There is limited information on the role of the Nociceptin/Orphanin FQ receptor (NOPR) in neuroinflammation, and there is growing interest in the participation of the NOPR in depression etiology. This study aims to evaluate the neuroinflammatory effects of the NOPR activation in mice submitted to social defeat protocol (SDP). Firstly, male Swiss mice were submitted to the social defeat protocol during 10 or 20 days and treated with the NOPR agonist Ro 65-6570 (1.5 or 2 mg/kg
ip). Subsequently, behavioral tests were applied to evaluate depressive-like behaviors. Finally, inflammatory cytokines were measured in the animals' brains and blood. A meta-analysis, including 11 experiments, was also conducted to evaluate if the NOPR activation contributes to inflammation. The studies' weights, odds ratios, and confidence intervals were used to calculate the average effect size as the main outcome measure. The software SPSS v.29 and R programming language were used to analyze the data. The SDP and/or NOP agonist reduced distance traveled and exploration rate in the open field test. The SDP and/or the NOP agonist also increased immobility time in the tail suspension test, as well as reduced social interaction. Additionally, the NOP agonist increased the concentration of IL-6 and TNF alpha in the hippocampus, as well as reduced the IL-10 concentration in the hippocampus, but not in prefrontal cortex and serum. The SDP increased the concentration of IL-6 and TNF alpha in animals' serum and prefrontal cortex, but not in the hippocampus. The role of NOPR in neuroinflammation was regardless of the social defeat stress in the hippocampus. Meta-analysis also demonstrated the participation of NOPR activation in inducing inflammation in mice models. We suggest that upregulation of NOPR can activate signaling pathways involved in neuroinflammation, contributing to depression etiology.