This dissertation explores the regulation and adaptation of mu-opioid receptors (MORs) within the paraventricular nucleus of the thalamus (PVT), a brain region critical for integrating stress and reward signals. Through a combination of electrophysiology, pharmacology, and imaging, it identifies distinct differences in MOR responses between anterior and posterior PVT neurons, including projection-specific adaptations to chronic morphine exposure. In the anterior PVT, I demonstrated varying degrees of opioid tolerance, withdrawal, and receptor desensitization, highlighting the PVT’s heterogeneous contributions to stress, motivation, and addiction. This work advances understanding of opioid modulation in neural circuits and identifies circuit-specific targets for addressing opioid use disorders.