key: cord-0297639-55lpwm1h
authors: Massaccesi, Claudia; Willeit, Matthaeus; Quednow, Boris B.; Nater, Urs M.; Lamm, Claus; Mueller, Daniel; Silani, Giorgia
title: Enhanced negative response to stress following morphine administration increases wanting of social reward
date: 2021-08-27
journal: bioRxiv
DOI: 10.1101/2021.08.13.456110
sha: 6b5c2bdcfe6480ba7419874ae3a97dd6d1c0c369
doc_id: 297639
cord_uid: 55lpwm1h

Animal research suggests a central role of the μ-opioid receptor (MOR) system in mediating contact seeking and the stress-buffering function of social touch. However, the human neurochemistry of social motivation in aversive situations is still poorly understood. In a randomized, double-blind, between-subject design, healthy female volunteers (N = 80) received either 10 mg of the µ-opioid agonist morphine sulfate or a placebo. Following psychosocial stress induction, participants engaged in a social reward task, in which the motivation (subjective ratings of wanting and physical effort) to obtain skin-to-skin social touch and the hedonic reactions (subjective ratings of liking and facial electromyography) elicited by it were assessed. Morphine administration prevented the increase of salivary cortisol, usually observed in response to acute stress exposure. The dampened physiological reaction to the psychosocial stress was associated with increased negative mood and subsequent higher subjective wanting of the most pleasurable touch. Furthermore, participants administered with morphine displayed greater activity of the corrugator muscle during reward anticipation, possibly tracking enhanced attention toward the social stimuli. Overall, the results provide novel evidence on the effect of exogenous opioids administration on the reactions to psychosocial stress and point to a state-dependent regulation of social motivation.

species. By providing fundamental benefits (e.g., promoting safety and enhancing stress resilience) 46 and by generating comfort and pleasure, social stimuli (e.g., social contact) gain rewarding value, 47 inducing approach motivation. Inability to form and maintain social bonds contributes to a range 48 of psychiatric and physical pathologies (e.g., Cacioppo & Cacioppo, 2014; Uchino, 2006) , 49 therefore highlighting the importance to better understand the neurobiological basis of social 50 motivation. 51

The Brain Opioid Theory of Social Attachment (BOTSA), originally inspired by the analogies 52 between opioid addiction and social dependence, pinpoint the μ-opioid receptor (MOR) system as 53

a key mediator of bonding and affiliation (Panksepp, 1998; Panksepp et al., 1980) . Specifically, 54 BOTSA predicts that social isolation results in reduced levels of basal opioid levels, which in turn 55 motivate social contact seeking, and that rewarding social interactions elicit release of endogenous 56 opioids, associated with euphoria and contentment. The two-fold role of the endogenous opioid 57 system in reward and pain (Leknes & Tracey, 2008 ) therefore seems to apply also to experiences 58 of social nature. In contexts of comfort, the activity of the MOR system during social contact 59 mediates the rewarding properties, and associated pleasure, of social stimuli, positively reinforcing 60 exploration and affiliation. In contexts of distress, the release of endogenous opioids via social 61 contact reduces pain and negative affect, negatively reinforcing social behaviors (Loseth et al., 62 2014) . 63

In line with this model, animal studies have shown that μ-opioids are released following physical 64 social contact, such as grooming and playing (Keverne et al., 1989; Panksepp & Bishop, 1981 ; 65 Vanderschuren et al., 1995) . Pharmacological studies on separation-distress in animals further 66 confirmed BOTSA predictions, showing that administration of MOR agonists reduces, and of (Keverne et al., 1989; Martel et al., 1995; Panksepp et al., 1980 In the last decade, preliminary confirmatory evidence on the μ-opioid mediation of the rewarding 72

