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Placebo analgesia is often conceptualized as a reward mechanism. However, by targeting only negative experiences, such as pain, placebo research may tell only half the story. We compared placebo improvement of painful touch (analgesia) with placebo improvement of pleasant touch (hyperhedonia) using functional MRI and a crossover design. Somatosensory processing was decreased during placebo analgesia and increased during placebo hyperhedonia. Both placebo responses were associated with similar patterns of activation increase in circuitry involved in emotion appraisal, including the pregenual anterior cingulate, medial orbitofrontal cortex, amygdala, accumbens, and midbrain structures. Importantly, placebo-induced coupling between the ventromedial prefrontal cortex and periaqueductal gray correlated with somatosensory decreases to painful touch and somatosensory increases to pleasant touch. These findings suggest that placebo analgesia and hyperhedonia are mediated by activation of shared emotion appraisal neurocircuitry, which down-or upregulates early sensory processing, depending on whether the expectation is reduced pain or increased pleasure.expectancy | neuroimaging | hedonic feelings M edical treatments aim to provide relief from pain and aversive states. Consequently, research on placebo effects has focused on relief of negative hedonic feelings, like pain and displeasure (1). In contrast, placebo improvement of positive hedonics has received little attention. However, pain and pleasure processes are tightly linked. Relief from pain can induce a pleasant experience underpinned by activation of reward neurocircuitry (2-4). Moreover, a painful stimulus can even be perceived as pleasant when it represents relief from a more severe outcome (5). In line with this pain-pleasure link, placebo analgesia can be conceptualized as a type of reward mechanism; pain relief is a better outcome than the alternative (6-8) and is typically framed as a gain (improvement of pain) (9).Like pain, pleasure is greatly affected by context and expectation (10). Manipulation of people's beliefs about the price of a wine (11), the amount of fruit in a sweet drink (12), the richness of a skin cream (13), and who is caressing them (14) alters the experienced pleasantness of these stimuli.Placebo-induced improvement of aversive experiences (e.g., pain, anxiety, unpleasant taste) is often underpinned by a decrease in central sensory processing. Placebo analgesia is characterized by decreases in the thalamus, posterior insula (pINS), and primary and secondary somatosensory areas (SI and SII) (15)(16)(17). Placebo reduction of affective responses to unpleasant visual stimuli is similarly underpinned by suppression of visual processing (8). It is not, however, known whether placeboenhanced pleasantness (i.e., hyperhedonia) also alters early stages of sensory processing, or if this change is encoded in higher-level valuation areas.Functional neuroimaging studies have revealed that the ventromedial prefrontal cortex (vmPFC), amygdala, ventral...

The bidirectional effect of agonist and antagonist treatment aligns with rodent findings showing that MOR manipulations most strongly affect the highest-calorie foods. We speculate that the MOR system promotes survival in part by increasing concordance between the objective (caloric) and subjective (hedonic) value of food stimuli, so that feeding behavior becomes more focused on the richest food available.

Modifying behavior to maximize reward is integral to adaptive decision-making. In rodents, the μ-opioid receptor (MOR) system encodes motivation and preference for high-value rewards. Yet it remains unclear whether and how human MORs contribute to value-based decision-making. We reasoned that if the human MOR system modulates value-based choice, this would be reflected by opposite effects of agonist and antagonist drugs. In a double-blind pharmacological cross-over study, 30 healthy men received morphine (10 mg), placebo, and the opioid antagonist naltrexone (50 mg). They completed a two-alternative decision-making task known to induce a considerable bias towards the most frequently rewarded response option. To quantify MOR involvement in this bias, we fitted accuracy and reaction time data with the drift-diffusion model (DDM) of decision-making. The DDM analysis revealed the expected bidirectional drug effects for two decision subprocesses. MOR stimulation with morphine increased the preference for the stimulus with high-reward probability (shift in starting point). Compared to placebo, morphine also increased, and naltrexone reduced, the efficiency of evidence accumulation. Since neither drug affected motor-coordination, speed-accuracy trade-off, or subjective state (indeed participants were still blinded after the third session), we interpret the MOR effects on evidence accumulation efficiency as a consequence of changes in effort exerted in the task. Together, these findings support a role for the human MOR system in value-based choice by tuning decision-making towards high-value rewards across stimulus domains.

