The Role of Mu-Opioids for Reward and Threat Processing in Humans: Bridging the Gap from Preclinical to Clinical Opioid Drug Studies

Abstract

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 regulation and anhedonia, have been linked to endogenous opioid signalling. 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 endogenous 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. Studies 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 endogenous opioids inhibit fear conditioning and reduce the sensitivity to aversive stimuli, although inconsistencies 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.

Keywords: Anhedonia; Mu-opioid system; Opioid misuse; Reward; Stress; Threat.

Fig. 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 BP_ND (binding potential relative to nondisplaceable radioligand in tissue, see Innis et al. [58]). 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://neurovault.org/collections/GCELSAIA/)

Fig. 2

Overview of behavioural results from our lab’s investigation into the role of endogenous mu-opioid signalling 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 pharmacological administration study, the expected pattern of results was found for most reward domains, with the exception 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 [21]; visual exploration and attention (fixations) to others’ eyes as measured with eye-tracking [22]. Gaze pattern illustrates a single trial. b Sweet liking ratings of high sucrose drinks [37]. c Ratio of time spent on most comfortable brush speed [70]. 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 [35]. * 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)