Dopamine Supersensitivity: A Novel Hypothesis of Opioid-Induced Neurobiological Mechanisms Underlying Opioid-Stimulant Co-use and Opioid Relapse

Abstract

Emergent harms presented by the co-use of opioids and methamphetamine highlight the broader public health challenge of preventing and treating opioid and stimulant co-use. Development of effective therapeutics requires an understanding of the physiological mechanisms that may be driving co-use patterns, specifically the underlying neurobiology of co-use and how they may facilitate (or be leveraged to prevent) continued use patterns. This narrative review summarizes largely preclinical data that demonstrate clinically-meaningful relationships between the dopamine and opioid systems with direct implications for opioid and stimulant co-use. Synthesized conclusions of this body of research include evidence that changes in the dopamine system occur only once physical dependence to opioids develops, that the chronicity of opioid exposure is associated with the severity of changes, and that withdrawal leaves the organism in a state of substantive dopamine deficit that persists long after the somatic or observed signs of opioid withdrawal appear to have resolved. Evidence also suggests that dopamine supersensitivity develops soon after opioid abstinence and results in increased response to dopamine agonists that increases in magnitude as the abstinence period continues and is evident several weeks into protracted withdrawal. Mechanistically, this supersensitivity appears to be mediated by changes in the sensitivity, not quantity, of dopamine D2 receptors. Here we propose a neural circuit mechanism unique to withdrawal from opioid use with implications for increased stimulant sensitivity in previously stimulant-naïve or inexperienced populations. These hypothesized effects collectively delineate a mechanism by which stimulants would be uniquely reinforcing to persons with opioid physical dependence, would contribute to the acute opioid withdrawal syndrome, and could manifest subjectively as craving and/or motivation to use that could prompt opioid relapse during acute and protracted withdrawal. Preclinical research is needed to directly test these hypothesized mechanisms. Human laboratory and clinical trial research is needed to explore these clinical predictions and to advance the goal of developing treatments for opioid-stimulant co-use and/or opioid relapse prevention and withdrawal remediation.

Keywords: cocaine; methamphetamine; opioid; relapse; stimulant; treatment; withdrawal.

Figure 1

Neural circuitry and dopamine disinhibition by opioid use. Neural circuitry involved in opioid use includes cortical, striatal, thalamic, mesencephalon, and brainstem structures. Dopamine cell bodies residing within the VTA receive GABAergic innervation from both GABAergic interneurons and projection neurons from the RMTg. GABA activates GABA-A receptors located on dopamine neurons, thus providing inhibition of dopamine neuronal activity. Through these terminals, dopamine excitability is maintained in homeostasis within an opioid-naïve system. When opioids are present, these compounds act as agonists at inhibitory (G_i/o) μ opioid receptors, which exerts inhibitory tone on GABAergic terminals synapsing onto dopamine cells. The net result is an enhancement of phasic dopamine release into terminal structures, including the NA. PFC, prefrontal cortex; HIPP, hippocampus; NA, nucleus accumbens, VTA; ventral tegmental nucleus; RMTg, rostromedial tegmental nucleus; LC, locus coeruleus; AMG, amygdala; DRN, dorsal raphe nucleus; 5-HT, serotonin.

Figure 2

Hypothesized Neural Circuit of D2 Hypersensitivity in Opioid Withdrawal. We hypothesize that D2 receptor activity is during withdrawal from chronic opioid use (1), which leads to decreased activity of GABAergic MSNs within the NA (2). This leads to a reduction in GABAergic inhibitory tone from the NA to the VP (3). Through the direct projection to the VP, disinhibition of the VP from reduced NA-derived GABAergic innervation leads to enhanced excitability of cells residing in the VP. It is also possible that MSNs co-expressing D1 and D2 receptors project from the NA to the VM, and play a critical role in enhancing dopaminergic signaling from the VM to output structures. As well, enhanced enkephalin activity may enhance neuronal excitability within the VP (4). This excitation leads to enhanced acetylcholine release into the MD (5), which may enhance reward. Through the direct GABAergic projection from the VP to the mesencephalon, there is less inhibitory tone and consequently, enhanced dopaminergic activity in cells residing in the VM and projecting back to the VP or to the MD (6). The net result of these neural adaptations is enhanced excitability of thalamic nuclei including the MD (7), and, consequently, enhanced use of dopamine agonists during opioid withdrawal (8). NA, nucleus accumbens; VP, ventral pallidum; VM, ventral mesencephalon; MD, mediodorsal thalamic nucleus; D2, dopamine receptor D2; D1, dopamine receptor D1; MSN, medium spiny neuron.