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W4323310426 abstract "Article Figures and data Abstract Editor's evaluation Introduction Results Discussion Materials and methods Data availability References Decision letter Author response Article and author information Metrics Abstract Relief of ongoing pain is a potent motivator of behavior, directing actions to escape from or reduce potentially harmful stimuli. Whereas endogenous modulation of pain events is well characterized, relatively little is known about the modulation of pain relief and its corresponding neurochemical basis. Here, we studied pain modulation during a probabilistic relief-seeking task (a ‘wheel of fortune’ gambling task), in which people actively or passively received reduction of a tonic thermal pain stimulus. We found that relief perception was enhanced by active decisions and unpredictability, and greater in high novelty-seeking trait individuals, consistent with a model in which relief is tuned by its informational content. We then probed the roles of dopaminergic and opioidergic signaling, both of which are implicated in relief processing, by embedding the task in a double-blinded cross-over design with administration of the dopamine precursor levodopa and the opioid receptor antagonist naltrexone. We found that levodopa enhanced each of these information-specific aspects of relief modulation but no significant effects of the opioidergic manipulation. These results show that dopaminergic signaling has a key role in modulating the perception of pain relief to optimize motivation and behavior. Editor's evaluation This is an important paper that is of interest to researchers interested in the psychological and neurochemical mechanisms of pain and pain relief. It shows that the perception of pain relief is modulated by controllability, surprise and novelty seeking. Moreover, these modulations are influenced by dopaminergic but not by opioidergic manipulations. These findings are supported by convincing evidence. https://doi.org/10.7554/eLife.81436.sa0 Decision letter Reviews on Sciety eLife's review process Introduction One of the most powerful and universally appreciated aspects of being in pain is the desire for relief, and the positive sensation of pleasure once achieved. However, in contrast to pain itself, much less is known about how the perception of relief is modulated by various behavioral and motivational factors (Becker et al., 2015; Leknes et al., 2008). Theories of pain have suggested that one reason pain itself is modulated is to help optimize the way in which it directs protective behavior (Walters and Williams, 2019). For instance, if pain is increased when learning and responding to it, but reduced in situations in which pain might actually interfere with optimal behavior will have a greater long-term benefit (Fields, 2018; Seymour, 2019). Whether this principle extends to relief has not been tested. Endogenous modulation of pain involves a number of different processes mediated by distinct descending signaling pathways, and involves at least two critical neurochemical systems: opioidergic and dopaminergic (Bannister, 2019). For instance, opioid signaling has been shown to play a key role in behavioral relief motivation (in rodents, Navratilova et al., 2015b), placebo analgesia (Benedetti, 1996; Eippert et al., 2009), conditioned pain modulation (King et al., 2013), and relief perception (Sirucek et al., 2021). Dopaminergic signaling has clearly been shown to play a role in conditioned place preference induced by pain relief (through activity in midbrain dopaminergic neurons, Navratilova et al., 2012; Navratilova et al., 2015a; Xie et al., 2014), suggesting similar mechanisms as in the well-studied role of dopamine in food rewards (dopaminergic ‘wanting’ versus opioidergic ‘liking’; Barbano and Cador, 2006; Barbano and Cador, 2007; Berridge et al., 2009; Smith et al., 2011). Dopaminergic signaling is also implicated in inhibition of pain by extrinsic rewards, that is rewards external to the pain system (Becker et al., 2013). Hence, whilst it is clear that both opioidergic and dopaminergic signaling play core roles in relief motivation, it isn’t known which system primarily shapes perceived relief as a function of motivation. The aim of the present study was therefore first to better characterize information processing aspects of relief motivation, and second to investigate the roles of dopaminergic and opioidergic signaling in pain relief perception and modulation. We expected that pain relief would be modulated by the value of information it carries, as hence enhanced by (i) active vs passive reception and thus controllability, since this reflects potential to exploit relief information; (ii) unpredictability, since this reflects the extra information carried by surprising events, and (iii) trait novelty-seeking, since this reflects individual information sensitivity. At the same time, we aimed to identify the potential role