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.
Highlights
An opioid epidemic has emerged over the past decade in the United States causing overdose deaths fast approaching numbers dying from car accidents, with about 17,000 annual deaths from opioid therapeutics and 8200 deaths from heroin overdose in 20141,2
Other factors have been proposed to account for these data[56], but it appears that there is a considerable underestimation of deaths due to opioid and benzodiazepine overdose[57]. These findings are attributed to an increase in midlife stress of White males, and we propose that a learned association of opioid drug taking to alleviate psychological aversive states is a contributing factor for the increased mortality
We propose that the relevant circuits driving the learning for relief of aversion to elicit craving are likely to be created in circuitry orchestrated by the paraventricular nucleus of the thalamus (PVT) and bed nucleus of the stria terminalis (BNST) and that modifications in learning circuitry modulate the basal lateral and central amygdala to drive craving
Summary
An opioid epidemic has emerged over the past decade in the United States causing overdose deaths fast approaching numbers dying from car accidents, with about 17,000 annual deaths from opioid therapeutics and 8200 deaths from heroin overdose in 20141,2. We will argue that it is not necessarily positive reinforcement or the negative reinforcement to avoid withdrawal that drives opioid addiction, but it is a learned association of drug relief from an aversive mental state, either pre-existing or created by withdrawal, that drives craving and the resultant addictive-like behaviors in susceptible individuals (Figure 1). With feed-forward allostasis likely occurring in most neurons of the brain following opioid dependence, circuitry perturbation will be extensive Such processes will create an allostatic load that, following drug cessation, will initiate cellular and network activities opposite to the initial acute drug action engaging the BNST, PVT, and amygdala circuitry. It is tempting to speculate that microglia may be critical for the neuroadaptations responsible for the learning component of associating relapse of drug use with withdrawal relief, including the alleviation of anxiety or negative affect (Figure 3).
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