properties of social stimuli in humans have been provided. These studies mainly focused on two 73 fundamental components: wanting, namely the motivational drive to obtain the social stimulus, 74 and liking, namely the pleasure elicited once it is received. Results showed that pharmacological 75 challenge of the MOR system affects wanting and/or liking of different kind of social stimuli, such 76 as erotic pictures (Buchel et al., 2018) , attractive faces (Chelnokova et al., 2014) , and social touch 77 (Korb, Götzendorfer, et al., 2020 ; but see also Løseth et al., 2019) . MOR activation has been also 78 associated with social laughter (Manninen et al., 2017) , and MOR blockade was shown to reduce 79 feelings of social connection (Inagaki et al., 2015 (Inagaki et al., , 2016 (Inagaki et al., , 2020 , as well as of interpersonal 80 closeness and social reward expectation (Tchalova & MacDonald, 2020) . Using PET, Hsu et al. 81 (2013) observed MOR activation in response to both social rejection and social acceptance. In the 82 first case, MOR activity was correlated with reduced negative affect, while in the latter it was 83 associated with increased desire for social interaction. These findings are consistent with a 84 "protective" and an "affiliative" role of the MOR system during social distress and social comfort, 85 respectively. Regarding the role of the MOR system in stress regulation, a recent study showed 86 that MOR agonist administration reduces individuals' physiological stress response (as measured 87 by cortisol), as well as the perceived difficulty of the stress task (Bershad et al., 2018). However, 88 direct evidence of an involvement of the MOR system in downregulating stress and how this 89 affects social contact seeking, as shown in non-human animal species, is still lacking. 90

Here, we aimed at filling this knowledge gap by investigating the effect of MOR agonist 91 administration (morphine) on social motivation and social pleasure following stress exposure. 92

Using a double-blind, placebo-controlled, randomized, between-subjects design, female 93 participants (N = 80) were orally administered with either 10 mg morphine sulfate (a highly 94 selective μ-opioid agonist) or placebo. Following a psychosocial stress induction procedure, the 95 motivation to obtain social touch (wanting) and the pleasure elicited by receiving it (liking) were 96 assessed (see Figure 1 for a detailed description). In order to enhance the translational value of the 97 study, the following steps were taken: i) as in previous animal research, which entailed social 98 separation, a stressor of social nature (via the Trier Social Stress Test, Kirschbaum et al., 1993) 99 was employed; ii) in addition to self-reports of wanting and liking, we assessed real physical effort 100 (via a hand-dynamometer) and hedonic facial reactions (via facial electromyography of corrugator 101 and zygomaticus muscles), approximating the motivational and hedonic (i.e., wanting and liking) 102 measures used in animal studies; iii) to parallel grooming in animals, skin-to-skin touch 103 administered at different speeds (6, 21, 27 cm/s, corresponding to high, low, and very low reward 104 levels) was employed as a social reward. 105

Based on the existing human and animal literature, we hypothesized that participants administered 106 with morphine, compared to placebo, would show reduced physiological and subjective responses 107 to stress, and that this would result in decreased social motivation. As previous studies had shown 108 an effect of stress on wanting rather than on liking of touch (Massaccesi et al., 2021) or food (e.g. 109 Pool et al., 2015) reward, we did not expect changes in the hedonic reactions to social contact. 110

Given that MOR manipulations have been shown to induce the strongest effects on the best reward 111 option available (Chelnokova et al., 2014; Eikemo et al., 2016) , and considering the stress 112 buffering function of C tactile (CT)-optimal touch (i.e., touch with stroking speed of 1 to 10 cm/s; 113 Morrison, 2016) , we expected the predicted effects to be stronger for the most valuable social 114 reward (touch at 6 cm/s). Massaccesi et al., 2021). Participants were seated in front of the monitor, holding the hand-121 dynamometer in the right hand. The left arm was rested on a cushion, next to a keyboard used to 122 express judgements during the task. The toucher was seated on the other side of a curtain used to 123 limit the participants' field of view to the monitor. Touch was administered on the participants' 124 left forearm using the index and middle finger, at 3 stroking speeds corresponding to 3 levels of 125 reward (high = 6 cm/s, low = 21 cm/s, very low = 27 cm/s). (C) Trial structure of the Social Reward 126 task: i) announcement of the best attainable social reward (high or low); ii) rating of subjective 127 wanting; iii) effort task requiring to squeeze a hand-dynamometer to obtain the announced reward. 128

