Xpro®1595 alleviates neuropathic pain by targeting spinal dorsal horn ADAM17-mediated inflammation

A disintegrin and metalloprotease 17 (ADAM17) mediates the shedding of key pro-inflammatory cytokines, yet its specific contribution to neuropathic pain remains elusive. Here, we investigated the role of ADAM17 in the rat spinal nerve ligation (SNL) model. Following nerve injury, ADAM17 expression was significantly upregulated in the spinal dorsal horn (SDH) and dorsal root ganglion (DRG). Specifically, ADAM17 colocalized with TRPV1 and IB4 positive afferents in the superficial SDH, and with IB4, CGRP, and TRPV1 positive neurons in the DRG. Intrathecal administration of exogenous ADAM17 to naive rats recapitulated neuropathic pain behaviors-inducing mechanical and thermal hypersensitivity-and significantly increased the levels of TNF-α, IL-1β, and IL-6 in the SDH. Conversely, therapeutic treatment with Xpro®1595 markedly attenuated SNL-induced pain behaviors. This analgesic effect correlated with the suppression of injury-induced ADAM17 upregulation and a consequent reduction in proinflammatory cytokines. These findings demonstrate that ADAM17 is a critical driver of the neuroinflammatory cascade in neuropathic pain. Moreover, our data suggest that the analgesic efficacy of Xpro®1595 is mediated, at least in part, by disrupting this ADAM17-dependent inflammatory feedback loop.