Our primary hypothesis was based on the previous literature which illustrated the role of endogenous opioids in mediating food, drug, and sex pleasure25,26,35,37,49,50; we predicted that blocking μ-opioid receptors with NTX would cause decreased physiological reactions to music for both positive and negative emotions. This was confirmed for both pleasurable and neutral music, compared to placebo, through EMG recordings of two different facial muscles (Fig. 1), supporting the NTX-induced anhedonia hypothesis.

Our secondary hypothesis was that these findings would be replicated with subjective, self-report measures of ongoing, real-time musical pleasure. This was confirmed for pleasurable music, but not neutral music. One might expect this, given that the neutral music is already attenuated in the two dimensions of valence and intensity. Here we face an inconsistency between the physiological and subjective measures. One possibility is that the physiological measures for neutral music have lower variability than the subjective measures (lower variability increases the likelihood of detecting statistical differences that exist). We confirmed this by computing coefficients of variation (CV), which were lower for the EMG measures than for the slider measure. For placebo, slider CV = 0.36, EMG ZYG CV = 0.34 and EMG COR CV = 0.09. For NTX, slider CV = 0.57, EMG ZYG CV = 0.30, EMG COR CV = 0.46.

Our subsidiary hypothesis was that the effects of the μ-opioid blockade would be greater for pleasurable music (because of its higher levels of emotional intensity and valence) than neutral music. This was confirmed for all three of our dependent measures. In addition, we collected supplementary psychobiological measures, BVPA, RR, and HR. Although none of them showed a main effect themselves, we adopted a meta-analytic approach and found that all three showed an effect in the hypothesized direction (p = 0.13) and, when taken together with the EMG measures, all five showed an effect in the hypothesized direction (p = 0.03).

Here, we’ve provided evidence for the NTX-induced anhedonia hypothesis, and thus evidence that musical pleasure is mediated by the brain’s endogenous opioid system. The fact that music listening triggers a well-defined neurochemical response suggests an evolutionary origin for music, although one must be cautious and not over-interpret these results; it is also possible that music has developed to exploit an already existing reward system that evolved for other purposes, such as recognizing and responding appropriately to various human and animal vocalizations.

The current experimental finding of reduced response from both the positive and negative valence EMGs (ZYG and COR respectively) reinforces the notion that music is complex and rarely conveys a single emotional valence. Listeners more often report finding music to be bittersweet than purely happy or purely sad51,52, and many listeners report that even sad music brings them pleasure53. This may appear to contradict some of the literature with regard to opioids, pain relief and induced sadness. Prior work showed that pain and induced sadness reduce μ-opioid transmission as reflected by an increase in μ-opioid receptor availability in vivo in an induced sadness condition (participants recalled a tragic autobiographical event) compared to a neutral mood condition54,55. However, sadness evoked by music is different from sadness induced by pain or by recalling a tragic event. According to Levinson56, some of the qualitative rewards of sad music include savoring the feeling, understanding the feeling, reassuring oneself of the ability to feel intense emotions and sharing the sadness with others (in many cases the composer). These rewards are not directed to any real-life circumstances and thus tend not to evoke the negative aspects of sadness (i.e. grieving over loss of a loved one), which in turn may not elicit the neurochemical response of sadness and depression caused by tragic events. To a certain extent this was verified by Panksepp57 who showed that sad music evokes more intense physiologically pleasurable responses (“chills”) than happy music.

Our administration of 50 mg NTX is known to block up to 80% of the μ-opioid and some δ-opioid receptors58; this underlies the observed decrease in pleasure relative to the placebo condition. An additional finding of interest in the EMG COR is found when neutral music condition is subtracted from that of pleasurable music condition for both placebo and NTX groups. We see a significant decrease in the difference between pleasurable and neutral music in the EMG COR (Figure S2) for the NTX group relative to the placebo group. This smaller difference further shows that NTX decreases the range of emotional response to music stimuli and adds to the weight of evidence that opioids don’t merely sub-serve pleasure and the positive valence emotions, but are implicated in any emotional changes, positive or negative35,37,50.

One limitation in this study is the inability to produce a double-dissociation between anticipatory (dopamine-mediated) and consummatory (opioid-mediated) pleasure, primarily because no selective dopamine antagonist exists that is safe for human administration. A second limitation is intrinsic. Music unfolds over time, and creates ongoing expectations. Although we selectively blocked the consummatory pleasure system, the pleasure phases play out differently in music than in, say, drugs, sex, and food, when the fulfillment of expectations is more well-defined in time. Anticipatory pleasures may exist during the consumption phase of music listening as new musical structures are introduced that build up ongoing expectation and release patterns. In fact, in a prior study, we demonstrated that musical anticipation is intimately bound with fulfillment of pleasure by showing that brain activity in the default mode network (as indexed by the BOLD response in fMRI) reaches a maximum during periods of silence, when no music is playing at section transitions in symphonic works59.

Further supporting the blurred distinction between anticipation and consumption reward in music, a previous study15 using positron emission tomography (PET) with the selective dopamine radiotracer [11C] raclopride found dopamine release during both anticipatory and consummatory phases of music listening, but in different neural networks. Dopamine may therefore mediate pleasure in both cases, and opioids could be acting in a more global fashion, as evidenced by the attenuation of both sadness and happiness that we found. Supporting this notion is that the μ-opioid and dopaminergic systems are linked: blocking the μ-opioid receptors in rats in the ventral tegmental area decreases dopamine levels as these μ-opioid receptors provide stimulation to dopaminergic neurons which project to the nucleus accumbens16,17,18,19,20,22.

Another limitation is the generalizability of our study. As is typically done in behavioral research, we selected participants from a university community and regardless of the statistical tests used, one should not assume that such a restricted population is representative of the general population.

We have shown here that the opioid system is responsible for mediating the elicitations of both positive (pleasurable) and negative (sadness) emotional responses to music. It remains to be seen exactly how the opioid system interacts with the dopaminergic system in emotional responses to music. Future studies using music stimuli in which anticipatory expectations are violated or computer generated music in which only the anticipatory component is included could be used to more clearly differentiate the anticipatory phase from the consumption phase in music60,61. In addition, future PET studies using both dopamine and opioid radiotracers can further shed light on how these two systems interact.