Lidocaine alleviates morphine tolerance via AMPK-SOCS3-dependent neuroinflammation suppression in the spinal cord

Background: morphine tolerance is a clinical challenge,and its pathogenesis is closely related to the neuroinflammation mediated by toll-like receptor 4 (tlr4). in chinese pain clinic,lidocaine is combined with morphine to treat chronic pain. we found that lidocaine sufficiently inhibited neuroinflammation induced by morphine and improved analgesic tolerance on the basis of non-affecting pain threshold. methods: cd-1 mice were utilized for tail-flick test to evaluate morphine tolerance. the microglial cell line bv-2 was utilized to investigate the mechanism of lidocaine. neuroinflammation-related cytokines were measured by western blotting and real-time pcr. the level of suppressor of cytokine signaling 3 (socs3) and adenosine 5'-monophosphate (amp)-activated protein kinase (ampk)-related signaling pathway was evaluated by western blotting,real-time pcr,enzyme-linked immunosorbent assay (elisa),and immunofluorescence staining. results: lidocaine potentiated an anti-nociceptive effect of morphine and attenuated the chronic analgesic tolerance. lidocaine suppressed morphine-induced activation of microglia and downregulated inflammatory cytokines,interleukin-1β (il-1β),and tumor necrosis factor-alpha (tnf-α) via upregulating socs3 by activating ampk. lidocaine enhanced ampk phosphorylation in a calcium-dependent protein kinase kinase β (camkkβ)-dependent manner. furthermore,lidocaine decreased the phosphorylation of p38 mitogen-activated protein kinase (mapk) and inhibited the nuclear factor-κb (nf-κb) in accordance with the inhibitory effects to tlr4. conclusions: lidocaine as a prevalent local anesthetic suppresses morphine tolerance efficiently. ampk-dependent upregulation of socs3 by lidocaine plays a crucial role in the improvement of analgesic tolerance. © 2017 the author(s).