Accepted in Current Addiction Reports PREPRINT Not the version of record.

The role of mu-opioids for reward and threat processing in humans: Bridging the gap from preclinical to clinical opioid drug studies

Isabell M. Meier1*, Marie Eikemo2 and Siri Leknes1,2

Purpose of review. Opioid receptors are widely expressed in the human brain. A number of features commonly associated with drug use disorder, such as difficulties in emotional learning, emotion regu- lation & anhedonia, have been linked to endogenous opioid signaling. Whereas chronic substance use and misuse are thought to alter the function of the mu-opioid system, the specific mechanisms are not well understood. We argue that understanding exogenous and endogenous opioid effects in the healthy human brain is an essential foundation for bridging preclinical and clinical findings related to opioid misuse. Here, we will examine psychopharmacological evidence to outline the role of the mu-opioid receptor (MOR) system in the processing of threat and reward, and discuss how disruption of these processes by chronic opioid use might alter emotional learning and reward responsiveness. Recent findings. In healthy people, studies using opioid antagonist drugs indicate that the brain’s en- dogenous opioids downregulate fear reactivity and upregulate learning from safety. At the same time, endogenous opioids increase the liking of and motivation to engage with high reward value cues. Stud- ies of acute opioid agonist effects indicate that with non-sedative doses, drugs such as morphine and buprenorphine can mimic endogenous opioid effects on liking and wanting. Disruption of endogenous opioid signalling due to prolonged opioid exposure is associated with some degree of anhedonia to non- drug rewards; however new results leave open the possibility that this is not directly opioid-mediated. Summary. The available human psychopharmacological evidence indicates that the healthy mu-opioid system contributes to the regulation of reward and threat processing. Overall, endogenous opioids can subtly increase liking and wanting responses to a wide variety of rewards, from sweet tastes to feelings of being connected to close others. For threat related processing, human evidence suggests that endog- enous opioids inhibit fear conditioning and reduce the sensitivity to aversive stimuli, although incon- sistencies remain. The size of effects reported in healthy humans are however modest, clearly indicating that MORs play out their role in close concert with other neurotransmitter systems. Relevant candidate systems for future research include dopamine, serotonin and endocannabinoid signalling. Nevertheless, it is possible that endogenous opioid fine-tuning of reward and threat processing, when unbalanced by e.g. opioid misuse, could over time develop into symptoms associated with opioid use disorder, such as anhedonia and depression/anxiety.

Despite increasing awareness of the risks of prob- et al., 2016; Kaye, 2017; Yoon et al., 2020). Opioid an- lematic opioid use, opioid analgesics are still com- algesics such as morphine and fentanyl primarily bind monly used to treat acute and chronic pain (Calcaterra to mu-opioid receptors (MORs), which are widely ex- pressed in the human brain (Figure 1b). In addition to pain relief and typical side effects such as nausea and 1Oslo University Hospital, Department of Radiology and Nuclear Med- constipation, drugs acting on MORs affect decision 2 icine, Sognsvannsveien 20, 0372 Oslo, Norway; University of Oslo, making and other cognitive and affective processes Department of Psychology, Blindern, 0317 Oslo, Norway *Corresponding author: [email protected] (e.g. Van Steenbergen et al., 2019). Knowledge of the processes modulated by mu-opioid signaling comes Funding information: This work was supported by European Research from extensive preclinical research as well as experi- Council under the European Union’s Horizon 2020 research and inno- mental and clinical observations of acute and chronic vation programme (grant agreement no. 802885) and the South-Eastern Norway Regional Health Authority (grant number 2020087) to SL. effects of opioid drugs, both agonists and antagonists. In the literature, the addictive potential of opioids is Preprint template by Brenton M. Wiernik, DOI strongly linked to their ability to induce pleasure and 10.17605/OSF.IO/HSV6A euphoria. Indeed, one of the more robust indicators

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Figure 1. a) Schematic illustration of the actions of endogenous (agonist) ligands, agonist and antagonist drugs at the receptor. Endogenous ligands and agonist drugs bind to and stimulate receptors. Antagonist drugs bind to and block receptors without stimulating them, thereby preventing other ligands (e.g. endorphins, enkephalins) from activating the receptor. b) Mu-opioid receptor distribution in the healthy human brain as measured by positron emission tomography using the [11C]carfentanil radioligand BPND (binding potential relative to nondisplaceable radioligand in tissue, see Innis et al. (2007)). Images are based on 204 subjects from Aivo database (http://aivo.utu.fi). Key structures implicated in reward and threat processing are densely innervated with MOR receptors, such as the nucleus accumbens (NAc), the nuclei of the amygdala, the thalamus, anterior cingulate cortex (ACC) and periaqueductal gray (PAG). This MNI-space atlas is available on @VaultNeuro (https://neu- rovault.org/collections/GCELSAIA/).

