'Defrosting' music chills with naltrexone: The role of endogenous opioids for the intensity of musical pleasure.

The endogenous opioid system has been implicated during experiences of pleasure (i.e., from food or sex). Music can elicit intense emotional and bodily sensations of pleasure, called 'Chills'. We investigated the effects of an opioid antagonist (50 mg naltrexone) or placebo (40 µg d3-vitamin) while listening to self-selected music or other 'control' music selected by another participant. We used a novel technique of continuous measurement of pleasantness with an eye tracker system, where participants shifted their eyes along a visual analogue scale, in the semblance of a thermometer so that, as the music unfolded, gaze positions indicated the self-reported hedonic experience. Simultaneously, we obtained pupil diameters. Self-reported pleasure remained unchanged by naltrexone, which - however - selectively decreased pupillary diameters during 'Chills'. Hence, the endogenous µ-opioid signaling is not necessary for subjective enjoyment of music but an opioid blockade dampens pupil responses to peak pleasure, consistent with decreased arousal to the music.

Anhedonia in chronic pain and prescription opioid misuse.

BACKGROUND: Both 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. METHODS: We 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. RESULTS: Compared 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. CONCLUSIONS: Study results suggest that both chronic pain and opioid misuse contribute to anhedonia, which may, in turn, drive further pain and misuse.

Opioid-Independent and Opioid-Mediated Modes of Pain Modulation.

Pain is regulated endogenously through both opioid and non-opioid mechanisms. We hypothesized that two novel pain modulation tasks, one drawing on context/expectations and one using voluntary reappraisal, would show differing levels of opioid dependence. Specifically, we expected that naloxone would block context-related analgesia, whereas mental imagery-based pain reappraisal would be opioid-independent.A double-blind, placebo-controlled intravenous naloxone versus saline crossover design was used. Twenty healthy volunteers completed the two modulation tasks with acute heat stimuli calibrated to induce moderate pain. In the mental imagery task, participants imagined either a "pleasant" or a "comparison" scenario during painful heat. In the relative relief task, moderate heat stimuli coincided with visual cues eliciting relief from the expectation of intense pain, and were compared with moderate heat stimuli delivered under the expectation of non-painful warmth. Both "pleasant imagery" and "relative relief" conditions significantly improved ratings of pain intensity and pleasantness during saline treatment. Indeed, the target stimuli in both tasks, which had been calibrated to induce moderate pain, were rated as mildly pleasant. Furthermore, consistently with the main hypothesis, blocking endogenous opioid signaling with naloxone did not significantly affect imagery-induced regulation of pain intensity or pleasantness. In contrast, the relative relief-induced pain regulation (i.e., context/expectation) was blocked by naloxone. We conclude that endogenous opioid signaling is necessary for expectation-related relative relief analgesia, but not for pain reappraisal through mental imagery. These results support mental imagery as a powerful and clinically relevant strategy for regulating pain affect also in patients where endogenous opioid mechanisms might be compromised.SIGNIFICANCE STATEMENT Neurotransmitter systems in the human brain can be probed through antagonist drugs. Studies using the opioid antagonist naloxone have demonstrated that the brain relies on both opioid and non-opioid mechanisms to downregulate pain. This holds clinical relevance given altered endogenous opioid processes in many chronic pain conditions. The present study used a double-blinded, placebo-controlled naloxone blockage of endogenous opioids in healthy humans to show differential opioid involvement in two pain modulation tasks. Context/expectation-driven (relative relief-related) analgesia was blocked by naloxone. In contrast, pain reappraisal through mental imagery was intact despite opioid receptor blockade, suggesting opioid independence. These results support mental imagery as a powerful, clinically relevant strategy for regulating pain as it does not rely on a functioning opioidergic system.

The role of the opioid system in decision making and cognitive control: A review.

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 "cognitive" 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.

Explaining illness with evil: pathogen prevalence fosters moral vitalism.