of dopamine and opioids for each of these factors, in particular to explore whether increased dopamine availability would enhance endogenous pain relief under these conditions, and whether modulation could be reduced by blocking opioid receptors. We expected increased dopamine availability to enhance phasic release of dopamine in response to rewards, and hence, to increase the effect of active compared to passive reception of pain relief. In contrast, we expected the inhibition of endogenous opioid signaling to decrease the effect of active controllability on pain relief. The latter is based on the observation that blocking of opioid receptors attenuates other types of endogenous pain inhibition such as placebo analgesia (Benedetti, 1996; Eippert et al., 2009) or conditioned pain modulation (King et al., 2013). Finally, we aimed to identify whether an increase or decrease in the modulation of perceived relief by dopamine and opioids is reflected in corresponding increases or decreases in the selection of a more advantageous option, that is decision-making during probabilistic learning. To test these hypotheses, we employed a previously developed wheel of fortune task utilizing relief of a tonic capsaicin-sensitive thermal pain stimulus as ‘wins’, and allowing to quantify endogenous pain inhibition induced by gaining pain relief in active versus passive conditions (Becker et al., 2015). To test the roles of dopamine and opioids, we analyzed and report data of N=28 healthy volunteers who ingested either a single dose of the dopamine precursor levodopa (150 mg), the opioid antagonist naltrexone (50 mg), or placebo in separate testing sessions (double-blinded, placebo controlled cross-over, i.e. within-subjects, design). To allow also the assessment of reinforcement learning, a probabilistic reward schedule associated with the participants’ choices in the wheel of fortune was implemented. Results Endogenous modulation of active pain relief seeking under placebo To test whether playing the wheel of fortune game induced endogenous pain inhibition by gaining pain relief during active (controllable) decision-making, a test condition in which participants actively engaged in the game and ‘won’ relief of a tonic thermal pain stimulus in the game was compared to a control condition with passive receipt of the same outcomes (Figure 1). As a further comparator the game included an opposite condition in which participants received increases of the thermal stimulation as punishment. This active loss condition was also matched by a passive condition involving receipt of the same course of nociceptive input. We implemented two outcome measures, an explicit rating of perceived intensity after pain relief or increase, and a behavioral measure of perceptual sensitization or habituation to the underlying tonic stimulation within each trial of the game (see Figure 1). The effects of controllability on pain perception were tested in separate linear mixed effects models predicting the outcome measures by the outcome condition, the trial type (active test trials vs. passive control trials), and their interaction in each drug condition. Comparing the effects of active versus passive trials between the pain relief and the pain increase condition (interaction ‘outcome × trial type’) allowed also to test for unspecific effects of arousal and/or distraction: if the effects seen in the active compared to the passive condition were due to such unspecific effects then actively engaging in the game should equally affect pain in both, win and lose trials. In contrast, if the effects were due to increased controllability then we expected to see pain inhibition in win trials but equal or increased pain perception in lose trials. We used post-hoc comparisons to test direction and significance of differences in either outcome condition and report standardized effect sizes (d) for these differences. Note that all reported effect sizes account for random variation within the sample, providing an estimate for the underlying population; due to considerable variance between participants in the present study, this resulted in comparatively small effect sizes. Figure 1 Download asset Open asset Time line of one trial with active decision-making (test trials) of the wheel of fortune game. Experimental pain was implemented using contact heat stimulation on capsaicin sensitized skin on the forearm. In each trial, the temperature increased from a baseline of 30 °C to a predetermined moderately painful stimulation intensity perceived as moderately painful. In each testing session, one of the two colors (pink and blue) of the wheel was associated with a higher chance to win pain relief (counterbalanced across subjects and drug conditions). Pain relief (win) as outcome of the wheel of fortune game (depicted in green) and, pain increase (loss; depicted in red) were implemented as phasic changes in stimulation intensity offsetting from the tonic painful stimulation. Based