used to assess the addictive potential of opioid drugs is drug liking (Comer et al., 2012). Interestingly, acute subjective responses to opioid administration in et al., 2013; McHugh et al., 2016; Rogers et al., 2019). healthy, pain-free subjects are highly variable, with Of note, high-stress conditions such as history of many reporting drug disliking (Angst et al., 2012; La- trauma, post-traumatic stress disorder (PTSD), low so- sagna, 1955; Zacny & de Wit, 2009). In chronic pain cio-economic status or poor social support are vulnera- patients receiving opioid treatment, prescription opioid bility factors for development of substance misuse and misuse can be driven by a desire for stress relief (Martel are frequently observed as comorbidities in opioid use

2 MEIER, EIKEMO & LEKNES PREPRINT disorder (Bedard et al., 2018; Clarke et al., 2014; Hel- non-sedative doses these drugs are thought to inform us merhorst et al., 2014; Hemsing et al., 2016; Pierce et about putative functions of endogenous mu-activity. al., 2019; Rosenbloom et al., 2017; Stone et al., 2012; Opioid antagonist drugs (such as naltrexone and nalox- Webster, 2017). These findings align with prominent one) bind to opioid receptors, thereby preventing en- addiction theories pointing towards two major path- dogenous ligands (i.e. endorphins) from binding to and ways into drug abuse, one related to drug liking and stimulating the receptors (see Fig 1a). All studies re- sensitization of the reward circuitry to drug related cues viewed here employed antagonists at doses thought to (Cofresí et al., 2019; Robinson & Berridge, 2001), and yield full MOR blockade (>90% MOR occupancy at another more driven by attempts to reduce negative af- the time of testing). Full blockade studies can test fective states and to cope with stressors (Koob, 2020). whether an endogenous system is necessary for, or in- Molecular imaging studies have reported changes in volved in, a behavioural function or experience. The binding potential after chronic exposure to opioid base assumption is that if endogenous ligands are nec- drugs, consistent with altered endogenous opioid func- essary for a behaviour, then that behaviour should be tion in opioid users (Colasanti et al., 2013; Williams et reduced by opioid antagonism. al., 2007). It is unclear whether chronic opioid exposure Specifically, the review will focus on causal evi- alters receptor density or endogenous mu-opioid re- dence on opioid drug effects on reward, stress and lease. For chronic pain, another condition associated threat in healthy people at the behavioural level. Corre- with altered mu-opioid binding potential, preclinical lational neuroimaging data from PET or fMRI are also work points to changes in receptor density (Thompson discussed where they complement behavioural effects. et al., 2018). At the behavioural level, chronic opioid Each section considers how the human psychopharma- intake has been proposed to reduce responsiveness to cology findings align with results from studies of opi- natural rewards (Garland et al., 2015; Lubman et al., oid function in non-human animals. Finally, we also 2009, but see Eikemo et al., 2019). Long-term opioid link the knowledge on acute drug effects with findings treatment has also been linked to reduced emotion reg- in chronic opioid exposed groups. For the sake of brev- ulation capacity (Garland et al., 2017), and is highly ity, opioid regulation of pain falls outside the scope of comorbid with heightened stress sensitivity and nega- the present review, which is also limited to the mu-opi- tive affect (Langdon et al., 2019; Rogers et al., 2019). oid receptor system. Most of the drugs used as antago- This leads to the question of whether chronic opioid use nists and some of the agonists are non-specific and also could paradoxically reinforce stress, negative affect bind to kappa and delta receptors, however doses are and anhedonia in the long-term. A similarly paradoxi- optimised for mu-opioid binding. The limited emerging cal effect of long-term opioid treatment has been docu- evidence on kappa specific activity is exciting, see e.g. mented for pain (opioid induced hyperalgesia), such Darcq & Kieffer (2018); Krystal et al. (2020); Piz- that people develop a heightened sensitivity to pain as zagalli et al. (2020) and we note that antagonist effects a result of the opioid therapy (Angst & Clark, 2006). currently attributed to mu-opioid signalling may also Before we can fully comprehend how chronic opioid reflect antagonism of kappa and to a lesser extent delta use affects behaviour and health, the field needs to es- receptors. tablish a thorough understanding of how endogenous opioids modulate behaviour and affect in the healthy human brain. Essentially, to understand what has gone Reward wrong in addiction, we must first establish how these processes function in the healthy, non-addicted human Both receiving and anticipating rewards can evoke brain. feelings of pleasure in humans. In evolutionary terms, This narrative review will give an overview of the the pleasures of play, food or sex are believed to moti- current state of knowledge on endogenous opioid func- vate the individual to engage in these behaviours, se- tion in humans, based on behavioural evidence from curing the individual’s survival and reproductive fit- opioid drug studies. A growing literature of preclinical ness. Reward processing is often parsed into several and human experimental research in healthy subjects components, including liking (the hedonic experience has investigated the effects of acute pharmacological when a reward is anticipated or obtained), wanting (the administration targeting the mu-opioid receptors. Here motivational component, often assessed as the drive we review studies that used drugs to block and/or stim- and/or effort spent to obtain a reward) and reward re- ulate the MOR system. Most opioid agonist drugs tar- lated learning (e.g. Berridge & Robinson, 2003). get mu-receptors (e.g. morphine, hydromorphone). In 4 MEIER, EIKEMO & LEKNES PREPRINT