Pathogens represent a significant threat to human health leading to the emergence of strategies designed to help manage their negative impact. We examined how spiritual beliefs developed to explain and predict the devastating effects of pathogens and spread of infectious disease. Analysis of existing data in studies 1 and 2 suggests that moral vitalism (beliefs about spiritual forces of evil) is higher in geographical regions characterized by historical higher levels of pathogens. Furthermore, drawing on a sample of 3140 participants from 28 countries in study 3, we found that historical higher levels of pathogens were associated with stronger endorsement of moral vitalistic beliefs. Furthermore, endorsement of moral vitalistic beliefs statistically mediated the previously reported relationship between pathogen prevalence and conservative ideologies, suggesting these beliefs reinforce behavioural strategies which function to prevent infection. We conclude that moral vitalism may be adaptive: by emphasizing concerns over contagion, it provided an explanatory model that enabled human groups to reduce rates of contagious disease.

Placebo improves pleasure and pain through opposite modulation of sensory processing.

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 up-regulates early sensory processing, depending on whether the expectation is reduced pain or increased pleasure.

Baseline reward circuitry activity and trait reward responsiveness predict expression of opioid analgesia in healthy subjects.

Variability in opioid analgesia has been attributed to many factors. For example, genetic variability of the µ-opioid receptor (MOR)-encoding gene introduces variability in MOR function and endogenous opioid neurotransmission. Emerging evidence suggests that personality trait related to the experience of reward is linked to endogenous opioid neurotransmission. We hypothesized that opioid-induced behavioral analgesia would be predicted by the trait reward responsiveness (RWR) and the response of the brain reward circuitry to noxious stimuli at baseline before opioid administration. In healthy volunteers using functional magnetic resonance imaging and the µ-opioid agonist remifentanil, we found that the magnitude of behavioral opioid analgesia is positively correlated with the trait RWR and predicted by the neuronal response to painful noxious stimuli before infusion in key structures of the reward circuitry, such as the orbitofrontal cortex, nucleus accumbens, and the ventral tegmental area. These findings highlight the role of the brain reward circuitry in the expression of behavioral opioid analgesia. We also show a positive correlation between behavioral opioid analgesia and opioid-induced suppression of neuronal responses to noxious stimuli in key structures of the descending pain modulatory system (amygdala, periaqueductal gray, and rostral-ventromedial medulla), as well as the hippocampus. Further, these activity changes were predicted by the preinfusion period neuronal response to noxious stimuli within the ventral tegmentum. These results support the notion of future imaging-based subject-stratification paradigms that can guide therapeutic decisions.

The Positive Consequences of Pain: A Biopsychosocial Approach.

Pain is mostly thought of as a problem-as debilitating or harmful. Despite its unpleasantness, however, under some conditions pain can be associated with positive consequences. In this review, we explore these positive biological, psychological, and social consequences of pain. We highlight three different domains in which pain may be considered to have positive consequences. First, pain facilitates pleasure by providing an important contrast for pleasurable experiences, increasing sensitivity to sensory input, and facilitating self-rewarding behavior. Second, pain augments self-regulation and enhancement by increasing cognitive control, reducing rumination, and demonstrating virtue. Third, pain promotes affiliation by arousing empathy from others, motivating social connection, and enhancing group formation. Drawing on evidence scattered across a range of academic fields, we provide for reflection on how pain is represented, generate insights into pain-seeking behavior, and draw attention to the role of painful experiences in maximizing positive outcomes.

Endogenous mu-opioid modulation of social connection in humans: a systematic review and meta-analysis.

Social bonding, essential for health and survival in all social species, depends on mu-opioid signalling in non-human mammals. A growing neuroimaging and psychopharmacology literature also implicates mu-opioids in human social connectedness. To determine the role of mu-opioids for social connectedness in healthy humans, we conducted a preregistered ( https://osf.io/x5wmq ) multilevel random-effects meta-analysis of randomised double-blind placebo-controlled opioid antagonist studies. We included data from 8 publications and 2 unpublished projects, totalling 17 outcomes (N = 455) sourced from a final literature search in Web of Science, Scopus, PubMed and EMBASE on October 12, 2023, and through community contributions. All studies used naltrexone (25-100 mg) to block the mu-opioid system and measured social connectedness by self-report. Opioid antagonism slightly reduced feelings of social connectedness (Hedges' g [95% CI) = -0.20] [-0.32, -0.07]. Results were highly consistent within and between studies (I2 = 23%). However, there was some indication of bias in favour of larger effects among smaller studies (Egger's test: B = -2.16, SE = 0.93, z = -2.33, p = 0.02), and publication bias analysis indicated that the effect of naltrexone might be overestimated. The results clearly demonstrate that intact mu-opioid signalling is not essential for experiencing social connectedness, as robust feelings of connectedness are evident even during full pharmacological mu-opioid blockade. Nevertheless, antagonism reduced measures of social connection, consistent with a modulatory role of mu-opioids for human social connectedness. The modest effect size relative to findings in non-human animals, could be related to differences in measurement (subjective human responses versus behavioural/motivation indices in animals), species specific neural mechanisms, or naltrexone effects on other opioid receptor subtypes. In sum, these results help explain how mu-opioid dysregulation and social disconnection can contribute to disability, and conversely-how social connection can buffer risk of ill health.