on a probabilistic reward schedule for these outcomes, participants could learn which color was associated with a better chance to win pain relief. In passive control trials and neutral trials participants did not play the game but had to press a black button after which the wheel started spinning and landed on a random position with no pointer on the wheel. Trials with active decision-making were matched by passive control trials without decision making but the same nociceptive input (control trials), resulting in the same number of pain increase and pain decrease trials as in the active condition. In neutral trials the temperature did not change during the outcome interval of the wheel. Two outcome measures were implemented in all trial types: (i) after the phasic changes during the outcome phase participants rated the perceived momentary intensity of the stimulation on a visual analogue scale (‘VAS intensity’); (ii) after this rating, participants had to adjust the temperature to match the sensation they had memorized at the beginning of the trial, i.e. the initial perception of the tonic stimulation intensity (‘self-adjustment of temperature’). This perceptual discrimination task served as a behavioral assessment of pain sensitization and habituation across the course of one trial. One trial lasted approximately 30 s, phasic offsets occurred after approximately 10 s of tonic pain stimulation. Adapted from Becker et al., 2015. Figure 1 is reproduced from Figure 1 in Becker et al., 2015. Ratings of perceived pain Replicating previous results, in the placebo (i.e. non-drug) condition participants rated the thermal stimulation as less intense after actively winning pain relief compared to the passive control condition, as rated on visual analogue scales (VAS) from ‘no sensation’ (0) over ‘just painful’ (100) to ‘most intense pain tolerable’ (200). Furthermore, participants also rated the stimulation as more intense after actively losing compared to the passive control condition (Figure 2A; interaction ‘outcome × trial type’, F(1,1040)=64.14, p<0.001; pairwise comparisons: win: test vs. control p<0.001, standardized effect size d=0.16; lose: test vs. control, p<0.001, d=0.27). This shows that perception of both relief and pain are enhanced by active (instrumental) controllability, as hypothesized. Figure 2 with 1 supplement see all Download asset Open asset Effects of active versus passive condition after pain relief and pain increase in each drug condition. Means (bars) and 95% confidence intervals of means (error bars) for VAS pain intensity ratings (A, B, C) and behaviorally assessed pain perception (D, E, F; within-trial sensitization in pain perception in °C) for each drug session (placebo: n=28, levodopa: n=27, naltrexone: n=28). d indicates the standardized effect size after controlling for random effects and residual variance. ** p<0.01, *** p<0.001, for post-hoc comparisons of test versus control trials. Behaviorally assessed pain perception In addition to the VAS ratings, participants performed a validated perceptual task (Becker et al., 2011; Kleinböhl et al., 1999) allowing to assess perception of the underlying tonic pain stimulus, which is specifically sensitive to perceptual sensitization and habituation. In this procedure, participants re-adjust the stimulation temperature themselves after the outcome of the wheel of fortune to match their perception at the beginning of each trial. Positive values (i.e. lower self-adjusted temperatures compared to the stimulation intensity at the beginning of the trial) indicate perceptual sensitization across the course of one trial of the game, negative values indicate habituation. For tonic stimulation at intensities that are perceived as painful, perceptual sensitization is expected to occur (Kleinböhl et al., 1999). Differences between the outcome conditions (win, lose) reflect the effect of the phasic changes on the perception of the underlying tonic stimulus. Differences between active and passive trials reflect the effect of controllability on the perception within each outcome condition. In contrast to the VAS ratings, behaviorally assessed pain perception did not significantly differ between test and control trials after winning as well as after losing in the placebo condition (Figure 2D; interaction ‘outcome × trial type’, F(1, 1040)=2.53, p=0.112). Levodopa increases endogenous pain modulation by active relief with no significant effects of naltrexone on the modulation We next examined whether endogenous modulation of pain perception within the wheel of fortune game was affected by a levodopa and naltrexone. Manipulation check: successful blinding of drug conditions After the intake of levodopa, one participant reported a weak feeling of nausea and headaches at the end of the experimental session. In 32 out of 83 experimental sessions subjects reported tiredness at the end of the session. However, the frequency did not significantly differ between the three drug