Acute opioid effects in preclinical research functions including peer-bonding (Spinka et al., 2001; Mu-opioid signalling is tightly linked to liking of Trezza, Campolongo, et al., 2011; Vanderschuren et al., palatable foods. Groundbreaking rodent research on the 2016). In rats, play is most frequently observed during role of the MOR system in reward has identified the adolescence. Infusion of a MOR agonist in the shell and areas in the rostrodorsal shell of the nucleus accumbens core of the NAc specifically enhanced social play be- (NAc), the caudal ventral pallidum (VP), the para- havior in adolescent rats (Trezza, Damsteegt, et al., brachial (PB) nucleus as well as the anterior orbitofron- 2011). Further, opioid antagonism reduced motivation tal cortex (OFC) and the posterior insula as hotspots for social play, the rewarding properties of play and the that can enhance ‘liking’ responses to food rewards expression of play behavior (Achterberg et al., 2019). (Berridge, 2009; Berridge & Kringelbach, 2015; Castro The opposite pattern was found after morphine. In ad- & Berridge, 2017; Peciña & Berridge, 2005). Mi- dition to promoting play behaviours, mu-opioids were croinjections of a mu-opioid agonist into each hedonic also reported to facilitate social novelty seeking in ju- hotspot resulted in increased liking responses to food venile rats (Smith et al., 2015). In voles, mu-opioid sig- rewards (Berridge, 2009; Castro & Berridge, 2017; nalling in the striatum was found to mediate hedonic Peciña & Berridge, 2005). Increased liking responses aspects of pair bonding (Resendez et al., 2013). have also been reported from microstimulation in these Indeed, neuropharmacological studies across sev- hotspots using other ligands, including kappa and delta eral species point to a role of opioids in mediating re- opioid agonists, orexin, and compounds binding to en- ward-related processing. Inhibition of mu-opioid sig- docannabinoid receptors (Castro et al., 2016; Castro & nalling prevented newborn mice (Moles et al., 2004) Berridge, 2014, 2017). Interestingly, microstimulation and lambs (Shayit et al., 2003) from developing a be- with mu-opioid antagonists to block endogenous opioid havioural preference for their mother, highlighting the signalling did not alter baseline ‘liking’ responses in importance of opioid signals for social bond formation rats (Smith & Berridge, 2007), although such antago- in these animals. Moreover, a study of five miniature nism has been reported to block hunger-induced in- pigs that were given an hour’s access to sweet foods creases in food liking (Wassum et al., 2009) and eating was broadly consistent with rodent work, indicating pu- (Castro et al., 2021). Instead, microstimulation with tative reward-related opioid release in the pig NAc opioid agonists in so-called hedonic ‘coldspots’ trig- (Winterdahl et al., 2019). Whereas in cats, opioid an- gers a decrease in food liking responses in rats (Peciña tagonism reduced cats’ engagement with catnip-like & Berridge, 2005). substances, putatively due to blockade of its intrinsic Does mu-opioid activation also enhance wanting of reward value (Uenoyama et al., 2021). Further to these food rewards? Rodent studies using striatal microstim- reports across mammals, opioids are even reported to ulation or systemic drugs indicate a clear role for mu- mediate certain types of singing in songbirds. For in- opioids in food wanting. When rats ate chocolate, stri- stance, fentanyl injections increased non-communica- atal enkephalin levels surged (DiFeliceantonio et al., tive, intrinsically rewarding singing in starlings (Ste- 2012), and microstimulation of the same area with a venson et al., 2020). mu-opioid agonist resulted in increased palatable food consumption (DiFeliceantonio et al., 2012). Opioid ag- Acute opioid effects in human research onism in the NAc shell of rodents also increased the Overall, animal research indicates that opioid sig- motivation of animals to work for food rewards nalling impacts a large range of potentially rewarding (Peciña, 2008; Zhang et al., 2003), consistent with ef- behaviours such as feeding, bonding, and play. Does fects reported after systemic drug administration in the human opioid system exhibit similar modulation of rats. Specifically, opioid agonism increases measures reward processing? Due to methodological limitations, of food wanting, whereas antagonism decreases it (e.g., it is as yet unknown whether the human brain contains Cleary et al., 1996). anything like the mu-opioid sensitive set of hedonic Rodent studies also indicate an important role for hotspots capable of enhancing food liking responses in the MOR system in encoding liking and wanting of rodents. PET imaging indicate rich expression of non-food rewards such as social play (Vanderschuren MORs in the human striatum, as well as in the thala- et al., 1995). Social play is an intrinsically rewarding mus, insulae, amygdala and anterior cingulate cortex behaviour (Trezza, Campolongo, et al., 2011; (Figure 1b). Overall however, the available evidence Vanderschuren, 2010; Vanderschuren et al., 2016). from systemic drug studies in healthy humans is con- Play is thought to be important for social and cognitive sistent with the rodent evidence that MOR signalling development across species and serves a variety of promotes liking and wanting of high-calorie foods. A

