The multiple facets of opioid receptor function: implications for addiction

Abstract

Addiction is characterized by altered reward processing, disrupted emotional responses and poor decision-making. Beyond a central role in drug reward, increasing evidence indicate that opioid receptors are broadly involved in all these processes. Recent studies establish the mu opioid receptor as a main player in social reward, which attracts increasing attention in psychiatric research. There is growing interest in blocking the kappa opioid receptor to prevent relapse, and alleviate the negative affect of withdrawal. The delta opioid receptor emerges as a potent mood enhancer, whose involvement in addiction is less clear. All three opioid receptors are likely implicated in addiction-depression comorbidity, and understanding of their roles in cognitive deficits associated to drug abuse is only beginning.

Figure 1. Opioid receptors are key players in most brain processes underlying addiction

Top. In addicted individuals, recreational drug use switches to compulsive drug intake. The addiction cycle typically includes intoxication/withdrawal/craving episodes [1]. Exiting the vicious cycle requires strict maintenance of abstinence. Drug abstinence in former addicts is characterized by a negative affect, which strongly contributes to relapse [44]. Bottom. The mu and kappa opioid receptors (MOR and KOR) exert opposing control over drug and social reward, with MOR enhancing and KOR reducing reward processing. MOR and delta (DOR) opioid receptors oppositely regulate inhibitory controls, with MOR and DOR activities increasing and decreasing motor impulsivity, respectively. MOR-mediated reward and impulsivity likely contribute to initiate drug use. The three opioid receptors fulfill distinct roles in addiction-related emotional disorders, with pro- and antidepressant-like activity for KOR and DOR, respectively, and a complex role for MOR [42]. The MOR may also be a key player in brain pathways encoding social pain. Arrows indicate the effects of opioid receptors activities.

Figure 2. The mu opioid receptor (MOR) controls a number of addiction-related neuronal processes throughout the brain

In rodents, the MOR is enriched in brain regions mediating: social reward and pain, cognition (impulsive behaviors and decision-making) and emotional responses. (a) Autoradiogram of a sagittal mouse brain section showing [³H]-DAMGO MOR binding (Courtesy of Pr Ian Kitchen [–62]), where highest densities are represented in dark red. (b) Corresponding absolute values of [³H]-DAMGO MOR binding in selected brain regions. (c) Addiction-related brain structures and neuronal functions for which a role of MOR is demonstrated (references between brackets, see also the main text) or suggested. MOR pools in the ventral tegmental area (VTA) and the frontal cortex (FCx) tightly control drug reward, and likely also regulate social reward. MORs in the dorsal raphe nucleus (DRN) and thalamus (Th) may modulate emotions and the affective dimension of social painful experiences, respectively. The potential relevance for addiction of MOR located in the medial habenula (MHb) – the highest MOR expression site in the brain – remains currently unknown. (d) Although rodent and human brain functions cannot be matched exactly, studies of human addiction similarly focus on social reward and dysfunction, the disruption of executive functions and the development of emotional comorbidities (courtesy of Pr Gunter Schuman [63]). Abbreviations: ACC, anterior cingulate cortex; Amy, amygdala; BLA, basolateral amygdala; IFC, infralimbic cortex; NAc, nucleus accumbens; OFC, orbitofrontal cortex; PFC, prefrontal cortex; SN, substancia nigra; VMPFC, ventromedial prefrontal cortex.