conditions (χ2 (2)=2.17, p=0.337) or between the placebo condition compared to the levodopa and naltrexone condition (χ2 (1)=1.06, p=0.304). No other side effects were reported. To ensure that participants were kept blinded throughout the testing, they were asked to report at the end of each testing session whether they thought they received levodopa, naltrexone, placebo, or did not know. In 43 out of 83 sessions that were included in the analysis (52%), participants reported that they did not know which drug they received. In 12 out of 28 sessions (43%), participants were correct in assuming that they had ingested the placebo, in 6 out of 27 sessions (22%) levodopa, and in 2 out of 28 sessions (7%) naltrexone. The amount of correct assumptions differed between the drug conditions (χ2 (2)=7.70, p=0.021). However, post-hoc tests revealed that neither in the levodopa nor in the naltrexone condition participants guessed the correct pharmacological manipulation significantly above chance level (p’s>0.997) and the amount of correct assumptions did not differ significantly between placebo compared to levodopa and naltrexone sessions on the other hand (χ2 (1)=0.11, p=0.737), suggesting that the blinding was successful. Effects of pharmacological manipulations on endogenous modulation by active controllability We next examined whether endogenous modulation of pain perception within the wheel of fortune game was affected by a levodopa and naltrexone. In addition to the models testing effects of controllability on pain perception within each drug condition, we calculated pain modulation in test trials for both outcome measures as the difference of each test trial to the mean of control trials for the respective outcome condition for each participant. We fitted linear mixed effects models to predict pain modulation by drug condition, outcome, and their interaction. As an additional covariate of no interest we included session order (and respective interaction effects) in these models, as the temporal order of sessions (independent of the order of the application of the drugs) was found to have a differential effect on win and lose outcomes (see Figure 3—figure supplement 1). Ratings of perceived pain As in the placebo condition, participants rated the thermal stimulation as significantly less intense after active relief winning in the wheel of fortune task, and as significantly more intense after receiving phasic pain increases (‘losing’) compared to the respective passive control condition under levodopa (pairwise comparisons: win: test vs. control p<0.001, d=0.31; lose: test vs. control, p<0.001, d=0.32; Figure 2B) as well as naltrexone (pairwise comparisons: win: test vs. control p<0.001, d=0.22; lose: test vs. control, p<0.001, d=0.27; Figure 2C). Moreover, the effect of active relief or increases on pain modulation was differentially modulated by the drugs (Table 1; interaction ‘drug × outcome’, F(2, 1587.30)=4.52, p=0.011). Specifically, the effect of active relief on perception was significantly larger in the levodopa condition compared to the placebo condition (post-hoc comparison p=0.007, d=0.23; Figure 3A). No significant difference was found for the naltrexone compared to the placebo condition (p=0.252, d=0.12). Endogenous modulation did not significantly differ between the levodopa and the naltrexone condition (p=0.368, d=0.11). Endogenous pain facilitation induced by actively receiving pain increases assessed with VAS ratings did not significantly differ between any drug conditions (all post-hoc comparisons p’s>0.591). Table 1 Means and standard deviation of means for pain modulation in VAS ratings of perceived intensity and the behaviorally assessed pain perception (negative values indicate pain inhibition; positive values indicate pain facilitation). Pain modulation in VAS ratings of pain intensityPain modulation in behavioral measure (°C)placebolevodopanaltrexoneplacebolevodopanaltrexonen=28n=27n=28n=28n=27n=28OutcomeMSDMSDMSDMSDMSDMSDwin–7.3121.51–12.9823.54–10.0923.79–0.090.64–0.140.66–0.050.74lose12.2121.1213.2920.4812.2622.270.030.590.030.540.060.68 Behaviorally assessed pain perception In contrast to the placebo condition, participants showed significantly less behaviorally assessed sensitization in active compared to passive trials when obtaining pain relief under levodopa (pairwise comparison test vs. control: p=0.020, d=0.11; Figure 2E) consistent with an extension of pain-inhibitory effects of winning pain relief through to the underlying tonic pain stimulus. Under naltrexone, test and control trials did not significantly differ in the behaviorally assessed pain perception (Figure 2F) as for the placebo condition. Across drugs, behaviorally assessed pain modulation did not significantly differ between placebo, levodopa, and naltrexone (interaction ‘drug × outcome’: F(2, 1592.73)=1. 