5 MEIER, EIKEMO & LEKNES PREPRINT study from our lab indicated modest increases in su- the ventral striatum, amygdala, hippocampus, orbito- crose liking after treatment with a low-dose mu-opioid frontal cortex and medial prefrontal cortex. Petrovic et agonist (Eikemo et al., 2016). There is also consistent al. (2008) similarly reported larger effects of naloxone evidence that opioid blockade decreases reports of food for high-value reward outcomes, which correlated with enjoyment and reduces high caloric food consumption activity reductions in the rostral anterior cingulate. Ad- in humans (Eikemo et al., 2016; Yeomans & Gray, ministration of naltrexone also reduced motivation to 1996, 1997; Ziauddeen et al., 2012). A recent study also exert effort for chocolate rewards in a pavlovian instru- reported decreased effort to obtain food reward after mental transfer task (Weber et al., 2016), attenuated MOR antagonism, but no effect on subjective ratings of motivational ratings following almost-wins in a gam- food liking or wanting (Korb et al., 2020). bling task (Porchet et al., 2013), diminished learning in In line with rodent work showing opioid modulation a reward driven reinforcement learning task (Efremidze specifically of high reward options in the food and so- et al., 2017), and decreased physical effort to obtain a cial domains, several human studies targeting mu-opi- reward (Korb et al., 2020). Some of these studies, in- oid receptors with systemic agonists and/or antagonists cluding our own, tested only men due to what we now report drug modulation of high-value reward responses. know is a misguided belief that female hormonal fluc- As illustrated in Figure 2, our lab conducted a random- tuations would add more noise than those of males ised, double-blind, placebo-controlled study in which (Shansky, 2019). However where women have been healthy young men were treated with naltrexone or tested, results are broadly comparable to studies of men morphine before exposure to social, food and abstract only. rewards. We found the expected bidirectional modula- Korb et al (2020) also reported opioid antagonist ef- tion of responses to high-calorie foods (Eikemo et al., fects on facial muscle activity (more frowning during 2016), attractiveness judgements and viewing time of reward anticipation; less smiling during consumption beautiful photographed faces (Chelnokova et al., 2014), of food rewards, in the absence of changes in subjective and for computationally derived measures of reward valuation of these rewards (Korb et al., 2020). In- preference and motivation for high-value monetary creased negative facial reactions after opioid blockade gains (Eikemo et al., 2017). We also found that mor- were also reported during viewing of smiling faces phine increased and naltrexone decreased visual atten- (Meier et al., 2016), consistent with a role for MOR sig- tion to the eyes of human faces (Chelnokova et al., nalling in automatic behavioural responses (mimicry) 2016), consistent with the interpretation that the human that support social bonding (Lakin et al., 2003). More- endogenous MOR system promotes attention to so- over, opioid antagonism has been reported to reduce cially relevant cues and thereby facilitates detection of ratings of the feeling of being connected to other people reward cues. This, in turn, could influence reward re- (Inagaki et al., 2016; Inagaki et al., 2020). The magni- lated learning and memory. In line with this idea, Syal tude of the shift in feelings of connectedness is modest, et al. (2015) reported MOR agonist effects on reward comparable to effect sizes of acute opioid drug effects related learning and memory, with increased recall of on other high-value rewards. The reviewed literature on social reward cues (happy faces) in an object relocation acute opioid drug effects broadly point towards human task (Syal et al., 2015). endogenous mu-opioids promoting approach of high- Results from other labs are broadly consistent with value rewards in humans, consistent with findings in the above pattern of results. Buchel et al. (2018) used non-human animals. However, there are also several fMRI together with MOR blockade and reported de- discrepancies in the literature. While most published creased pleasure ratings when young men viewed erotic findings are consistent with opioids promoting appreci- photographs and cues of monetary reward, as well as ation and approach of rewards (van Steenbergen et al., reduced reward related activation to erotic stimuli in 2019), at least three studies have

