Abstract
Purpose of ReviewOpioid 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 FindingsIn 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.SummaryThe 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.
Highlights
Despite increasing awareness of the risks of problematic opioid use, opioid analgesics are still commonly used to treat acute and chronic pain [15, 60, 136]
High-stress conditions such as history of trauma, posttraumatic stress disorder (PTSD), low socio-economic status or poor social support are vulnerability factors for development of substance misuse and are frequently observed as comorbidities in opioid use disorder [5, 23, 51, 52, 94, 103, 113, 131]. These findings align with prominent addiction theories pointing towards two major pathways into drug abuse, one related to drug liking and sensitization of the reward circuitry to drug related cues [25, 101], and another more driven by attempts to reduce negative affective states and to cope with stressors [63]
Groundbreaking rodent research on the role of the mu-opioid receptor (MOR) system in reward has identified the areas in the rostrodorsal shell of the nucleus accumbens (NAc), the caudal ventral pallidum (VP), the parabrachial (PB) nucleus as well as the anterior orbitofrontal cortex (OFC) and the posterior insula as hotspots that can enhance ‘liking’ responses to food rewards [8, 9, 19, 92]
Summary
Despite increasing awareness of the risks of problematic opioid use, opioid analgesics are still commonly used to treat acute and chronic pain [15, 60, 136]. To understand what has gone wrong in addiction, we must first establish how these processes function in the healthy, non-addicted human brain This narrative review will give an overview of the current state of knowledge on endogenous opioid function in humans, based on behavioural evidence from opioid drug studies. The limited emerging evidence on kappa-specific activity is exciting, see e.g. Darcq & Kieffer [28]; Krystal et al [65]; Pizzagalli et al [95], and we note that antagonist effects currently attributed to mu-opioid signalling may reflect antagonism of kappa and to a lesser extent delta receptors Both receiving and anticipating rewards can evoke feelings of pleasure in humans. Reward processing is often parsed into several components, including liking (the hedonic experience when a reward is anticipated or obtained), wanting (the motivational component, often assessed as the drive and/or effort spent to obtain a reward) and reward-related learning (e.g. [7])
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