Mu-opioid and nociceptin receptors show divergent, cell-type-specific actions in the mesocorticolimbic reward system in opioid use disorder.

The mu-opioid receptor (MOR) and the nociceptin/orphanin FQ receptor (NOPR) are closely related yet functionally distinct modulators of rewards, motivation, and affect. Within the mesocorticolimbic system, including the prefrontal cortex (PFC), the ventral tegmental area (VTA) and the nucleus accumbens (NAc), these receptors exhibit divergent, cell type-specific expression patterns that drive opposing behavioral outcomes. For example, MOR activation enhances rewards processing and reinforcement by facilitating dopamine transmission, whereas NOPR signaling in the VTA can reduce dopamine cell activity. In addition, MOR and NOPR are positioned within cortical circuits to preferentially reduce GABA and glutamate transmission, respectively. This review synthesizes current knowledge on how MOR and NOPR coordinate motivational and affective states through distinct neuronal populations across the mesocorticolimbic circuit. We also discuss emerging evidence for functional interactions between these systems and the therapeutic implications of pharmacological strategies targeting both receptors, including dual-acting MOR/NOPR ligands that enhance analgesic efficacy with reduced abuse liability. By integrating behavioral, molecular, and circuit-level findings, this synthesis aims to clarify how MOR and NOPR signaling jointly shape rewards and stress pathways, and provide insight into the development of safer and more effective treatments for opioid use disorders.