The Negative Affect of Protracted Opioid Abstinence: Progress and Perspectives From Rodent Models

Abstract

Opioid use disorder (OUD) is characterized by the development of a negative emotional state that develops after a history of long-term exposure to opioids. OUD represents a true challenge for treatment and relapse prevention. Human research has amply documented emotional disruption in individuals with an opioid substance use disorder, at both behavioral and brain activity levels; however, brain mechanisms underlying this particular facet of OUD are only partially understood. Animal research has been instrumental in elucidating genes and circuits that adapt to long-term opioid use or are modified by acute withdrawal, but research on long-term consequences of opioid exposure and their relevance to the negative affect of OUD remains scarce. In this article, we review the literature with a focus on two questions: 1) Do we have behavioral models in rodents, and what do they tell us? and 2) What do we know about the neuronal populations involved? Behavioral rodent models have successfully recapitulated behavioral signs of the OUD-related negative affect, and several neurotransmitter systems were identified (i.e., serotonin, dynorphin, corticotropin-releasing factor, oxytocin). Circuit mechanisms driving the negative mood of prolonged abstinence likely involve the 5 main reward-aversion brain centers (i.e., nucleus accumbens, bed nucleus of the stria terminalis, amygdala, habenula, and raphe nucleus), all of which express mu opioid receptors and directly respond to opioids. Future work will identify the nature of these mu opioid receptor-expressing neurons throughout reward-aversion networks, characterize their adapted phenotype in opioid abstinent animals, and hopefully position these primary events in the broader picture of mu opioid receptor-associated brain aversion networks.

Keywords: Mood; Mu opioid receptor (MOR); Neural circuits; Opioid use disorder (OUD); Opioid withdrawal; Rodent behavior.

Figure 1.. MOR-expressing brain centers traditionally studied in addiction, including OUDs.

A. The addiction cycle is conceptualized as a 3-stage cycling process, and applies to OUDs. Addiction develops when recreational use switches to binge/intoxication episodes. Each of these events is followed by withdrawal when the opioid drug clears out, and the development of an aversive state. A preoccupation/anticipation stage follows, where the urge for relief from withdrawal, as well as cue-induced craving, causes the next intoxication episode. When withdrawal is maintained for a long time, the negative affect increases with time, making abstinence difficult to sustain. B. MOR function in brain centers involved in OUDs. Brain regions are represented as colored squares (orange, binge/intoxication; blue, withdrawal/aversive state; red, preoccupation/anticipation), and MOR expression levels are indicated in light grey to black. The NAc, Amygdala (CeA and BLA), BNST and DRN are major contributing brain centers in the context of aversive aspects of addiction (see also Figure 2). MORs in GABAergic interneurons of the VTA (GABA-MOR) facilitate dopamine release and drug reward (34). MORs in the striatum, expressed mainly in D1R-type neurons (D1-MOR), regulate opioid reward and the motivation for opioid consumption (33, 80). MORs in the MHb (Chnrb4-MOR) reduce aversive states, which are revealed by naloxone blockade (95). MORs in the DRN drive adaptations leading to depressive-like states and social withdrawal in protracted heroin abstinence (54). ACA, anterior cingulate cortex; BNST, bed nucleus of the stria terminalis; BLA, basolateral amygdala; CeA, central amygdala; DRN, dorsal raphe nucleus; HIP, hippocampus; InsC, insular cortex; MHb, medial habenula; PFC, prefrontal cortex; NAc, nucleus accumbens; VTA, ventral tegmental area. Adapted from (5).

Figure 2.. Neuronal populations involved in reward/aversion responses in four major aversion brain centers.

A. Brain template representing brain regions of interest to study the negative affect of protracted opioid abstinence. ACA, anterior cingulate area; BLA, basolateral amygdala; BNST, bed nucleus of the stria terminalis; CeA, central nucleus of the amygdala; DRN, dorsal raphe nucleus; HIP, hippocampus; InsC, insular cortex; MHb, medial habenula; mPFC, medial prefrontal cortex; NAc, nucleus accumbens; PVT, paraventricular thalamus; tVTA, tail of the ventral tegmental area; VTA, ventral tegmental area. B. Summary of data obtained from selected optogenetic studies focused on the NAc, BLA/CeA, BNST and DRN. Photostimulation of the identified neuronal populations produce approach (arrow) or avoidance (dashed arrow) behavior in real-time preference testing. Glutamatergic neurons are in green, GABAergic neurons in blue and unspecified neuron types in black. *, photo-inhibition produced the opposite behavior. Other affect-related behaviors are also reported in these studies (see Supplementary information and Supplementary Table 1).