87, p=0.154; Figure 3B). Figure 3 with 4 supplements see all Download asset Open asset Effects of drug manipulation on endogenous pain modulation. Effects of drug manipulation on endogenous pain modulation assessed by VAS ratings of pain intensity (A) and behaviorally assessed pain perception (B) after winning and losing in the wheel of fortune game, respectively (placebo: n=28, levodopa: n=27, naltrexone: n=28). Bars show group level means and error bars show 95% confidence interval of the group level mean. d indicates the standardized effect-size after controlling for random effects and residual variance. While the temporal order of sessions did affect pain modulation (Figure 3—figure supplement 1), measures of pain sensitivity, that were not experimentally manipulated (Figure 3—figure supplement 2), and measures of mood (Figure 3—figure supplement 3) did not significantly differ between drug conditions. For individual effects of the drug manipulations on endogenous pain modulation see Figure 3—figure supplement 4. Levodopa and naltrexone influence relief reinforcement learning in the wheel of fortune task To investigate whether pain relief gained in active relief seeking was associated with an impact on choice related to reinforcement learning, one of the 2 choices in the wheel of fortune was associated with a fixed 75% chance of winning pain relief (choicehigh prob) while the other choice only had a 25% chance to win pain relief (choicelow prob). Participants were not informed of these probabilities in advance. We tested if the proportion of choices of the more rewarding option was higher in the last two out of five blocks of four test trials each of the game, when the subjects already had the chance to explore and learn the different outcome probabilities. Participants selected the color of the wheel of fortune associated with a higher likelihood for winning relief in 64% (SD = 28%) of trials in the placebo condition, consistent with a reinforcement learning effect. Thus, participants chose the color associated with the higher likelihood for winning above chance (χ2(1)=6.64, p=0.010) on a group level, indicating successful learning. However, participants’ performance significantly differed between the placebo and the drug conditions (main effect of ‘drug’: χ22 = 11.89, p=0.003). In contrast to the placebo condition (post-hoc comparison p<0.001), under levodopa and under naltrexone participants’ choices did not significantly differ from chance (post-hoc comparisons p’s>0.759). Correspondingly, post-hoc comparisons show that choice behavior significantly differed in the placebo compared to the levodopa condition (p=0.015) and compared to the naltrexone condition (post-hoc comparison p=0.004), while choices did not significantly differ between levodopa and naltrexone (post-hoc comparison p=0.915; Figure 4). This shows that both, dopamine and opioids, may have an influence on relief-related learning and choice. Figure 4 with 1 supplement see all Download asset Open asset Proportion of choices of the color associated with a higher chance of winning pain relief. Bars show group level means and error bars show 95% confidence interval of the group level mean (placebo: n=28, levodopa: n=27, naltrexone: n=28). OR indicates odds ratios as effect size of estimated effects between drugs. *p<0.05, ** p<0.01. In an additional exit interview at the end of each session, participants were asked whether they believed that one color of the wheel was associated with a higher chance of winning pain relief. The proportion of participants who reported this color correctly was not above chance (binomial test: p’s>0.5; placebo: 50%, levodopa: 37%, naltrexone: 39.3%). Nevertheless, participants’ belief whether one color of the wheel of fortune task was associated with a higher chance of winning or not significantly influenced their choices (p<0.001) and this influence on choices, and thus on learning, depended on the drug condition (interaction ‘drug × belief’: F(2) = 6.91, p=0.032). Group effects of successful learning, i.e. selecting the color with a higher chance of winning, were driven by participants who were able to report this association (p(choicehigh prob|correct belief) = 0.737, p(choicehigh prob|false or no belief) = 0.545; post-hoc comparison: p=0.007) under placebo and naltrexone (p’s<0.001) but not under levodopa (p=0.922). This suggests that successful decision-making was associated with contingency awareness in our task. However, the current data does not allow a conclusion on whether this contingency awareness was a prerequisite for or a consequence of successful learning here. Unpredictability and endogenous pain modulation We next tested whether outcome unpredictability, indicated by reward prediction errors of winning (pain relief) and losing (pain increase) in the game, was associated with endogenous pain modulation, and whether this association differed between drugs. Using hierarchical Bayesian modeling, we fit reinforcement learning models that captured the update of expected values for choice through outcomes of the wheel of fortune (Glimcher, 