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Figure 2. Overview of behavioural results from our lab’s investigation into the role of endogenous mu-opioid sig- nalling for reward liking and wanting in healthy young men. We reasoned that behaviours increased by 10 mg per- oral morphine and decreased by 50 mg of the non-specific opioid antagonist naltrexone, would be behaviours likely to be promoted by endogenous mu-opioid signalling in the healthy human brain. In this repeated-measures pharma- cological administration study, the expected pattern of results was found for most reward domains, with the excep- tion of gentle caress-like touch. Notably, these bidirectional drug effects are unlikely to result from mood and/or side effects of the drugs; after the three sessions, participants remained fully blinded to the drug order (chance level guesses). a) Faces: liking ratings most attractive opposite-sex faces; effort exerted to see most attractive faces (Chelnokova et al., 2014); visual exploration and attention (fixations) to others’ eyes as measured with eye-tracking (Chelnokova et al., 2016). Gaze pattern illustrates a single trial. b) Sweet liking ratings of high sucrose drinks (Eikemo et al., 2016) c) ratio of time spent on most comfortable brush speed (Løseth et al., 2019) d) Monetary reward: parameters indicating response bias for a high reward stimulus (shift in decision starting point, z) and total effort exerted (motivation; drift rate, v) from a Bayesian drift diffusion model (Eikemo et al., 2017). * denotes p<0.05, ** < .01,*** p<0.001, where frequentist statistics were used (a-c). P(M>N) denotes the posterior probability of the contrast - that the decision parameter estimate of naltrexone is greater than morphine(N>M). 7 MEIER, EIKEMO & LEKNES PREPRINT

reported comparable or even more enjoyment of ca- vated with mu-opioid receptors: the nuclei of the amyg- ress-like touch after opioid blockade (Case et al., 2016; dala, the thalamus, anterior cingulate cortex (ACC) and Korb et al., 2020; Løseth et al., 2019 - see Figure 2C). periaqueductal gray (PAG) (McNally et al., 2004; Pou- Differences in reported drug effects could be related to lin et al., 2006). distinct processing of reward types (magnitude/type) as well as other study design choices. Considering the rel- Acute opioid effects in preclinical research atively modest effect sizes and typical sample sizes There is abundant evidence of MOR modulation of ranging from 10 to 50 healthy participants in these psy- threat related learning in rodents. Endogenous mu-opi- chopharmacological studies, statistical power is also a oid signaling inhibits fear conditioning (Good & West- concern. More research is needed to provide a full un- brook, 1995) and facilitates fear extinction (McNally et derstanding of the functions of the healthy opioid sys- al., 2004). Moreover, administration of a MOR agonist tem. interfered with the aversive conditioning process, de- Importantly, the human literature using antagonists creasing its efficacy, whereas administration of the unequivocally demonstrates that a substantial amount MOR antagonist naloxone enhanced threat condition- of reward liking can be observed (see Figure 2) even ing in rodents (McNally, 2009; McNally & Westbrook, after so-called opioid blockade, defined as 90-100% of 2003). The peri-acqueductal gray (PAG) emerges as a MOR bound by naloxone/naltrexone or other antago- key structure mediating opioid regulation of threat re- nists. It is also pertinent in this context to recall that lated learning. Opioid receptors in the ventrolateral part while several PET studies have yielded results con- of the PAG (vlPAG) are suggested to mediate discrep- sistent with release of endogenous mu-opioids during ancies between an actual and an expected outcome of a and/or after engagement in rewards such as social ac- conditioning trial which is known as the prediction er- ceptance (Hsu et al., 2013), eating pizza (Tuulari et al., ror and therewith influence both, the acquisition of con- 2017) or enjoying comedy TV (Manninen et al., 2017), ditioned fear responses as well as extinction learning other studies have yielded opposite findings, e.g. for (McNally, 2009; McNally et al., 2004). For example, pleasant touch (Nummenmaa et al., 2016). In other when outcomes are less aversive than expected, opioid words, it is clear that while endogenous mu-opioids signaling from the vlPAG accompanies these (relative) contribute to the fine-tuning of reward processing in safety cues, triggering a downregulation of threat re- healthy humans, mu-opioid receptors are not the only sponses in the amygdala and thereby reducing the dis- neurochemical system capable of signalling reward lik- crepancy between expected and experienced outcomes, ing and motivation in the human brain. Other important facilitating extinction learning (McNally, 2009). A re- modulators and mediators of reward processing in hu- cent study found that MORs in the dorsal midline thal- mans include endocannabinoids, serotonin and dopa- amus contribute to opioid modulation of extinction mine, e.g. (Bershad et al., 2019; Ferreri et al., 2019; learning (Bengoetxea et al., 2020) and effects in the Mayo et al., 2020; Rutledge et al., 2015). In the next same direction were found in a study using systemic section, we discuss the role of opioids for negatively blockade of the MOR system (Kim & Richardson, valenced events, stress and fear. 2009). The MOR system also regulates stress responses. Early infant-attachment studies in different mammalian Stress and Fear species showed that opioid blockade increased distress Being able to adequately respond to threat cues in vocalizations in young animals after separation from the environment is crucial for human social function- their mothers (for a review, see e.g. Løseth et al., 2014). ing. Hypersensitivity to threat and impaired threat re- Administration of MOR agonists on the other hand, re- lated learning processes are associated with affective sulted in a decrease of distress vocalizations (Panksepp disorders such as anxiety or PTSD (Hartley & Phelps, et al., 1978). Human and non-human animal research 2010; Rauch et al., 2006). Rodent and human experi- reports that endogenous opioids are released in re- mental research indicates a regulative and supportive sponse to stress and are directly involved in regulating role of MOR signalling in adaptive responses to threat the HPA axis response to stressors (al’Absi et al., 2020; (Eippert et al., 2008; Haaker et al., 2017; McNally, degli Uberti et al., 1995; Morris et al., 1990; Rushen et 2009). As illustrated in Figure 1, key brain structures al., 1993; Wand et al., 2011, 2012) in a sex-specific involved in the processing of threat are densely inner- manner. Rodent research investigating the interactive role of the MOR system and the corticotropin releasing