Impact of childhood adversity on acute subjective effects of stimulant and opioid drugs: Evidence from placebo-controlled studies in healthy volunteers.

BACKGROUND AND AIMS: Early-life adversities are known to alter drug reward processing in rodents. Despite the well-known link between early adversity and the risk of substance use disorder, few studies have measured how childhood adversity affects human drug reward. Here, we assessed the relationship between historical childhood adversities and responses to single doses of methamphetamine, d-amphetamine or buprenorphine in healthy participants. METHODS: Using a secondary analysis approach, we assessed the impact of childhood adversity on drug effects from three randomised, placebo-controlled studies in which healthy volunteers received methamphetamine (20 mg oral; n = 35), d-amphetamine (20 mg oral; n = 54) or buprenorphine (0.2 mg sublingual; n = 35). Ratings of feeling effect, liking, disliking, feeling high and wanting more of the drug were collected 15-210 min post-administration, and heart rate changes were analysed using random-intercept mixed-effect models. The area under the curve from these and previous studies was calculated to visualise the relationship between childhood adversity severity and drug effects. RESULTS: Greater childhood adversity was associated with reduced feel effects (significant three-way interactions b = -0.07, 95% CI [-0.12, -0.02], p = 0.009), like effects (b = -0.07, 95% CI [-0.13, -0.00], p = 0.038) and feel high (b = -0.06, 95% CI [-0.10, -0.01], p = 0.020) towards the stimulant drugs 90-180 min post-administration. CONCLUSIONS: Childhood adversity was not significantly associated with other subjective or heart rate responses to the drugs. Overall, participants with more childhood adversities reported dampened subjective responses to stimulant drugs, but not to buprenorphine. Future studies should examine the generalisability of these relationships, to identify the mechanisms underlying the link between childhood adversity and drug responsiveness.

Factors associated with use of opioid rescue medication after surgery.

BACKGROUND: Opioid exposure after surgery increases risk of persistent opioid use. Here, we characterize at-home use of opioid rescue medication during 1-2 days after outpatient surgery (N=270) in a postoperative opioid-sparing context at a Norwegian hospital. METHODS: The postsurgical pain management plan included non-steroidal anti-inflammatory drugs and up to six pills of 5 mg oxycodone as rescue analgesics. In this observational study we assessed risk factors for taking rescue opioids after surgery, by comparing patients who did, with those who did not. RESULTS: Only 35% (N=228) of patients reported taking rescue opioids 1-2 days after discharge. Patients taking rescue opioids after surgery (opioid-takers) differed from non-takers by prevalence of preoperative chronic pain (>3 months; 74% vs 48%), higher pain severity and interference before and after surgery, reporting lower ability to cope with postsurgical pain, higher nervousness about the surgery, being younger, and having received more opioid analgesics in the recovery room. Exploratory predictive modeling identified opioid administration in the recovery room as the most important predictor of at-home rescue medication use. Follow-up after >4 months indicated low acute pain levels (mean±SD = 1.1±1.8), with only four patients (2%, N=217) reporting opioid analgesic use. CONCLUSION: Factors related to at-home rescue medication use closely mirrored known risk factors for persistent opioid use after surgery, such as prior chronic pain, prior substance use, affective disturbances, and pain severity before surgery. These findings are potential targets in patient-centered care. Nevertheless, and reassuringly, findings are consistent with the idea that opioid-sparing postsurgical care can prevent large-scale chronic opioid use.

Supraphysiological testosterone levels from anabolic steroid use and reduced sensitivity to negative facial expressions in men.