Participants' force exerted was indicated in real-time by a vertical bar filling in red. group average scores were generally low, and no side-effect was on average rated as moderate or 149 strong (see Figure S2 in Supplementary Material). 150 No significant drug effects were observed in the autonomic nervous system (ANS) response to 180 stress, assessed via salivary alpha-amylase (sAA) and heart rate. Grey bars represent the TSST 181 time window (anticipation, speech, and arithmetic task); error bars represent standard error of the 182 mean; asterisks indicate significant differences between drug groups (* p <.05, *** p < .001). Participants were announced with either high (6 cm/s, CT-optimal touch 2 ) or low (21 cm/s, non-196 CT-optimal touch) social reward and rated their wanting of the stimulus. Based on an effort task, 197 they could then receive the announced or the very low (27 cm/s, non-CT-optimal touch) social 198 reward and had to rate their liking of the received stimulus. 199

We first examined whether the number of high, low and very low rewards obtained during the task 200 was similar for the two groups. A linear model on number of trials was fitted, including Drug 201 (MORPH, PLB) and Reward Level (high, low, and very low). We observed only a main effect of 202 Reward Level (F(2,369.5) = 11.28, p < 0.001), indicating that participants obtained more often 203 high rewards as compared to low and very low rewards. We also tested for group differences in 204 the average maximum voluntary contraction (MVC), assessed before and after the Social Reward 205 task and used to calibrate the effort task. No significant differences emerged (all t < -0.84, all 206 p > 0.40), indicating no drug effects on participants' grip force at rest. Last, we tested for group 207 differences in the baseline activity of the corrugator and zygomaticus muscles. No significant 208 differences emerged (all t < 1.27, all p > 0.21). 209

To investigate the effects of morphine administration on subjective wanting and liking of social 211 touch under stress, we fitted two linear mixed-effects models (LMM) on the ratings of wanting 212 and liking, including Drug (MORPH, PLB) and Reward Level (high, low for wanting ratings, and 213 high, low, very low for liking ratings) as fixed effects, and by-subject random intercepts and slopes 214 for Reward Level. During the announcement of the gained reward (Anticipation Post-Effort), greater zygomaticus 257 (ZM) activity was associated with greater subjective wanting, but no significant drug effects were 258 observed for this muscle. Error bars represent standard error of the mean; black dots represent 259 group means; colored dots represent individual means; asterisks indicate significant differences 260 between conditions (* p < .05). VAS, Visual Analogue Scale; MORPH, morphine group; PLB, 261 placebo group. 262 bonding, affiliation) are fundamental to the individual's physical and psychological well-being. 265

Despite the important role of social contact in stress resilience, the neurochemical mechanisms 266 underlying social contact seeking following stress exposure in humans are still poorly understood. 267

In this study, we pharmacologically challenged the µ-opioid receptor (MOR) system to investigate 268 its role in the regulation of the motivational and hedonic components of social reward processing 269 following stress induction. To parallel previous animal research, participants were exposed to a 270 stressor of social nature and interpersonal touch was used as a social reward. Further, force exerted 271 to obtain the reward as well as hedonic facial reactions during its anticipation and consumption 272

were assessed, together with subjective ratings of wanting and liking. Following the enhancement 273 of the MOR system activity via administration of its agonist morphine, we observed suppression 274 of the HPA axis activity (as indicated by a reduced cortisol response) and increased negative affect 275 in response to psychosocial stress. Notably, this increased negative response to stress following 276 morphine administration was associated with enhanced motivation for the most pleasurable social 277 reward. 278

In this study, single administration of the µ-opioid agonist morphine prior to TSST exposure 280 resulted in blunted salivary cortisol response, indicating suppression of the HPA axis reactivity to 281 stress. This is in line with previous animal and human evidence indicating an inhibitory role of μ-282 opioids on cortisol release following stress exposure (Pechnick, 1993) . Recently, two studies 283 investigated the effects of partial (buprenorphine) and full (hydromorphone) MOR agonists on 284 psychosocial stress, induced via TSST (Bershad et al., 2016, 2018) . Akin to the present findings, 285 reduced cortisol responses to stress were observed. Buprenorphine and hydromorphone also 286 reduced the perceived threat and the appraisal of how challenging the participants found the stress 287 task, respectively. While the authors interpret the findings on cortisol and stress appraisal as 288 indicators of a reduced stress response, no mood-buffering effects of the drug were observed. This 289 is in contrast with the current study, where we find that the dampened cortisol response is 290 accompanied by an enhanced aversive reaction to stress, as shown by higher negative affect 291

