The effect of opioid receptor blockade on the neural processing of thermal stimuli

Abstract

The endogenous opioid system represents one of the principal systems in the modulation of pain. This has been demonstrated in studies of placebo analgesia and stress-induced analgesia, where anti-nociceptive activity triggered by pain itself or by cognitive states is blocked by opioid antagonists. The aim of this study was to characterize the effect of opioid receptor blockade on the physiological processing of painful thermal stimulation in the absence of cognitive manipulation. We therefore measured BOLD (blood oxygen level dependent) signal responses and intensity ratings to non-painful and painful thermal stimuli in a double-blind, cross-over design using the opioid receptor antagonist naloxone. On the behavioral level, we observed an increase in intensity ratings under naloxone due mainly to a difference in the non-painful stimuli. On the neural level, painful thermal stimulation was associated with a negative BOLD signal within the pregenual anterior cingulate cortex, and this deactivation was abolished by naloxone.

Figure 1. Experimental paradigm.

Each trial began with a reaction time (RT) task during which the subject had to press a button whenever a red square appeared (arrow). The squares were presented randomly and appeared for 1 s. Thereafter, cross-hairs appeared and eventually blinked to warn that a thermal stimulus was coming. The blink was sandwiched between a 3–5 s and 4–6 s jitter. Following the second jitter came the thermal stimulus of 6 s (44°C, 45.5°C, 47°C, or 48°C) within a 12 s cross-hair presentation. The visual analogue rating (VAS) scale then appeared, which consisted of two anchors at 0 “nothing” and 100 “intolerable pain” with a third anchor at 50 to mark the pain threshold. The subject could move the edge of the right-hand side of the scale back and forth to the appropriate spot for as long as desired. The starting point of the VAS scale varied randomly for each trial. Once a subject selected a position on the VAS, a cross-hair appeared for 5 s until the start of the next reaction time task.

Figure 2. Time course of ratings per temperature.

The graph illustrates the average VAS score (± sem) for the ten time points of each temperature. Time point 1 would be the first time that temperature had been presented and time point 10 the last. A capital S indicates the saline session and a capital N the naloxone session. 1 stands for 44°C, 2 for 45.5°C, 3 for 47°C and 4 for 48°C. To test for habituation or sensitization, we compared the average rating over the second half of the session to the average rating over the first half of the session. There was no significant difference for any temperature.

Figure 3. Main effect of intensity on brain activation.

Left: Activation (visualization threshold p<0.001 uncorrected) related to painful vs. non-painful stimulus intensities across treatment, overlaid on the axial slice of a T1-weighted template image. The image shows bilateral activation in the insula and thalamus; see Table 1 for a complete listing of results. The color bar represents t-values. Right: Plotted are the percent signal changes (+sem) for the peak voxel in the right insula [33 12 9] for the 2 intensities (non-painful or painful) under each treatment condition (naloxone or saline session). Percent signal change was computed using rfxplot .

Figure 4. Treatment by intensity interaction.

Left: Results (visualization threshold p<0.001 uncorrected) related to the treatment (naloxone vs. saline session) by intensity (painful vs. non-painful) interaction, overlaid on the axial slice of a T1-weighted template image. The image shows the cluster around the peak voxel in the pregenual ACC. The color bar represents t-values. Right: Plotted are the percent signal changes (+sem) for the peak voxel [−15 42 12] for the intensities under each condition. Percent signal change was computed using rfxplot .

Figure 5. FIR Analysis of the BOLD response in the pgACC.

Finite Impulse Response (FIR) analysis of the BOLD response to non-painful and painful thermal stimulation in the pregenual ACC for the peak voxel from the interaction analysis [−15 42 12]. Peri-stimulus time is in scans. The dashed lines demarcate the beginning and end of the thermal stimuli, including ramp-time (mean length ± std, 3.66±0.14 scans). The dash-dot line demarcates the beginning of the VAS rating procedure.