Dopamine D3 receptor-based medication development for the treatment of opioid use disorder: Rationale, progress, and challenges

Opioid abuse and related overdose deaths continue to rise in the United States, contributing to the current national opioid crisis. Although several opioid-based pharmacotherapies are available (e.g., methadone, buprenorphine, naloxone), they show limited effectiveness in long-term relapse prevention. In response to the opioid crisis, the National Institute on Drug Abuse proposed a list of pharmacological targets of highest priority for medication development for the treatment of opioid use disorders (OUD). Among these are antagonists of dopamine D3 receptors (D3R). In this review, we first review recent progress in research of the dopamine hypothesis of opioid reward and abuse and then describe the rationale and recent development of D3R ligands for the treatment of OUD. Herein, an emphasis is placed on the effectiveness of newly developed D3R antagonists in the animal models of OUD. These new drug candidates may also potentiate the analgesic effects of clinically used opioids, making them attractive as adjunctive medications for pain management and treatment of OUD.