Abstract
Neuroinflammation is central to neuropathic pain pathogenesis. While ropivacaine demonstrates anti-neuroinflammatory effects through NF-κB pathway suppression, its mechanistic link to analgesia remains unclear. This study investigates ropivacaine's neuromodulatory role in neuroinflammatory responses during pain progression, specifically targeting NF-κB signaling. Our findings reveal how ropivacaine alleviates neuropathic pain by inhibiting this pathway, offering critical insights into its therapeutic potential via neuroinflammatory modulation. The spared nerve injury (SNI) model was established in rats according to standardized protocols. Ropivacaine was administered intrathecally daily for 7 days after SNI surgery. Behavioral Assessment: Paw Withdrawal Mechanical Threshold (PWMT) was quantified using von Frey filaments at preoperative baseline and postoperative days 1, 3, 7, 10, and 14. Tissue Processing: L4-L6 spinal cord tissues were processed for (1) immunofluorescence analysis of microglial activation marker Iba-1, (2), quantitative real-time PCR to determine mRNA levels of proinflammatory cytokines (TNF-α, IL-1β, and IL-6), and (3) western blotting to evaluate NF-κB signaling pathway activation. Consecutive daily intrathecal injections of ropivacaine for 7 days resulted in sustained alleviation of mechanical allodynia in the treatment group, persisting for at least 14 days post-surgery despite treatment cessation. It suppressed neuroinflammation by downregulating TNF-α, IL-1β, and IL-6 mRNA levels and reducing Iba-1 expression. These effects were mechanistically linked to inhibition of the TRAF2/PI3K/Akt/NF-κB pathway, evidenced by decreased phosphorylation of key signaling components. Ropivacaine alleviates neuropathic pain by suppressing the TRAF2/PI3K/Akt/NF-κB signaling cascade, linking its anti-neuroinflammatory effects to sustained analgesia. This novel mechanism clarifies its pharmacodynamic basis and provides a foundation for developing targeted therapies against neuroinflammation-driven pain disorders.