8 MEIER, EIKEMO & LEKNES PREPRINT factor (CRF) in the locus coeruleus, shows that at con- the MOR system resulted in a stronger negative subjec- frontation with an acute stressor the MOR system is in- tive experience of losing money in a gambling task in volved in downregulating the effects of CRF, promot- an fMRI set-up. Experiencing losses was associated ing recovery after stress. This mechanism is highly with enhanced activity in the anterior insula and the adaptive in the short-term, however, confrontation with caudal anterior cingulate cortex (Petrovic et al., 2008). repeated stress resulted in chronic inhibitory action via Overall, there is some support of the idea that endoge- mu-opioid receptors in the locus coeruleus, with long- nous opioid activity in healthy humans reduces the sen- term modifications of neural circuits involved in stress sitivity to negative affective cues (Bershad et al., 2016; regulation (Valentino & Van Bockstaele, 2015). Ipser et al., 2013; Løseth et al., 2018; Petrovic et al., 2008; but see Wardle et al., 2016), but effects tend to Acute opioid effects in human research be small. In line with rodent evidence (Good & Westbrook, In addition to mu-opioid fine-tuning of threat re- 1995; McNally & Cole, 2006), two psychopharmaco- lated learning and perception of negative affective logical neuroimaging studies demonstrated an inhibi- cues, endogenous opioid signaling also impacts the tory role for the MOR system in the acquisition of con- body’s stress response via its actions on the hypotha- ditioned fear in humans (Eippert et al., 2008; Haaker et lamic–pituitary–adrenal (HPA) axis (al’Absi et al., al., 2017). Blocking the MOR system with naloxone re- 2020; Lovallo et al., 2015; Wand et al., 2011). These sulted in a modest increase in behavioural conditioned effects are sex-dependent. For instance, opioid antago- responses, defined as faster identification of the stimu- nism has revealed a substantial tonic mu-opioid inhibi- lus location of conditioned stimuli, and reduced habit- tion of cortisol and ACTH that appears to be specific to uation to conditioned stimuli in pain- and threat related women (Lovallo et al., 2015). pathways (Eippert et al., 2008). Further, administration The role of MOR for (hypothetical) social rejection of naltrexone was associated with a lack of habituation was tested using PET: the bilateral amygdala, the ven- response to threat cues in the amygdala over time. More tral striatum, thalamus and the subgenual anterior cin- recently, these findings were extended to the social gulate cortex showed decreased binding after rejection learning context. Haaker et al. (2017) showed that con- (Hsu et al., 2013). As has also been reported for physi- ditioned responses acquired through observational cal pain, e.g. (Zubieta et al., 2001), MOR activity (or learning were enhanced after blocking the MOR system alternatively a change in mu-opioid receptor expres- with naltrexone as indicated by increased signaling re- sion) was positively correlated with measures of suc- sponses in amygdala, PAG and midline thalamus. Be- cessful downregulation of negative affect (Hsu et al., haviourally, MOR blockade also led to stronger long- 2013). Nevertheless, the role of MOR signalling in reg- term expression of learned threat responses (Haaker et ulating the human subjective experience of distress al., 2017). Together, the results support the idea that may be substantially smaller than its effect on physio- endogenous opioid signaling dampens aversive learn- logical stress responses. Administration of the MOR ing processes through first-hand experience as well as agonists compared to placebo reduced the cortisol through social learning. stress-response in humans (Bershad et al., 2015, 2018), Does human MOR signalling regulate sensitivity to as reported in abundant rodent studies (Drolet et al., negative affective cues outside of a fear learning con- 2001; Ribeiro et al., 2005; Valentino & Van Bock- text? There is some evidence in support of this notion staele, 2015). Unexpectedly, this dampening of cortisol from behavioural studies. Administration of a MOR ag- was not associated with opioid-induced decreases of onist reduced sensitivity to fearful facial expressions in subjective ratings of anxiety or negative emotions (Ber- an emotion recognition task (Ipser et al., 2013), whe- shad et al., 2015, 2018). Conversely, opioid antagonism reas Løseth et al. (2018) reported reduced perceived an- increased cortisol after stress induction without altering ger in images with neutral and ambiguous facial ex- subjective stress responses (al’Absi et al., 2020). pressions only. In another study, administration of bu- Overall, the evidence of acute opioid effects on prenorphine resulted in an initial attention bias to fear- stress and threat processing in healthy humans suggests ful emotional expressions, as measured by direction of a modest, protective function of enodogenous opioid gaze with electrooculography (Bershad et al., 2016). signalling – reducing the physiological stress response Notably, the effects in these studies were small and and fine-tuning sensitivity as well as learned responses somewhat inconsistent, pointing to a relatively minor to negative stimuli. Whether chronic dysregulation of role of mu-opioid activation in perception of emotional endogenous opioid signalling, through e.g. chronic opi- expressions. Beyond emotion perception, blockade of

