parameter estimates in the opIFG show reduced activity during the treatment phase in the remifentanil group compared to the NaCl group. (B) A brain region that shows a significantly higher activity during remifentanil treatment is the anterior cingulate gyrus (ACC). Parameter estimates show that this region is less deactivated under remifentanil than under saline. Region of interest (ROI)-masked statistical t-maps are overlaid on an average structural T1 image in Montreal Neurological Institute (MNI) template space and the visualization threshold is set to pcorr<0.05, which is indicated as a dashed line in the color bar. Dashed circles indicate the cluster from which peak voxel parameter estimates are plotted. Error bars represent standard error of the mean.
Figure 2—figure supplement 1
Intensity-dependent pain activation.
(A) In the brain and (B) spinal cord.
Figure 2—figure supplement 2
Intensity-dependent pain activation in the spinal cord.
Figure 2—figure supplement 3
Uncorrected interaction results.
(A) NaCl > Remi. (B) Remi >NaCl.
Figure 3 with 1 supplement
Spinal regions responding to remifentanil treatment.
Spinal regions that show a significant reduction in activity during remifentanil treatment comprise the left dorsal horn (DH) and layer X (LX). Parameter estimates show that spinal activity in the DH is reduced during remifentanil treatment compared to saline. Region of interest (ROI)-masked statistical t-maps are overlaid on an average mean echo planar imaging (EPI) image in PAM50 template space and the visualization threshold is set to pcorr<0.05, which is indicated as a dashed line in the color bar. The dashed circle indicates the cluster from which peak voxel parameter estimates are plotted. Error bars represent standard error of the mean.
Figure 3—figure supplement 1
Uncorrected interaction results in the spinal cord.
Figure 4 with 1 supplement
Negative correlation between neural activity and analgesia.
(A) Brain regions that show a significant negative correlation between activity and perceived analgesia comprise the supramarginal gyrus (SMG), short insular gyri (sIns), thalamus (Thal), opercular part of the inferior frontal gyrus (opIFG), and periaqueductal gray (PAG). Parameter estimates in the frontal operculum show that the reduction in brain activity between baseline and treatment phase correlates negatively with perceived analgesia across all groups. (B) Time courses extracted from the opIFG correspond to the shape of both stimulus types but are diminished during opioid treatment (dashes denote stimulus onset and offset). Region of interest (ROI)-masked statistical t-maps are overlaid on an average structural T1 image in Montreal Neurological Institute (MNI) template space and the visualization threshold is set to pcorr<0.05, which is indicated as a dashed line in the color bar. Dashed circles indicate the cluster from which peak voxel parameter estimates are plotted. Shaded areas represent standard error of the mean.
Figure 4—figure supplement 1
Uncorrected correlation results.
(A) Negative correlation. (B) Positive correlation.
Figure 5 with 1 supplement
Positive correlation between neural activity and analgesia.
(A) Brain regions that show a significant positive correlation between activity and perceived analgesia across all groups comprise the medial orbital sulcus (OFC) and anterior cingulate gyrus (ACC). Parameter estimates in the ACC show that the reduction in brain activity between baseline and treatment phase correlates positively with perceived analgesia across all groups. (B) Time courses extracted from the ACC show a deactivation during noxious stimulation that disappears during opioid treatment (dashes denote stimulus onset and offset). Region of interest (ROI)-masked statistical t-maps are overlaid on an average structural T1 image in Montreal Neurological Institute (MNI) template space and the visualization threshold is set to pcorr<0.05, which is indicated as a dashed line in the color bar. Dashed circles indicate the cluster from which peak voxel parameter estimates are plotted. Shaded areas represent standard error of the mean.
Figure 5—figure supplement 1
Overlay interaction and correlation results.
(A) NaCl > Remi plus negative correlation. (B) Remi > NaCl plus positive correlation.
Figure 6
Neurological pain signature (NPS) results.