following morphine compared to placebo administration. Human cortisol permeates the blood-292 brain barrier to feedback the Our results are opposite to our a priori hypothesis based on previous evidence from animal studies 300 on separation distress indicating a reduction of stress indices, such as distress vocalizations, 301 following MOR agonist administration (Panksepp et al., 1980) . The paradoxical morphine effect 302 of enhanced aversive stress reaction observed in the current study vs. the previous animal literature 303 may be explained by experimental differences, such as route and timing of administration of the 304 opioid compounds. For instance, in animal research morphine is typically delivered intravenously 305 after stress induction, possibly allowing the system to prepare to face the stressor via an initial 306 mounting of the physiological stress response. In this study, morphine was administered orally to 307 minimize the invasiveness of the administration procedure. Unlike intravenous administration, 308 per-oral morphine has a slow pharmacokinetic profile and requires an average time of 60 min to 309 reach the peak blood concentration. As the subjective response to acute stress, especially its effect 310 on mood, typically lasts only for short periods of time after laboratory stress induction, orally 311 administering the drug and waiting for it to reach peak concentration after the TSST would not 312 have been feasible. For these reasons here the compound was administered prior to stress exposure. 313

However, the resulting suppression of the HPA axis activity before the beginning of the stress 314 induction may have led to the observed difference in the mood response. Accordingly, the raising 315 of cortisol levels, via cortisol administration, prior to stress induction has been shown to have a 316 protective role in women, lowering the negative subjective reaction to stress (Het & Wolf, 2007) . 317

Morphine-induced increased negative reaction to stress is associated with enhanced social 318 motivation 319 BOTSA posits that when facing stressors, individuals seek physical social contact with others in 320 order to down-regulate the negative state and re-store comfort, via endogenous release of beta-321 endorphins, unless opioids are externally provided. Contrary to our initial hypotheses, morphine 322 increased, rather than reduced, participants' negative reactions to the TSST, and such increased 323 stress responses were accompanied by enhanced social motivation. Specifically, we observed 324 greater subjective wanting of the most pleasurable social reward (CT-optimal touch) following 325 morphine administration, compared to placebo. This enhanced subjective wanting was also 326 accompanied by greater differentiation of the high and low social rewards (CT-optimal and non-327 CT-optimal touch) in terms of effort exerted to obtain them in the morphine group compared to 328 placebo, but the effect did not reach statistical significance. Based on previous evidence, we predicted that the effects of morphine administration on social 375 touch processing under stress would be specific for the motivational component, without affecting 376 the hedonic aspect. Accordingly, we did not observe a significant effect of drug on the ratings of 377 liking or in the facial hedonic reactions during the reward consumption phase. However, we 378 nevertheless observed that the ratings of liking were generally higher in the morphine group 379 compared to the placebo group (FDR p = 0.065), and we therefore refrain to exclude an effect of 380 the manipulation on social pleasure. 381

Some limitations of the study should be considered. First, while the use of a within-subject design 383 is usually preferable in pharmacology, in this study we employed a between-subjects design. The well as other methodological aspects (e.g., use of a curtain separating participant and toucher), 391 might have affected our results. Nevertheless, in humans an involvement of the MOR system in 392 bond formation, rather than just maintenance, has also been observed (Tchalova & MacDonald, 393 2020) . Third, the current study tested a sample of healthy female participants, therefore a 394 generalization to male individuals is not possible, especially given the known sex differences in 395 stress reactivity and MOR system functioning. Finally, it is unlikely that a complex behavior such 396 as social motivation can be fully explained by the activity of a single neurochemical system only. and increases dopamine release in the nucleus accumbens (Pan, 1998) . To investigate how these 402 systems interact in driving social contact seeking during aversive states seems therefore necessary 403 to understand the neurobiology of social motivation. 404

To conclude, our findings show that enhancing µ-opioid signaling before psychosocial stress 406 exposure increases, rather than reduces, the aversive reaction to stress, leading to an increased 407 subjective motivation for the attainment of highly rewarding social contact. Specifically, we 408 showed that morphine administration blunted cortisol reactivity to stress and increased the 409 processing (see Fig.1A for an overview of the session timeline). Here we will focus on the last 468 two, while the others will be reported elsewhere. Approximately 180 min. after pill administration, 469 a blood sample was taken to confirm drug uptake (see Table S2 

