The Opioid-Addicted Tetrapartite Synapse

Abstract

Opioid administration in preclinical models induces long-lasting adaptations in reward and habit circuitry. The latest research demonstrates that in the nucleus accumbens, opioid-induced excitatory synaptic plasticity involves presynaptic and postsynaptic elements as well as adjacent astroglial processes and the perisynaptic extracellular matrix. We outline opioid-induced modifications within each component of the tetrapartite synapse and provide a neurobiological perspective on how these adaptations converge to produce addiction-related behaviors in rodent models. By incorporating changes observed at each of the excitatory synaptic compartments into a unified framework of opioid-induced glutamate dysregulation, we highlight new avenues for restoring synaptic homeostasis that might limit opioid craving and relapse vulnerability.

Transcriptional alterations in opioid use disorder reveal an interplay between neuroinflammation and synaptic remodeling

“…Consistent with this, preclinical opioid studies implicate structural changes to the ECM with accompanying changes to dendritic and synaptic plasticity(135,146). For example, ECM reorganization in the NAc via matrix metalloproteinases (MMPs), which facilitate matrix degradation and reassembly, is associated with increases in glutamatergic synaptic potentiation(147) and opioid relapse behaviors(135). Importantly, our analyses identified a critical new hub linking ECM remodeling via MMPs, neuroinflammation, and OUD.…”

“…We therefore posit that opioid-induced changes in CS-GAG signaling driven by neuroinflammation disrupt ECM structure and have profound consequences on dendritic and synaptic plasticity. Consistent with this, preclinical opioid studies implicate structural changes to the ECM with accompanying changes to dendritic and synaptic plasticity(135,146). For example, ECM reorganization in the NAc via matrix metalloproteinases (MMPs), which facilitate matrix degradation and reassembly, is associated with increases in glutamatergic synaptic potentiation(147) and opioid relapse behaviors(135).…”

Interruption of continuous opioid exposure exacerbates drug-evoked adaptations in the mesolimbic dopamine system

“…Stimulation of these receptors is positively reinforcing [ 3 , 4 ] and enhances mesolimbic dopamine release in rodents [ 5 , 6 ], though this latter effect has been difficult to detect in humans [ 7 , 8 ]. While dopamine manipulations have mixed effects on acute opioid reward [ 6 , 9 ], chronic opioid exposure produces transcriptional and epigenetic changes in the nucleus accumbens, leading to structural and functional circuit remodeling that are hypothesized to promote addiction and vulnerability to relapse [ 10 – 12 ]. Prevention strategies that minimize these iatrogenic effects might facilitate safer opioid use for clinical indications [ 13 ].…”

Chromatin accessibility mapping of the striatum identifies tyrosine kinase FYN as a therapeutic target for heroin use disorder

“…Glutamate receptor trafficking and function is well known to have a central role in neuronal adaptations that underlie the abuse of various substances 20 , 47 . Furthermore, long-lasting activation of Fyn has been previously described by Ron and colleagues during alcohol use 23 – 25 .…”