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Chronic pain is the principal clinical manifestation of knee osteoarthritis (KOA) and an essential indicator of the diagnosis and treatment effect. Changes in brain functional activity are related with chronic pain in KOA. Bushen Zhuangjin Decoction (BZD) has been proved to reduce inflammation of arthritis, improve cartilage degeneration and analgesia, but whether it plays a role through the change of brain function activity is not clear. Here, three experiments were performed: (1) network pharmacology evaluation to discover the potential targets of BZD to relieve pain in KOA; (2) verification of the therapeutic effects of BZD treatment on KOA pain with histomorphology, behavioral assessments, suspension chip analysis, and ultra-performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) assays; and (3) functional magnetic resonance imaging to explore the effects of BZD treatment on brain function associated to KOA. The analgesic effect of BZD on KOA was found to be related to the neurotransmitters of pain signals through network pharmacology and the therapeutic effect of BZD on KOA pain was verified in vivo, and related to neuropeptides and neurotransmitters. Functional magnetic resonance imaging showed that BZD treatment could reverse the regional homogeneity/amplitude of low-frequency fluctuation analysis in pain-related brain regions of KOA, suggesting that the analgesic mechanism of BZD is related to neural regulation. This study confirmed the key position of pain-related neuromodulation mechanisms in the analgesic therapy of BZD and provide a theoretical basis for the treatment of KOA pain with BZD as a traditional Chinese medical.

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