In order to induce a stress reaction in the participants, the Trier Social Stress Test (TSST;  483 Kirschbaum et al., 1993) was employed. In the TSST, participants were given 3 minutes to prepare 484 a 5-minute speech for a mock-job interview, followed by a 5-minute arithmetic task, in which they 485 were asked to count backwards from 2043 in steps of 17 as fast and as accurate as possible. The 486 speech and arithmetic tasks were completed in front of an evaluating panel (one male and one 487 female confederates). Participants were told that these tasks would be video recorded via a camera 488 located next to the examiners (no video was actually taped). 489 2018), and increasing heart rate variability (Triscoli et al., 2017) . The suitability of these stroking 497 speeds has been confirmed in three previous independent studies from our group (Korb, 498 delivered over a previously-marked nine-cm area on participants' left forearm (measurement 500 started from the wrist towards the elbow) by a female experimenter, moving her index and middle 501 fingers back and forth in the marked area of the forearm ( Figure 1B) . Touch delivery was guided 502 by auditory rhythms, which matched the frequency of the stimulation, over headphones. The 503 experimenter administering the touch was seated on the other side of a curtain, used to limit the 504 participants' field of view to the monitor ( Figure 1B) . All experimenters were presented as trained 505 masseurs, wore standardized clothes (white t-shirt and beige trousers) to minimize differences in 506 their appearance, and underwent extensive training on the tactile stimulation delivery. 507

Task 508

The Social Reward task (Korb, Götzendorfer, et al., 2020; Massaccesi et al., 2021) consisted of 509 two blocks of 16 trials, separated by a 5-minute break. To avoid habituation to the touch, the site 510 of application (left or right area of the forearm) was alternated within the two blocks, in a counter-511 balanced order. Before starting the task, participants experienced each type of touch once and 512 performed two training trials. Each trial was structured as follow (see Figure 1C ): i) announcement 513 of the best attainable reward (high or low, 16 trials each, 3s); ii) rating of subjective wanting via a 514 VAS ranging from -10 (not at all) to +10 (very much) (no time limit); iii) effort task (4s), requiring 515 to squeeze a hand-dynamometer (HD-BTA, Vernier Software & Technology, USA) with the right 516 hand, in order to obtain the announced reward -the applied force, displayed via an online visual-517 feedback, was expressed as percentage of the participants' MVC, measured immediately before 518 the task, and translated into the probability of obtaining the announced reward (0-100%); iv) 519 announcement of the reward obtained (high, low, or -if insufficient force had been exerted -very 520 low; 2s); v) reward delivery (6s); vi) relax phase (5s); vii) rating of subjective liking via a VAS 521 ranging from -10 (not at all) to +10 (very much) (no time limit). At the end of the task, participants' 522 MVC was measured again. 523

The task was implemented in MATLAB 2014b (MathWorks, Inc) and presented on an LCD 524 monitor with a resolution of 1280 × 1024 pixels. 525

Facial EMG was recorded throughout the Social Reward task, using a g.USBamp amplifier (g.tec 527

Medical Engineering GmbH) and the software Matlab (MathWorks, Inc). Participants' face areas 528 were prepared using alcohol, water and an abrasive paste. Reusable Ag/AgCl electrodes were then 529 attached bipolarly according to guidelines (Fridlund & Cacioppo, 1986 ) on the left corrugator 530 supercilii (corrugator), and zygomaticus major (zygomaticus) muscles. A ground electrode was 531 attached to the participants' forehead and a reference electrode on the left mastoid. The EMG data 532 were sampled at 1200 Hz with impedances below 20 kΩ. Data preprocessing included filtering 533 with a 20 to 400 Hz bandpass filter, rectification and smoothing with a 40 Hz low-pass filter. 534

