Safinamide Attenuates Systemic Inflammatory Hyperalgesia Through Modulation Of Neuroimmune Signaling And Nav1.7 Expression

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Abstract Systemic inflammatory states are associated with neuroimmune activation and peripheral sensitization mediated by dysregulation of ion channels and inflammatory mediators. Safinamide, a multi-target drug approved for Parkinson’s disease, exhibits sodium channel–blocking and anti-inflammatory properties, suggesting potential relevance in inflammatory pain. This study investigated the analgesic and neuroimmune modulatory effects of safinamide in a systemic lipopolysaccharide (LPS)-induced inflammatory hyperalgesia model in rats. Thirty-two male Wistar rats were divided into control, LPS, safinamide-treated, and indomethacin-treated groups. Thermal nociception was assessed using Tail-Flick and Hot Plate tests, and motor coordination was evaluated using the Rotarod assay. Expression of NaV1.7, TLR4, TNF-α, and IL-1β was evaluated by qRT-PCR and ELISA, whereas NF-κB p65 protein expression was assessed by Western blot. LPS administration induced significant thermal hyperalgesia and increased expression of NaV1.7, TLR4, NF-κB p65, TNF-α, and IL-1β in DRG tissue. Safinamide significantly attenuated thermal hyperalgesia while reducing NaV1.7 expression and these neuroinflammatory markers, with effects comparable to or greater than indomethacin, without impairing motor coordination. These findings suggest that safinamide alleviates inflammatory pain through coordinated modulation of neuroimmune signaling and NaV1.7 expression, supporting its further evaluation as a candidate therapy for inflammatory pain.

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