RATIONALE: Anabolic-androgenic steroids (AAS) are used to improve physical performance and appearance, but have been associated with deficits in social cognitive functioning. Approximately 30% of people who use AAS develop a dependence, increasing the risk for undesired effects. OBJECTIVES: To assess the relationship between AAS use (current/previous), AAS dependence, and the ability to recognize emotional facial expressions, and investigate the potential mediating role of hormone levels. METHODS: In total 156 male weightlifters, including those with current (n = 45) or previous (n = 34) AAS use and never-using controls (n = 77), completed a facial Emotion Recognition Task (ERT). Participants were presented with faces expressing one out of six emotions (sadness, happiness, fear, anger, disgust, and surprise) and were instructed to indicate which of the six emotions each face displayed. ERT accuracy and response time were recorded and evaluated for association with AAS use status, AAS dependence, and serum reproductive hormone levels. Mediation models were used to evaluate the mediating role of androgens in the relationship between AAS use and ERT performance. RESULTS: Compared to never-using controls, men currently using AAS exhibited lower recognition accuracy for facial emotional expressions, particularly anger (Cohen's d = -0.57, pFDR = 0.03) and disgust (d = -0.51, pFDR = 0.05). Those with AAS dependence (n = 47) demonstrated worse recognition of fear relative to men without dependence (d = 0.58, p = 0.03). Recognition of disgust was negatively correlated with serum free testosterone index (FTI); however, FTI did not significantly mediate the association between AAS use and recognition of disgust. CONCLUSIONS: Our findings demonstrate impaired facial emotion recognition among men currently using AAS compared to controls. While further studies are needed to investigate potential mechanisms, our analysis did not support a simple mediation effect of serum FTI.

A common neurobiology for pain and pleasure.

Pain and pleasure are powerful motivators of behaviour and have historically been considered opposites. Emerging evidence from the pain and reward research fields points to extensive similarities in the anatomical substrates of painful and pleasant sensations. Recent molecular-imaging and animal studies have demonstrated the important role of the opioid and dopamine systems in modulating both pain and pleasure. Understanding the mutually inhibitory effects that pain and reward processing have on each other, and the neural mechanisms that underpin such modulation, is important for alleviating unnecessary suffering and improving well-being.

Opioid antagonism in humans: a primer on optimal dose and timing for central mu-opioid receptor blockade.

Non-human animal studies outline precise mechanisms of central mu-opioid regulation of pain, stress, affiliation and reward processing. In humans, pharmacological blockade with non-selective opioid antagonists such as naloxone and naltrexone is typically used to assess involvement of the mu-opioid system in such processing. However, robust estimates of the opioid receptor blockade achieved by opioid antagonists are missing. Dose and timing schedules are highly variable and often based on single studies. Here, we provide a detailed analysis of central opioid receptor blockade after opioid antagonism based on existing positron emission tomography data. We also create models for estimating opioid receptor blockade with intravenous naloxone and oral naltrexone. We find that common doses of intravenous naloxone (0.10-0.15 mg/kg) and oral naltrexone (50 mg) are more than sufficient to produce full blockade of central MOR (>90% receptor occupancy) for the duration of a typical experimental session (~60 min), presumably due to initial super saturation of receptors. Simulations indicate that these doses also produce high KOR blockade (78-100%) and some DOR blockade (10% with naltrexone and 48-74% with naloxone). Lower doses (e.g., 0.01 mg/kg intravenous naloxone) are estimated to produce less DOR and KOR blockade while still achieving a high level of MOR blockade for ~30 min. The models and simulations form the basis of two novel web applications for detailed planning and evaluation of experiments with opioid antagonists. These tools and recommendations enable selection of appropriate antagonists, doses and assessment time points, and determination of the achieved receptor blockade in previous studies.

The partial µ-opioid agonist buprenorphine in autism spectrum disorder: a case report.

