Shugan Bushen decoction alleviates lumbar disc herniation-related pain and affective disturbances by modulating amygdala synaptic plasticity and neuroinflammation.

ETHNOPHARMACOLOGICAL RELEVANCE: Shugan Bushen decoction (SGBS) is widely used for lumbar disc herniation (LDH)-related pain and emotional disturbances, yet its central mechanisms remain unclear. AIM OF THE STUDY: To investigate the therapeutic effects of SGBS on LDH-induced nociceptive and affective behavioral abnormalities and to explore the amygdala-related central mechanisms underlying these effects. MATERIALS AND METHODS: An LDH rat model was established by autologous nucleus pulposus implantation. Behavioral assays were conducted to evaluate pain sensitivity and affective states. Targeted cerebrospinal fluid metabolomics, amygdala transcriptomics, Western blot, ELISA, immunofluorescence, and electrophysiological recordings were performed to assess neurotransmitter alterations, synaptic-related proteins, inflammatory mediators, and neuronal activity. Network pharmacology analysis was used to identify potential signaling pathways associated with SGBS. RESULTS: SGBS alleviated mechanical and thermal hypersensitivity and improved affective behavioral abnormalities in LDH rats. LDH induced increased Glu levels, decreased GABA levels, and an elevated Glu/GABA ratio in the amygdala, which were partially reversed by SGBS. Transcriptomic analysis revealed enrichment of synapse-related pathways in the amygdala. SGBS reduced glutamatergic synaptic markers, including GRIN2B, GRIA1, PSD95, p-CaMKII, mGluR1A, and VGLUT1, while increasing inhibitory-associated markers, including GAD1 and VGAT. Double immunofluorescence showed that SGBS reduced PSD95/GRIA1 colocalization and enhanced p-CREB labeling in GAD1-positive neurons. Whole-cell current-clamp recordings showed that SGBS reduced LDH-induced spontaneous action potential firing in BLA neurons. In addition, SGBS modulated PI3K/AKT/CREB-related signaling and suppressed IL-17A/NF-κB-associated inflammatory responses, accompanied by reduced IL-1β, TNF-α, Iba1, and CD68 levels in the amygdala. CONCLUSION: SGBS alleviates LDH-related pain and affective behavioral abnormalities, potentially through modulation of amygdala neuroimmune-synaptic remodeling and attenuation of abnormal neuronal activation in the amygdala.