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Local anesthesia has been shown to render severe spinal cord neurotoxicity. This study used an in vitro model to explore the expression and function of tumor necrosis factor (TNF) signaling pathway in bupivacaine-induced apoptotic injury in spinal cord dorsal root ganglia (DRG). DRG was prepared from adult C57BL/6 mice and incubated with 10 mM bupivacaine in vitro to induce apoptosis. QRT-PCR and western blot demonstrated that bupivacaine upregulated TNF-alpha (TNF-α) and TNF receptor 1 (TNF-R1), but left TNF receptor 2 (TNF-R2) unaffected in DRG. SiRNA-mediated TNF-α or TNF-R1 inhibition, but not TNF-R2 inhibition, rescued bupivacaine-induced DRG apoptosis. In addition, qRT-PCR and western blot demonstrated that downstream substrates of apoptotic and TNF signaling pathways, caspase-9, MAP3K and JNK, were all significantly downregulated by TNF-α or TNF-R1 inhibition, but not by TNF-R2 inhibition, in bupivacaine-injured DRG. Thus, our work suggested that TNF-α and TNF-R1 are the major contributors of TNF signaling pathway in anesthesia-induced spinal cord neurotoxicity. Targeting TNF-α / TNF-R1, not TNF-R2 signaling pathway may be the key component to rescue or prevent anesthesia-induced apoptotic injury in spinal cord neurons.