9 MEIER, EIKEMO & LEKNES PREPRINT oid drug use, could paradoxically reinforce stress re- medication assisted treatment (MAT) with opioid ago- sponses and negative affect is of yet unknown. Current nist drugs are rarely stable in treatment, and often con- evidence indicates co-occurrence of opioid use disorder sume illegal drugs on-top of treatment. and anxiety related symptoms (Langdon et al., 2019; A number of studies observe blunted sensitivity to Martel et al., 2013; McHugh et al., 2016; Rogers et al., natural rewards in, or following, long-term opioid use 2019), (history of) life stressors such as trauma or low as measured by behavioural tests and/or brain imaging socio-economic status (Helmerhorst et al., 2014), and and higher self-reported anhedonia (Garfield et al., poor emotion regulation capacities (Garland et al., 2017; Garland et al., 2015; Huhn et al., 2016; Lubman 2017). More systematic research of the healthy human et al., 2000; Martinotti et al., 2008; Stevens et al., 2007; brain, addressing the role of the MOR system in fear Zijlstra et al., 2009) compared to control participants. related learning and other negatively valenced pro- Other studies report little change in reward experience cesses, is necessary to understand how regulation of and behaviour following long-term opioid use. For in- negative affect or learning processes could be altered in stance, we have reported intact objective and subjective individuals with chronic opioid use. reward responsiveness in women in stable long-term MAT with buprenorphine or methadone relative to healthy volunteers (Eikemo et al., 2019). We have also Anhedonia and reward sensitivity following pro- found that self-reported anhedonia was not elevated in longed opioid use chronic pain patients treated with opioids, compared to Disrupted reward processing related to drug-in- patients who did not use opioids (Garland et al., 2020). duced disturbances of the mu-opioid (and dopamine) Pain patients who specifically reported misusing their reward system is a key element in neurobiological the- opioid analgesics however, showed higher levels than ories of drug addiction (e.g. Hyman et al., 2006; Koob, non-misusing patients. Notably, these results did not 2020; Robinson & Berridge, 2001). While the effects change when adjusting for variance in depression of acute administration of opioids on reward sensitivity symptoms (Garland et al., 2020). Moreover, in the do- in healthy participants are broadly consistent, the evi- main of sweet taste reward, long-term opioid use has dence for anhedonia following long-term opioid use been associated with increased sucrose liking, motiva- and dependence is mixed (Garfield et al., 2014; Hat- tion and consumption (Nolan & Scagnelli 2007), indi- zigiakoumis et al., 2011; Kiluk et al., 2019). cating a lack of anhedonia for sweet foods in this pop- The knowledge of anhedonia in chronic opioid use ulation. However, this apparent increase in reward re- and opioid use disorder is largely based on individuals sponsivity may be caused by a blunted sweet taste re- with an established opioid use disorder. Consequently, ward experience and need for higher sucrose content to disentangling opioid-induced changes in reward behav- reach ‘optimal’ sweetness (Green et al., 2013). iour and experience from pre-existing anhedonia is Several reviews on anhedonia in substance use dis- challenging. Additionally, opioid use disorder is asso- orders show that the most convincing evidence for an- ciated with a range of psychosocial vulnerability fac- hedonia in OUD and other SUDs is related to discom- tors (Degenhardt et al., 2014) that in themselves in- fort during early abstinence in patients who have crease risk of anhedonia and blunted reward respon- started treatment, and correlates with drug craving and siveness. For example, comorbid mental health symp- opioid use (Garfield et al., 2014; Hatzigiakoumis et al., toms and disorders (e.g. Grella et al., 2009); stressful 2011; Kiluk et al., 2019). In a recent study, Garfield et life events, (history of) trauma and even PTSD (e.g. al. (2017) found evidence to suggest that illicit opiate Mills et al., 2007); unstable social relations and eco- use is a potential cause of self-reported anhedonia nomic resources (Donoghoe et al., 1992) and somatic among patients in MAT with opioid agonist drugs. disorder such as chronic pain (Garland et al., 2013) may Across samples reported in the literature, we find independently impact reward experience and behav- broadly comparable anhedonia scores in chronic pain iour. Further, the existing literature typically reports and substance use disorder (Trøstheim et al., 2020); it data from polydrug users who regularly use nicotine is conceivable that anhedonia in these conditions is and sometimes have high alcohol consumption and use more related to discomfort and suffering than to direct other psychotropic medication (e.g. anxiolytics, hyp- effects on opioid receptors in the reward system. notics). As substance use disorder by definition is a In a large-scale systematic review and meta-analy- chronic relapsing disorder, the patients tested during sis previously published by our group (Trøstheim et al., 2020), we also show that the degree of anhedonia re- ported in substance use disorder is typically much