Each trial was divided in 4 epochs: Anticipation Pre-Effort (announcement of best attainable 535 reward, 3s), Anticipation Post-Effort (announcement of attained reward, 2s), Delivery (touch 536 administration, 6s), and Relax (relax phase after reward delivery, 5s). EMG was first averaged 537 over 1s time-windows and then over the epoch total duration. For each trial, values in the four 538 epochs were expressed as percentage of the average amplitude during the fixation cross at the 539 beginning of that trial (baseline, 2s). Outliers in baseline (defined as values more than 3 SDs away 540 from the subjects' average baseline) were substituted with the average amplitude of the baseline 541 preceding and following that trial. The extracted epochs were visually inspected in order to identify 542 signal artifacts which were then removed (33 epochs for corrugator and 51 epochs for zygomaticus 543 movements, for each subject, epochs over the subject's mean ± 3 SD were removed (average 545 removed epochs per subject: corrugator: M = 2.4, SD = 1.2; zygomaticus: M = 3.1, SD = 1.1), and 546 the remaining data were transformed using natural logarithmic transformation. 547

During the session, participants completed self-report questionnaires assessing their mood and 549 subjective state at regular intervals. Happiness, calmness, relaxation, feeling good, as well as 550 stress, tension, anxiety and feeling bad were assessed via visual analogue scales ranging from +1 551 ("not at all") to +101 ("very much") at 7 time points (T1-T7; see Figure 1A ). Positive and negative 552 mood items were averaged to constitute the "Positive mood" and "Negative mood" scales used for 553 statistical analyses. The German short version Profile of Mood States (POMS; Albani et al., 2005) , 554 consisting of 4 subscales for current mood (depression, vigor, fatigue, and displeasure), was 555 administered at 5 time points (T1, T2, T3, T5, T6; see Figure 1A ). During the preparation phase 556 of the TSST (T4), anticipatory cognitive appraisal (PASA; Gaab et al., 2005) was also assessed. 557

Lastly, after completion of the TSST (T5), participants' satisfaction towards their performance at 558 the speech and math tasks was assessed on a VAS scale ranging from 1 ("not at all") to +101 ("very 559 much"). 560

Heart rate was recorded using a chest strap (Polar H10; Polar Electro Oy, Kempele, Finland). Data 562 were collected over a 10-minute period at baseline, during TSST, and during the Social Reward 563 task. Values in each time window were then averaged for statistical analyses. 564 at 6 time points (T1, T2, T3, T5, T6, T7 ; see Figure 1A ). Free cortisol concentration in saliva was 566 determined by using commercial luminescence immunosorbent assay (LUM; IBL, Hamburg, 567

Germany). Salivary alpha-amylase activity was measured using a kinetic colorimetric test and 568 reagents obtained from DiaSys Diagnostic Systems (Holzheim, Germany). For heart rate, salivary 569 cortisol and alpha-amylase analyses, outliers were defined as subjects with a baseline value (T1) 570 3 SDs over the mean baseline of the sample. This procedure led to the exclusion of two participants 571 for cortisol (1 MORPH, 1 PLB) and of one participant for alpha-amylase (MORPH). 572

To assess potential drug effects on cognitive functions, participants completed the Trail Making 574

Test (TMT; Reitan, 1958) and the Digit Symbol Substitution Test (DSST; Wechsler, 1939) 55 min 575 after drug administration. Regarding subjective drug effects, participants filled out a self-report 576 questionnaire assessing nausea, dry mouth and other 24 possible side-effects on a 4-point Likert 577 scale (with the anchors 1 = "not at all" and 4 = "very much") at baseline (T1), as well as 50 min 578 (T2) and 160 min (T7) after drug administration (see Figure 1A) . Figure S2 . Drug side-effects assessed at baseline (T1), 60 min (T2) and 160 min (T7) after drug 953 administration using a 4-point Likert scale (with the anchors 1 = "not at all" and 4 = "very much"). 954

A blood sample was drawn at the end of the session (~180 min after drug administration). Analyses 956 were performed at the Institute of Clinical Chemistry, University Hospital Zurich, using liquid 957 chromatography coupled to mass spectrometry (LC-MS) to identify serum levels of morphine and 958 its two major metabolites: morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). 959

Blood samples from 3 participants could not be obtained and 10 samples were lost because of 960 storage problems. Results from the available samples confirmed drug uptake, as shown in Table  961 S2. 962 Table S2 . Serum levels (nmol/l) of morphine and its major metabolites at the end of the 963 experimental session (~180 min after drug administration 

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