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Dopamine-based reward and learning mechanisms have been suggested to contribute to placebo effects. However, the exact role of dopaminergic neurotransmission in their generation and maintenance is still unclear. This study aimed to shed light on the causal role of dopamine in establishing positive treatment expectations, as well as on the magnitude and duration of their effect on pain. To this end, we used an established placebo analgesia paradigm in combination with 2 opposing pharmacological modulations of dopaminergic tone, i.e., the dopamine antagonist sulpiride and the dopamine precursor L-dopa which were both applied in an experimental, double-blind, randomized, placebo-controlled trial with a between-subject design in N = 168 healthy volunteers. The study medication successfully altered dopaminergic tone during the conditioning procedure. Contrary to our hypotheses, the medication did not modulate the formation of positive treatment expectation and placebo analgesia tested 1 day later. Placebo analgesia was no longer detectable on day 8 after conditioning. Using a combined frequentist and Bayesian approach, our data provide strong evidence against a direct dopaminergic influence on the generation and maintenance of placebo effects. Further exploration of the neurochemical mechanisms underlying placebo analgesia remains paramount in the quest to exploit these effects for optimal treatment outcomes. Trial registration: ClinicalTrials.gov German Clinical Trials Register, ID: DRKS00029366, https://drks.de/search/en/trial/DRKS00029366. Dopamine signalling has been linked to pain analgesia and placebo effects but whether there is causal relationship remains unclear. This pre-registered study shows that enhancing dopaminergic tone does not alter the generation of positive treatment expectations or placebo analgesia. [ABSTRACT FROM AUTHOR]

Prior information about features of a stimulus is a strong modulator of perception. For instance, the prospect of more intense pain leads to an increased perception of pain, whereas the expectation of analgesia reduces pain, as shown in placebo analgesia and expectancy modulations during drug administration. This influence is commonly assumed to be rooted in altered sensory processing and expectancy-related modulations in the spinal cord, are often taken as evidence for this notion. Contemporary models of perception, however, suggest that prior information can also modulate perception by biasing perceptual decision-making - the inferential process underlying perception in which prior information is used to interpret sensory information. In this type of bias, the information is already present in the system before the stimulus is observed. Computational models can distinguish between changes in sensory processing and altered decision-making as they result in different response times for incorrect choices in a perceptual decision-making task (Figure S1A,B). Using a drift-diffusion model, we investigated the influence of both processes in two independent experiments. The results of both experiments strongly suggest that these changes in pain perception are predominantly based on altered perceptual decision-making.

Prior information about features of a stimulus is a strong modulator of perception. For instance, the prospect of more intense pain leads to an increased perception of pain, whereas the expectation of analgesia reduces pain, as shown in placebo analgesia and expectancy modulations during drug administration. This influence is commonly assumed to be rooted in altered sensory processing and expectancy-related modulations in the spinal cord, are often taken as evidence for this notion. Contemporary models of perception, however, suggest that prior information can also modulate perception by biasing perceptual decision-making - the inferential process underlying perception in which prior information is used to interpret sensory information. In this type of bias, the information is already present in the system before the stimulus is observed. Computational models can distinguish between changes in sensory processing and altered decision-making as they result in different response times for incorrect choices in a perceptual decision-making task (Figure S1A,B). Using a drift-diffusion model, we investigated the influence of both processes in two independent experiments. The results of both experiments strongly suggest that these changes in pain perception are predominantly based on altered perceptual decision-making.

This scientific commentary discusses a study by Schenk et al. that explores the potential for side effects to enhance the efficacy of a drug. The study involved 77 healthy volunteers who were given a placebo nasal spray, either alone or with experimentally induced side effects. The results showed that the placebo with side effects led to a stronger analgesic effect and increased engagement of the pain modulatory network in the brain. The study suggests that the belief that more potent treatments have more side effects can influence treatment expectations and outcomes. However, it is important to consider the limitations and ethical implications of using side effects to enhance treatment effectiveness. [Extracted from the article]

Recent research on moral decision-making has suggested that many common moral judgments are based on immediate intuitions. However, some individuals arrive at highly counterintuitive utilitarian conclusions about when it is permissible to harm other individuals. Such utilitarian judgments have been attributed to effortful reasoning that has overcome our natural emotional aversion to harming others. Recent studies, however, suggest that such utilitarian judgments might also result from a decreased aversion to harming others, due to a deficit in empathic concern and social emotion. The present study investigated the neural basis of such indifference to harming using functional neuroimaging during engagement in moral dilemmas. A tendency to counterintuitive utilitarian judgment was associated both with "psychoticism", a trait associated with a lack of empathic concern and antisocial tendencies, and with "need for cognition", a trait reflecting preference for effortful cognition. Importantly, only psychoticism was also negatively correlated with activation in the subgenual cingulate cortex (SCC), a brain area implicated in empathic concern and social emotions such as guilt, during counterintuitive utilitarian judgments. Our findings suggest that when individuals reach highly counterintuitive utilitarian conclusions, this need not reflect greater engagement in explicit moral deliberation. It may rather reflect a lack of empathic concern, and diminished aversion to harming others. (Contains 4 figures and 4 footnotes.)