Abstract
OBJECTIVE: Lumbar disc herniation (LDH) often resolves spontaneously through inflammation-mediated resorption of the extruded nucleus pulposus (NP). While spinal manipulative therapy (SMT) is clinically used to alleviate LDH-related pain, its role in modulating NP resorption and the underlying molecular mechanisms remain unclear. This study aimed to determine whether SMT promotes NP clearance and to elucidate its signaling pathways. METHODS: A rat model of LDH was established by autologous NP implantation onto the L5 nerve root. Animals received either SMT (every other day), epidural betamethasone (SHD, weekly), or sham treatment. Mechanical allodynia was assessed over 28 days. Histology, immunohistochemistry, ELISA, RT-qPCR, and Western blotting were performed on NP tissues. To confirm pathway specificity, experiments were replicated in JNK2-knockout (JNK-KO) mice. RESULTS: SMT significantly attenuated mechanical allodynia from day 3 onward and promoted near-complete NP resorption by day 28-outperforming SHD in both analgesia and tissue restoration. Unlike SHD's broad anti-inflammatory suppression, SMT maintained a balanced microenvironment: moderately elevating TNF-α, IL-1β, VEGF, and MMP-3 to support macrophage recruitment, neovascularization, and matrix remodeling, while reducing NP cell apoptosis via Bax/Bcl-2 regulation. These effects were accompanied by selective inhibition of NF-κB and MAPK (p38, ERK, JNK) phosphorylation. Crucially, all benefits of SMT were abolished in JNK-KO mice, confirming JNK as an essential upstream mediator. CONCLUSION: SMT promotes pain relief and nucleus pulposus resorption in LDH by inhibiting inflammation and accelerating tissue remodeling through a JNK-dependent mechanism.