Safinamide attenuates systemic inflammatory hyperalgesia associated with reduced neuroimmune signaling and NaV1.7 expression

Systemic inflammatory states are associated with neuroimmune responses and peripheral sensitization involving 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 effects of safinamide in a 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, while motor coordination and exploratory behavior were evaluated using the Rotarod and Open Field tests, respectively. NaV1.7 mRNA expression was evaluated by qRT-PCR, while TLR4, TNF-α, and IL-1β levels were quantified by ELISA and NF-κB p65 protein levels by Western blot in dorsal root ganglion (DRG) tissues. LPS administration induced significant thermal hyperalgesia and increased NaV1.7, TLR4, NF-κB p65, TNF-α, and IL-1β levels in DRG tissue. Safinamide significantly attenuated thermal hyperalgesia and reduced NaV1.7 expression and inflammatory markers, with effects comparable to or greater than indomethacin, without impairing motor coordination. These findings suggest that safinamide attenuates inflammatory hyperalgesia in association with reduced inflammatory marker expression and NaV1.7 expression, supporting further investigation of its potential role in inflammatory pain.