Background: Post-surgical pain is a common clinical complication following surgical procedures, significantly impacting patient comfort, functional recovery, and long-term prognosis. Its pathological mechanisms, particularly those involving vascular and inflammatory pathways, remain incompletely understood, which limits therapy options and necessitates the exploration of novel therapeutic targets. Angiopoietin-1 (Ang-1), a crucial growth factor, is essential for vascular homeostasis and inflammatory regulation, processes implicated in pain pathogenesis, while playing an unknown role in post-surgical pain. Herein, we aimed to elucidate the role of Ang-1 in post-surgical pain and its potential molecular mechanisms for pain relief.

Methods: Post-surgical pain rat models were established using skin/muscle incision and retraction (SMIR), followed by assessment of pain hypersensitivity (paw withdrawal threshold (PWT) and paw withdrawal latency (PWL)). After Ang-1 treatment, examinations were performed on oxidative stress and inflammation in dorsal root ganglion (DRG) neurons, as well as whether NADPH oxidase 4 (NOX4)–reactive oxygen species (ROS)–nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway was implicated.

Results: SMIR induced pronounced pain hypersensitivity, reflected by downregulated PWT and PWL, accompanied by reduced Ang-1 expression in DRG neurons (p < 0.001). Elevation of Ang-1 alleviated post-surgical pain behaviors and attenuated the upregulation of ROS, NOX4, Tumor Necrosis Factor-alpha (TNF-α), and Interleukin-6 (IL-6) in SMIR-exposed DRG neurons (p < 0.001). Moreover, NF-κB level was enhanced by SMIR, yet later suppressed by Bay (p < 0.001). Ang-1 also reduced DRG neuronal apoptosis and inflammation, suggesting the inhibitory role of NF-κB (p < 0.001).

Conclusion: Ang-1 alleviates post-surgical pain by modulating oxidative stress and inflammatory responses via NOX4/ROS/NF-κB signaling pathway in DRG neurons. These findings identify Ang-1 as a promising candidate for effective post-surgical pain management and the development of novel analgesic strategies.