Opioids such as morphine, oxycodone, and fentanyl effectively relieve acute and post-operative pain, but long-term use can lead to tolerance. Chronic opioid use leads to cellular and circuit level adaptations that mediate tolerance, but how different opioids can differentially regulate the activity of the µ opioid receptor (MOR) and downstream effectors is not known. Additionally, MORs have different regulatory mechanisms based on whether they are in the somatodendritic or presynaptic terminal compartment. The mechanisms that mediate tolerance in the presynaptic compartment are also unknown. The goal of this dissertation is to advance our understanding of tolerance induced by opioids in both the somatodendritic and presynaptic terminal compartments.