10 MEIER, EIKEMO & LEKNES PREPRINT smaller than that measured in for example major de- More research is warranted to gain a better under- pressive disorder or PTSD. The relatively intact re- standing of opioid modulation of reward, threat and sponsiveness to non-drug reward exhibited across stud- stress related processing in the healthy human brain as ies of substance use disorder samples is somewhat un- well as in opioid users. Despite high co-occurrence of expected, considering the adversities and risk factors opioid misuse and anxiety, it is unclear whether anxiety associated with OUD. Overall, we conclude that there predates or could result from chronic opioid exposure. is little evidence to suggest that the anhedonia and re- Anhedonia is often, but not always observed in opioid ward changes are due to opioid specific effects. Instead, using populations, but changes in reward sensitivity ob- anhedonia in OUD may be explained by other co-oc- served after chronic opioid use may be explained by curring factors. An account of how opioid gene varia- other co-occurring vulnerability factors rather than opi- bility is related to OUD is reviewed in Darcq & Kieffer, oid system dysregulation. (2018) and Moningka et al. (2019). Notably, the num- ber of participants in most studies is modest due to the References participant group being notoriously hard to recruit, test and follow over time. The very heterogenous samples Achterberg, E. J. M., van Swieten, M. M. H., Hou- give the studies ecological validity, but prevents re- wing, D. J., Trezza, V., & Vanderschuren, L. J. M. J. searchers from determining the unique role of opioid (2019). Opioid modulation of social play reward in ju- agonist exposure on reward responsiveness. We believe venile rats. 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Anesthesiology, 104(3), 570–587. liking and wanting to a range of reward modalities, in- https://doi.org/10.1097/00000542-200603000-00025 cluding foods, social information, abstract rewards and Angst, M. S., Lazzeroni, L. C., Phillips, N. G., social connectedness. Whilst most studies report signif- Drover, D. R., Tingle, M., Ray, A., Swan, G. E., & icant effects to especially high-reward stimuli, incon- Clark, J. D. (2012). Aversive and Reinforcing Opioid sistencies with regard to reward type (e.g. touch) re- Effects. Anesthesiology, 117(1), 22–37. main. With regard to threat processing human evidence https://doi.org/10.1097/aln.0b013e31825a2a4e points toward an inhibitory role of the MOR system in Bedard, N. A., DeMik, D. E., Dowdle, S. B., & the acquisition of fear associations. However, whilst Callaghan, J. J. (2018). Trends and risk factors for the direction of the effects is consistent with findings in prolonged opioid use after unicompartmental knee ar- rodents, the magnitude of effects is not comparable to throplasty. The Bone & Joint Journal, 100-B(1_Sup- those reported in rodent work. Results from perception ple_A), 62–67. https://doi.org/10.1302/0301- studies are mixed but suggest a subtle reduction of sen- 620X.100B1.BJJ-2017-0547.R1 sitivity to negative affective stimuli via endogenous Bengoetxea, X., Goedecke, L., Blaesse, P., Pape, opioid signalling. Similarly, human studies investigat- H.-C., & Jüngling, K. (2020). The µ-opioid system in ing the regulatory role of the MOR system in stress re- midline thalamic nuclei modulates defence strategies sponses indicate subtle effects on the subjective expe- towards a conditioned fear stimulus in male mice. rience of stress, but large effects on the physiological Journal of Psychopharmacology, 34(11), 1280–1288. level. We venture that the role of endogenous mu-opi- https://doi.org/10.1177/0269881120940919 oids for human reward and threat is limited to fine-tun- Berridge, K. C., & Robinson, T. E. (2003). Parsing ing the responses, and that the human brain also draws reward. Trends in Neurosciences, 26(9), 507–513. on other neurotransmitter systems such as the dopa- Berridge, Kent C. (2009). ‘Liking’ and ‘wanting’ mine, serotonin and endocannabinoid systems in re- food rewards: Brain substrates and roles in eating dis- ward and threat-related processing. orders. Physiology & Behavior, 97(5), 537–550. https://doi.org/10.1016/j.physbeh.2009.02.044 11 MEIER, EIKEMO & LEKNES PREPRINT

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