IMPORTANCE Anhedonia, a reduced capacity for pleasure, is described for many psychiatric and neurologic conditions. However, a decade after the Research Domain Criteria launch, whether anhedonia severity differs between diagnoses is still unclear. Reference values for hedonic capacity in healthy humans are also needed. OBJECTIVE To generate and compare reference values for anhedonia levels in adults with and without mental illness.

Paying attention to others' faces and eyes is a cornerstone of human social behavior. The µ-opioid receptor (MOR) system, central to social reward-processing in rodents and primates, has been proposed to mediate the capacity for affiliative reward in humans. We assessed the role of the human MOR system in visual exploration of faces and eyes of conspecifics. Thirty healthy males received a novel, bidirectional battery of psychopharmacological treatment (an MOR agonist, a non-selective opioid antagonist, or placebo, on three separate days). Eye-movements were recorded while participants viewed facial photographs. We predicted that the MOR system would promote visual exploration of faces, and hypothesized that MOR agonism would increase, whereas antagonism decrease overt attention to the information-rich eye region. The expected linear effect of MOR manipulation on visual attention to the stimuli was observed, such that MOR agonism increased while antagonism decreased visual exploration of faces and overt attention to the eyes. The observed effects suggest that the human MOR system promotes overt visual attention to socially significant cues, in line with theories linking reward value to gaze control and target selection. Enhanced attention to others' faces and eyes represents a putative behavioral mechanism through which the human MOR system promotes social interest.

The opioid system regulates affective processing, including pain, pleasure, and reward. Restricting the role of this system to hedonic modulation may be an underestimation, however. Opioid receptors are distributed widely in the human brain, including the more Bcognitive^regions in the frontal and parietal lobes. Nonhuman animal research points to opioid modulation of cognitive and decision-making processes. We review emerging evidence on whether acute opioid drug modulation in healthy humans can influence cognitive function, such as how we choose between actions of different values and how we control our behavior in the face of distracting information. Specifically, we review studies employing opioid agonists or antagonists together with experimental paradigms of reward-based decision making, impulsivity, executive functioning, attention, inhibition, and effort. Although this field is still in its infancy, the emerging picture suggests that the mu-opioid system can influence higher-level cognitive function via modulation of valuation, motivation, and control circuits dense in mu-opioid receptors, including orbitofrontal cortex, basal ganglia, amygdalae, anterior cingulate cortex, and prefrontal cortex. The framework that we put forward proposes that opioids influence decision making and cognitive control by increasing the subjective value of reward and reducing aversive arousal. We highlight potential mechanisms that might underlie the effects of mu-opioid signaling on decision making and cognitive control and provide directions for future research.

BackgroundBoth acute and chronic pain can disrupt reward processing. Moreover, prolonged prescription opioid use and depressed mood are common in chronic pain samples. Despite the prevalence of these risk factors for anhedonia, little is known about anhedonia in chronic pain populations.MethodsWe conducted a large-scale, systematic study of anhedonia in chronic pain, focusing on its relationship with opioid use/misuse, pain severity, and depression. Chronic pain patients across four distinct samples (N = 488) completed the Snaith–Hamilton Pleasure Scale (SHAPS), measures of opioid use, pain severity and depression, as well as the Current Opioid Misuse Measure (COMM). We used a meta-analytic approach to determine reference levels of anhedonia in healthy samples spanning a variety of countries and diverse age groups, extracting SHAPS scores from 58 published studies totaling 2664 psychiatrically healthy participants.ResultsCompared to healthy samples, chronic pain patients showed higher levels of anhedonia, with ~25% of patients scoring above the standard anhedonia cut-off. This difference was not primarily driven by depression levels, which explained less than 25% of variance in anhedonia scores. Neither opioid use duration, dose, nor pain severity alone was significantly associated with anhedonia. Yet, there was a clear effect of opioid misuse, with opioid misusers (COMM ⩾13) reporting greater anhedonia than non-misusers. Opioid misuse remained a significant predictor of anhedonia even after controlling for pain severity, depression and opioid dose.ConclusionsStudy results suggest that both chronic pain and opioid misuse contribute to anhedonia, which may, in turn, drive further pain and misuse.