2011), with a drift diffusion process as the choice rule to participants’ choice and reaction time data. The best predictive accuracy was found for model 4 that used an individually scaled outcome sensitivity, and a sigmoid function to map expected values for the two choices to the drift rate of the diffusion process (Table 2; see Materials nd methods, section Estimation of prediction errors and their role in endogenous pain modulation for details on parametrization of reward learning models). Table 2 Model comparison. Models are ordered by their expected log pointwise predictive density (ELPD). ELPDdiff: difference to the ELPD of winning model 4. se(ELPDdiff): standard error of the difference in ELPD. ModelELPDELPDdiffse(ELPDdiff)Model 4–837.7100Model 3–845.44–7.731.51Model 2–997.33–159.6215.77Model 1–998.33–160.6215.95 Posterior predictive simulations from the best-fitting model appropriately describe the observed choices (Figure 5). However, none of the model parameters could exclusively explain the differences between levodopa and naltrexone compared to placebo: the 95% highest density intervals (HDI) for the difference between all group level parameters of the drug effect enclosed zero (see Figure 5—figure supplement 1). Figure 5 with 1 supplement see all Download asset Open asset Posterior distributions of the proportion of choices in favor of choicehigh prob. Colored areas show 95% highest density interval (HDI95). Dashed lines indicate observed proportion of choices in favor of choicehigh prob . Placebo (n=28): pchoicehigh prob = 0.641, HDI95 = [0.614,0.655], posterior (p-value (pp)=0.320); levodopa (n=27): pchoicehigh prob = 0.507, HDI95 = [0.491,0.530], p=0.679; naltrexone (n=28): pchoicehigh prob = 0.467, HDI95 = [0.443,0.494], p=0.611. Figure 5—figure supplement 1 shows comparison of drug conditions for each parameter of winning model 4. Prediction errors estimated by using subject level parameters of the model showed a significant main effect for the prediction of endogenous pain modulation indicated by VAS ratings (F(1, 1600.3)=452.9, p<0.001). A negative estimate of the prediction error (βPE = –0.36) indicates that outcomes that are better than expected (positive prediction errors, which occur when receiving relief) were related to increased relief perception (pain inhibition). Conversely outcomes that are worse than expected (negative prediction errors, occurring with pain increases) were associated with increased pain facilitation (Figure 6). In other words, the more unexpected the relief, the greater the perception of that relief; and the more unexpected the pain increase, the greater the perception of that pain. Figure 6 Download asset Open asset Pain modulation in VAS ratings predicted by prediction errors for each condition. Regression lines indicate prediction from the mixed effects model with predictors ‘PE’, ‘drug’, and their interaction (placebo: n=28, levodopa: n=27, naltrexone: n=28). The effect of prediction errors on pain modulation showed a significant interaction with the drug condition (F(2, 1599.5)=7.529, p<0.001). Post-hoc analysis confirmed that the negative linear relationship significantly differed from zero for all conditions (p’s<0.001), but this relationship was significantly stronger for levodopa compared to placebo (p<0.001) with no significant differences for naltrexone compared to placebo (p=0.083). Overall, this shows that relief is enhanced to unpredictability, and this effect is sensitive to dopamine. Estimated prediction errors also showed a significant main effect for the prediction of behaviorally assessed pain modulation (F(1, 1602.1)=9.00, p=0.003), with a negative estimate (βPE = –0.06) suggesting that sensitization decreased with smaller prediction errors. No significant interaction with of prediction error with drug conditions was found for behaviorally assessed pain perception (interaction ‘PE × drug’: F(2, 1600.1)=0.96, p=0.384). Novelty seeking is linearly associated with increased endogenous pain modulation by pain relief under levodopa Previous data suggest that endogenous pain inhibition induced by actively winning pain relief is associated with a novelty seeking personality trait: greater individual novelty seeking is associated with greater relief perception (pain inhibition) induced by winning pain relief (Becker et al., 2015). Similar to these results, we found here that endogenous pain modulation, assessed using self-reported pain intensity, induced by winning was associated with participants’ scores on novelty seeking in the NISS questionnaire (Need Inventory of Sensation Seeking; Roth and Hammelstein, 2012; subscale ‘need for stimulation’ (NS)), a" @default.
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W4323310426 title "Author response: Evidence for dopaminergic involvement in endogenous modulation of pain relief" @default.
W4323310426 doi "https://doi.org/10.7554/elife.81436.sa2" @default.
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