Inhibition of the Rho/Rho Kinase Pathway Prevents Lipopolysaccharide-induced Hyperalgesia and the Release of TNF-α and IL-1β in the Mouse Spinal Cord

Administration of lipopolysaccharide (LPS) by various routes produces profound inflammatory pain hypersensitivity. However, the molecular events that induce this response remain largely uncharacterized. In the present study, we sought to elucidate the role of the Rho/Rho kinase (ROCK) pathway in the release of tumor necrosis factor-α (TNF-α) and interleukin 1β (IL-1β) following injection of LPS into the mouse paw, which is associated with nociceptive behavior. The spinal cord of LPS-treated mice showed increased active GTP-bound RhoA and upregulation of ROCK2 and c-fos compared to the normal saline group. Furthermore, the inflammation-related cytokines TNF-α and IL-1β were markedly increased in the spinal dorsal horn after intraplantar injection of LPS. However, the latter effects were prevented by prophylactic intrathecal administration of the Rho inhibitor (C3 exoenzyme) or the ROCK inhibitor (Y27632). Collectively, our results suggest that the Rho/ROCK signaling pathway plays a critical role in LPS-induced inflammatory pain and that this pathway is coincident with the release of the pro-nociceptive cytokines TNF-α and IL-1β, which produces hyperalgesia.