Background: Neuropathic pain is a common and severely disabling state that affects millions of people worldwide. Microglial activation in the spinal cord plays a critical role in the pathogenesis of neuropathic pain. However, the mechanisms underlying spinal microglial activation during neuropathic pain remain incompletely understood. Here, we investigated the role of Dickkopf (DKK) 3 and its interplay with microglial activation in the spinal cord in neuropathic pain. Methods: In this study, we investigated the effects of intrathecal injection of recombinant DKK3 (rDKK3) on mechanical allodynia and microglial activation in the spinal cord after spared nerve injury (SNI) in rats by western blot (WB), immunofluorescence (IF), quantitative polymerase chain reaction (qPCR), and enzyme-linked immunosorbent assay (ELISA). Results: We found that SNI induced a significant decrease in the levels of DKK3, Kremen-1 and Dishevelled-1 (DVL-1) and up-regulated the expression of phosphorylated apoptosis signal-regulating kinase 1 (p-ASK1), phosphorylated c-JUN N-terminal kinase (p-JNK), phosphorylated p38 (p-p38) in the spinal cord. Moreover, our results showed that exogenous intrathecal administration of rDKK3 inhibited expression of p-ASK1, p-JNK, p-p38, promoted the transformation of microglia from M1 type to M2 type, and decreased the production of pro-inflammatory cytokines compared to the rats of SNI + Vehicle. However, these effects were reversed by intrathecal administration of Kremen-1 siRNA or Dishevelled-1 (DVL-1) siRNA. Conclusions: These results suggest that DKK3 ameliorates neuropathic pain via inhibiting ASK-1/JNK/p-38-mediated microglia polarization and neuroinflammation, at least partly, by the Kremen-1 and DVL-1 pathways.

Background. Neuropathic pain is a debilitating disease with few effective treatments. Emerging evidence indicates the involvement of mitochondrial dysfunction and oxidative stress in neuropathic pain. Nuclear factor erythroid 2‐related factor 2 (Nrf2) is a potent regulator of the antioxidant response system. In this study, we investigated whether RTA‐408 (RTA, a novel synthetic triterpenoid under clinical investigation) could activate Nrf2 and promote mitochondrial biogenesis (MB) to reverse neuropathic pain and the underlying mechanisms. Methods. Neuropathic pain was induced by chronic constriction injury (CCI) of the sciatic nerve. Pain behaviors were measured via the von Frey test and Hargreaves plantar test. The L4‐6 spinal cord was collected to examine the activation of Nrf2 and MB. Results. RTA‐408 treatment significantly reversed mechanical allodynia and thermal hyperalgesia in CCI mice in a dose‐dependent manner. Furthermore, RTA‐408 increased the activity of Nrf2 and significantly restored MB that was impaired in CCI mice in an Nrf2‐dependent manner. Peroxisome proliferator‐activated receptor‐gamma coactivator‐1alpha (PGC‐1α) is the key regulator of MB. We found that the PGC‐1α activator also induced a potent analgesic effect in CCI mice. Moreover, the antinociceptive effect of RTA‐408 was reversed by the preinjection of the PGC‐1α inhibitor. Conclusions. Nrf2 activation attenuates chronic constriction injury‐induced neuropathic pain via induction of PGC‐1α‐mediated mitochondrial biogenesis in the spinal cord. Our results indicate that Nrf2 may be a potential therapeutic strategy to ameliorate neuropathic pain and many other disorders with oxidative stress and mitochondrial dysfunction.