BACKGROUND: There are currently no approved medications for impaired social cognition and function, core symptoms of autism spectrum disorder. We describe marked improvement of these symptoms with long-term low-dose administration of the partial µ-opioid agonist buprenorphine. We discuss these observations in the context of a role for endogenous opioid systems in social attachment, and theories integrating those findings mechanistically with autism spectrum disorder. CASE PRESENTATION: M, a 43-year-old Caucasian male, is medically healthy. Despite social difficulties since childhood, he completed high school with better-than-average grades, but failed university education. A psychiatric evaluation in his twenties diagnosed attention deficit hyperactivity disorder but also noted symptoms of coexisting autism spectrum disorder. M accidentally came across buprenorphine in his late twenties and experienced progressively improved social functioning on a low daily dosage (0.5-1.0 mg/day), an effect maintained for 15 years. He lived independently and maintained a part-time occupation. After abrupt discontinuation of treatment, his autistic symptoms returned, and function deteriorated. Following evaluation by our team, buprenorphine was resumed, with gradual return to prior level of functioning. An attempt to formally evaluate M both on and off medication was agreed with him and approved by the Swedish Ethics Authority, but medication had to be resumed when the patient worsened following discontinuation. CONCLUSIONS: According to the µ-opioid receptor balance model, both excessive and deficient µ-receptor activity may negatively influence social behavior, and accordingly both opioid agonist and opioid antagonist treatment may be able to improve social functioning, depending on an individual's opioid tone before treatment. Our case report is consistent with these hypotheses, and given the extensive unmet medical needs in individuals with autism spectrum disorders, randomized controlled trial appears warranted.

Emotional distress and pain catastrophizing predict cue-elicited opioid craving among chronic pain patients on long-term opioid therapy.

BACKGROUND: Individuals who use illicit substances exhibit cue-elicited craving and autonomic cue-reactivity when exposed to cues associated with past drug use. However, little is known about this phenomenon among chronic pain patients on long-term opioid therapy (LTOT). Negative cognitive-emotional reactivity in general (e.g., distress) and cognitive-emotional reactivity specific to pain (e.g., pain catastrophizing) might drive cue-reactivity independent of pain severity. Here we examined emotional distress and pain catastrophizing as predictors of cue-reactivity among a sample of chronic pain patients receiving LTOT. We also tested whether associations between distress, catastrophizing, and cue-reactivity differed as a function of opioid misuse status. MATERIALS AND METHODS: Patients receiving LTOT (N = 243) were classified as exhibiting aberrant behavior consistent with opioid misuse (MISUSE+, n = 145) or as using opioids as prescribed (MISUSE-, n = 97). Participants completed assessments of pain catastrophizing and emotional distress and then participated in an opioid cue-reactivity task one week later. Cue-elicited opioid craving and autonomic cue-reactivity were measured with craving ratings and high-frequency heart rate variability (HRV), respectively. RESULTS: Distress and catastrophizing predicted cue-elicited craving and HRV, whereas pain severity did not. Misuser status moderated the relationship between emotional distress and self-reported craving, such that higher levels of distress predicted craving among the MISUSE+ group, but not among the MISUSE- group. No moderating effects were found for catastrophizing. CONCLUSIONS: Findings suggest that although opioids are prescribed for analgesia, the exacerbating influence of negative cognitive-emotional reactivity, both in general and specific to pain, on cue-elicited opioid craving extends beyond the effects of pain severity alone.

Stress recovery with social support: A dyadic stress and support task.

How does social support bolster resilience? Here, we present a new dyadic paradigm to study causal mechanisms of acute and ecologically valid social support in the laboratory. The Dyadic Stress and Support Task (DSST) consists of a psychosocial stress phase and a recovery phase. During DSST stress, a pair of participants take turns to perform public speaking and mental arithmetic in front of a panel. Unable to see or touch each other, they witness each other's performance and feedback. During DSST recovery, the pair either interact freely with each other for 5 min (social support condition) or interact separately with an experimenter (non-support condition). To establish the validity of the DSST, we tested 21 pairs of long-term close friends in a pilot study. Primary outcome measures were ratings of affective state and bodily arousal (VAS scales 0-100). Secondary outcome measures were heart rate and salivary cortisol. DSST stress successfully induced subjective Stress Activation, increased Negative Affect and decreased Positive Affect. We also observed increased heart rate and salivary cortisol. After DSST recovery, Stress Activation and Negative Affect ratings were reduced in both groups. Positive Affect was completely restored to pre-stress baseline levels in the Social support group, while remaining significantly lower in the Non-support group. The DSST successfully induced stress and negative affect and captured stress recovery in both groups. Free-form interaction with the friend enhanced recovery of affective state, supporting the validity of spontaneous interaction between friends as a model of social support.