Altered Pain Processing Associated with Administration of Dopamine Agonist and Antagonist in Healthy Volunteers

Abstract

Striatal dopamine dysfunction is associated with the altered top-down modulation of pain processing. The dopamine D2-like receptor family is a potential substrate for such effects due to its primary expression in the striatum, but evidence for this is currently lacking. Here, we investigated the effect of pharmacologically manipulating striatal dopamine D2 receptor activity on the anticipation and perception of acute pain stimuli in humans. Participants received visual cues that induced either certain or uncertain anticipation of two pain intensity levels delivered via a CO₂ laser. Rating of the pain intensity and unpleasantness was recorded. Brain activity was recorded with EEG and analysed via source localisation to investigate neural activity during the anticipation and receipt of pain. Participants completed the experiment under three conditions, control (Sodium Chloride), D2 receptor agonist (Cabergoline), and D2 receptor antagonist (Amisulpride), in a repeated-measures, triple-crossover, double-blind study. The antagonist reduced an individuals' ability to distinguish between low and high pain following uncertain anticipation. The EEG source localisation showed that the agonist and antagonist reduced neural activations in specific brain regions associated with the sensory integration of salient stimuli during the anticipation and receipt of pain. During anticipation, the agonist reduced activity in the right mid-temporal region and the right angular gyrus, whilst the antagonist reduced activity within the right postcentral, right mid-temporal, and right inferior parietal regions. In comparison to control, the antagonist reduced activity within the insula during the receipt of pain, a key structure involved in the integration of the sensory and affective aspects of pain. Pain sensitivity and unpleasantness were not changed by D2R modulation. Our results support the notion that D2 receptor neurotransmission has a role in the top-down modulation of pain.

Keywords: D2 receptor; EEG; amisulpride; anticipation; cabergoline; dopamine; pain; source localisation; uncertainty.

Figure A1

A schematic diagram of the action of the dopamine D2 receptor and how low and high doses of agonists and antagonists have different effects on postsynaptic D2 receptor activity. Presents the scientific rationale for using a high dose of both drugs in the current study.

Figure 1

A schematic diagram of a single trial of the experimental paradigm. A computer monitor showed the participant a visual cue of “Low”, “High” or “Unknown” from −3 s to +2 s. A 3-second countdown of auditory cues at −3, −2 and −1 allowed accurate anticipation of the laser stimuli at time 0s (red bar). The presentation of the visual cue at −3 s was concurrent with the first auditory cue. At +2 s, an 11-point numerical rating scale (NRS) was presented for the participant to rate the laser stimulus.

Figure 2

The eye-blink rate (EBR) calculated for each dopamine manipulation condition produced a significant linear relationship between striatal dopamine activity and EBR (p < 0.05). The D2 receptor agonist increased the EBR and the antagonist reduced the EBR in comparison to the control condition. Data are presented as mean and 95% confidence intervals (cf. [100]).

Figure 3

Source estimates during mid-anticipation for Control versus agonist (Cabergoline) and antagonist (Amisulpride). The time window of mid anticipation [−1500–1000 ms] was baseline corrected to [−2500–2000 ms]. Clusters are shown at FWE correction and regions labelled using the AAL2 atlas. The agonist (blue) reduced activity within the right mid-temporal and angular regions in contrast to the control. The antagonist (pink) reduced activity within the right postcentral, mid-temporal, and inferior parietal regions. The xyz position of the slices are aligned with the peak-voxel at peak-level inference and reported in mm according to the MNI atlas. In comparison to the control, the agonist reduced activity within the right mid temporal and angular regions, and the antagonist reduced activity within the right postcentral, mid temporal, and inferior parietal region.

Figure 4

The drug effect reported using source localisation for post-stimulus TWOI [200 600 ms]. The TWOI was baseline corrected to −500 ms prior to the noxious stimuli. There was a significant difference between the control and antagonist conditions, showing a lower degree of activity within the right insula in the antagonist condition. The antagonist condition also reported a lower activity in comparison to the agonist within the right hippocampus, mid/inferior temporal lobe, insula, and Heschl’s gyrus.