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. Copyright © 2019 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.