Neurobiology of opioid dependence in creating addiction vulnerability

Abstract

Opioid drugs are potent modulators of many physiological and psychological processes. When given acutely, they can elicit the signature responses of euphoria and analgesia that societies have coveted for centuries. Repeated, or chronic, use of opioids induces adaptive or allostatic changes that modify neuronal circuitry and create an altered normality - the "drug-dependent" state. This state, at least that exhibited by those maintained continuously on long-acting opioid drugs such as methadone or buprenorphine, is generally indistinguishable from the drug-naïve state for most overt behaviors. The consequences of the allostatic changes (cellular, circuit, and system adaptations) that accompany the drug-dependent state are revealed during drug withdrawal. Drug cessation triggers a temporally orchestrated allostatic re-establishment of neuronal systems, which is manifested as opposing physiological and psychological effects to those exhibited by acute drug intoxication. Some withdrawal symptoms, such as physical symptoms (sweating, shaking, and diarrhea) resolve within days, whilst others, such as dysphoria, insomnia, and anxiety, can linger for months, and some adaptations, such as learned associations, may be established for life. We will briefly discuss the cellular mechanisms and neural circuitry that contribute to the opioid drug-dependent state, inferring an emerging role for neuroinflammation. We will argue that opioid addictive behaviors result from a learned relationship between opioids and relief from an existing or withdrawal-induced anxiogenic and/or dysphoric state. Furthermore, a future stressful life event can recall the memory that opioid drugs alleviate negative affect (despair, sadness, and anxiety) and thereby precipitate craving, resulting in relapse. A learned association of relief of aversive states would fuel drug craving in vulnerable people living in an increasingly stressful society. We suggest that this route to addiction is contributive to the current opioid epidemic in the USA.

Keywords: Learned Associative Model; aversive states; opioid epidemic; pass-forward allostasis; withdrawal relief.

Figure 1.. Learned association of relief of aversive states.

Initial opioid use is reinforced by euphoria and positive mood, promoting further drug use. However, the motivation for opioid taking changes with repeated use, where positive reinforcing effects of the drug wane in comparison to the drive to alleviate withdrawal effects (negative reinforcement). With repeated drug use, opioid dependence develops and the learned association with relief of the aversive withdrawal state is reinforced. Following abstinence, the risk of relapse can be driven by three paths. The first is by direct negative reinforcement and relief of withdrawal. The second path would be sensory or drug cues (e.g., drug paraphernalia, familiarity of location to previous drug use, scent, etc.) and drug access (left side of figure), where incentive salience drives craving and loss of inhibitory control drive relapse. The other (right side of figure) is the trigger of life stress events that recall the memory of learned association between drug taking and aversion relief. In individuals with pre-existing negative affective states, the prediction is that the initial opioid use would immediately be associated with negative reinforcement in alleviating dysphoric symptoms and a) memory consolidation would be established more rapidly and b) the opioid would have increased salience during withdrawal for creating associative memories due to exacerbated dysphoria.

Figure 2.. Laura’s pathway to heroin addiction.

Here we provide a hypothetical scenario of how learned association of relief of aversive states could lead to the development of addiction and the key role of opioid dependence. Let us consider a disappointed teenager (Laura) who sprained her ankle during tryouts for the cheerleading team and was rejected, not making the squad. Knowing that opioids will alleviate the pain caused by the sprained ankle, Laura takes an opioid analgesic pill she knows is in the bathroom medicine cabinet, left over from her older brother’s prescription for a wisdom tooth extraction. The opioid pill takes away Laura’s pain from the sprained ankle and makes her feel relaxed (mellow and with elevated mood). She is less bothered about the tryout rejection while under the influence of the opioid. The next day, Laura decides to take another pill as the drug effects have worn off and both the ankle (physical) pain and the (psychological) pain of rejection have returned and are just as bad as the day before. The taking of the opioid medication again relieves the physical pain and takes her mind off her failure. Over the next 10 days, the drug taking cycle continues, but each day the pain-relieving effects are less (development of tolerance) and she develops a modest anxiogenic state prior to taking the drug each day (early signs of withdrawal). As the pain from the ankle sprain subsides, the association of drug taking becomes the relief of the anxious and dysphoric states that emerge as the drug wears off. On day 10, the supply of drugs from the medicine cabinet is exhausted and withdrawal sets in. Drug seeking would be a consequence during this withdrawal phase given the learned association that the aversive symptoms she is experiencing could be effectively relieved by taking the opioid (negative reinforcement). Although unlikely, given the ready access to illicit opioids throughout society, let’s assume that at this point in Laura’s life, she doesn’t actively seek out prescription or other opioids. The teen goes through physical withdrawal (over days) with protracted mood disturbances accompanied by drug craving that is triggered by memories that she could relieve dysphoric states by taking opioids. She doesn’t continue to seek opioids at this stage because the pain of rejection has dissipated and she is now engaged with other activities in her peer group. Over a year later, her boyfriend breaks up with her, her grades are not stellar, and she may not get accepted to the colleges she wants to go to. Laura becomes extremely stressed and feels unable to cope. The emergence of these negative symptoms initiates a craving for opioids that is triggered by learned associative memories. At this point in her life, she has the resources to access heroin and relapses. Laura’s relapse reinforces the associative memories that aversive states are relieved by opioids and the foundation for further addictive behaviors is strengthened. In this example, drug dependence and withdrawal contributes to the addiction vulnerability and the learned associative memories are of the negative reinforcement provided by opioid relief of anxiogenic and dysphoric states, and are triggered by a different stressor.

Figure 3.. Cellular adaptations to opioids.

In the ‘Opioid Naïve’ state, mu opioid receptor expressing cells (e.g., GABAergic neuron; top panel, neuron A) modulate reward circuitry and many other neurons (top panel, neuron B) in the brain and periphery. Brain microglia (top panel, cell C) are normally in a quiescent surveillance state. Acute opioid administration activates mu opioid receptors, which couple to inhibitory G proteins and generate an active mu-signalosome (μ) that inhibits cell activity and neurotransmitter release. In the brain, mu opioid receptors are often on GABAergic inhibitory neurons and thus can activate adjacent neurons (B) via disinhibition. Microglia may also be activated directly by opioid drugs, although this is debated. In the ‘Opioid Dependent’ state, opioid receptor expressing neurons adapt to the continued presence of drug. Modifications occur in the µ-signalosome, neuronal proteome, and transcriptome, alongside modifications to neuronal morphology (e.g., spine density and dendritic arborization). Maintained activation of mu-opioid receptors begins a process of cellular, network, and system adaptations. On drug cessation withdrawal is triggered, and the adaptive (allostatic) changes that occur in the drug-dependent state rebound in a temporally (hours to years) orchestrated resetting of neurons and networks. Withdrawal symptoms are opposing the acute actions of opioids whereby neurons inhibited by opioid activation become excited during withdrawal. Other cells are engaged during withdrawal, including microglia (Cell C) and neurons within the anxiogenic learning circuitry (Cell D). Eventually, weeks to months after drug cessation, many networks re-establish a close-to-normal state, but neurons encoding memory circuits of withdrawal (cell D) and associated memories that drugs relieve aversive states can be triggered by stressful or aversive life events following ‘Protracted Abstinence’. Green: resting state, blue: inhibited state, yellow: near-normal dependent state, red: activated state. Arrows denote transition between states.