(A) The NPS scores extracted for every participant and experimental phase show a significant reduction during remifentanil treatment. (B) The difference between baseline and treatment NPS scores correlates negatively with perceived analgesia (baseline – treatment). (C) The time course of NPS estimates shown for both stimulus types and experimental phases reflects online ratings and shows a reduction of activity in the remifentanil group. Error bars/shaded areas represent standard error of the mean.
Figure 7 with 2 supplements
Coupling strength analyses between modulatory regions.
(A) Schematic overview of regions that were examined for opioid-related coupling changes. (B) Treatment-related coupling between the anterior cingulate gyrus (ACC) (seed region) and right periaqueductal gray (PAG) correlates more negatively in participants that received saline than in participants that received remifentanil. (C) Treatment-related coupling between the spinal cord dorsal horn (seed region) and left PAG correlates more negatively in participants that received saline than in participants that received remifentanil. Region of interest (ROI)-masked statistical t-maps are overlaid on an average structural T1 image in Montreal Neurological Institute (MNI) template space and the visualization threshold is set to pcorr<0.05, which is indicated as a dashed line in the color bar.
Figure 7—figure supplement 1
Uncorrected psycho-physiological interaction (PPI) results.
(A) PPI with seed region in the anterior cingulate gyrus (ACC). (B) PPI with seed region in the spinal cord dorsal horn.
Figure 7—figure supplement 2
Psycho-physiological interaction (PPI) results of periaqueductal gray (PAG) – spinal cord.
PPI analysis in the spinal cord with a seed region in the PAG. This seed region was chosen based on the result from the PPI with a seed region in the anterior cingulate gyrus (ACC).
Figure 8 with 2 supplements
Experimental design.
(A) During the first four functional MRI (fMRI) sessions, all participants received constant and stepwise noxious heat stimuli in a pseudo-randomized order without any treatment (Baseline). Before the fifth session, the infusion pump was started, delivering either saline or remifentanil based on group assignment and the same stimulation protocol was repeated for another four sessions (Treatment). (B) Participants were assigned to three different experimental groups. Two groups (Remi50, Remi100) received the opioid receptor agonist remifentanil during the treatment phase while the NaCl group received saline. Participants in the NaCl and Remi50 groups were told that they had a 50% chance of receiving the active drug but remained blind with respect to the actual treatment. The Remi100 group was told that they would receive the drug during the treatment phase, thereby having a 100% probability of receiving the drug. (C) Temperature profile of both types of noxious heat stimuli that were applied in the study. The constant stimulus (light gray) was calibrated to be perceived on average as 50 visual analog scale (VAS) and had the same temperature for 15 s. The stepwise stimulus (dark gray) started with a higher temperature (+1.5°C) relative to the calibrated temperature for 5 s (T1) after which the temperature was lowered to the same temperature as the constant stimulus for the remaining 10 s (T2). In the middle of stimulation, a star appeared on the screen for several seconds and participants were instructed to retrospectively rate the painfulness during the 5 s intervals preceding and following the star.
Figure 8—figure supplement 1
Geometric setup for the corticospinal functional MRI (fMRI) imaging approach.
(A) Field of view in the brain and spinal cord (light blue) with head and neck coil (yellow and red) and saturation pulses (dark blue). (B) Respective adjustment volumes in the brain and spinal cord. (C) Movement parameters calculated as root-mean-square translations within-session (left) and between-session (right).
Figure 8—figure supplement 2
Masks covering regions of interest for small-volume correction.
(A) Pain-related brain regions. (B) Prefrontal cortex. (C) Left spinal cord dorsal horn. (D) Periaqueductal gray (PAG).
Author response image 1
Additional files
-
Supplementary file 1
Supplementary tables 1a-h.
- https://cdn.elifesciences.org/articles/74293/elife-74293-supp1-v1.docx
-
Transparent reporting form
- https://cdn.elifesciences.org/articles/74293/elife-74293-transrepform1-v1.pdf
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Opioid analgesia alters corticospinal coupling along the descending pain system in healthy participants
eLife 11:e74293.
https://doi.org/10.7554/eLife.74293
