Opioid use disorder is a chronic relapsing disease. Relapse is precipitated by cravings for the euphoric, rewarding effects of opioids as well as a desire to alleviate physical and emotional pain. Cravings can be triggered by external cues and negative emotional states associated with previous drug use. Identifying the neuronal mechanisms that underlie cue-induced cravings is critical for developing treatments that can prevent relapse. In this dissertation, I describe pathological behavioral and neuronal plasticity that emerges during abstinence from chronic prescription opioid use and contributes to heightened responding for opioid-associated cues.