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.
Highlights
Impaired dopaminergic transmission has been associated with chronic pain conditions [1–3] such as Fibromyalgia [4,5], atypical facial pain [6], and pain in Parkinson’s disease [7,8]
One interpretation we propose is that the dose of the agonist or antagonist was not sufficiently high enough to increase or decrease dopaminergic transmission, respectively, and instead both conditions result in a decrease/increase in dopamine signalling
The study highlights the involvement of the dopaminergic system in top-down pain processing, and its involvement in sensory integration and accurate perception, rather than pain sensitivity
Summary
Impaired dopaminergic transmission has been associated with chronic pain conditions [1–3] such as Fibromyalgia [4,5], atypical facial pain [6], and pain in Parkinson’s disease [7,8]. In terms of pain processing, recent theories of dopamine have focussed on its potential top-down modulatory function by considering its role within predictive coding, in which dopamine is hypothesised to modulate the precision (reliability) and confidence of subjective predictions about pain [27,28], such as those occurring during the anticipation of a painful event [29]. On this basis, one possibility is that the analgesic qualities of dopamine are related to the top-down cognitive and affective modulation of pain rather than modulation of afferent nociception [30–32]. There is currently a lack of evidence in support of dopamine modulating the anticipation of pain
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