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Peripheral nerve injury‐induced spinal microglial proliferation plays a pivotal role in neuropathic pain. So far, key intracellular druggable molecules involved in this process are not identified. The nuclear factor of activated T‐cells (NFAT1) is a master regulator of immune cell proliferation. Whether and how NFAT1 modulates spinal microglial proliferation during neuropathic pain remain unknown. Here it is reported that NFAT1 is persistently upregulated in microglia after spinal nerve ligation (SNL), which is regulated by TET2‐mediated DNA demethylation. Global or microglia‐specific deletion of Nfat1 attenuates SNL‐induced pain and decreases excitatory synaptic transmission of lamina II neurons. Furthermore, deletion of Nfat1 decreases microglial proliferation and the expression of multiple microglia‐related genes, such as cytokines, transmembrane signaling receptors, and transcription factors. Particularly, SNL increases the binding of NFAT1 with the promoter of Itgam, Tnf, Il‐1b, and c‐Myc in the spinal cord. Microglia‐specific overexpression of c‐MYC induces pain hypersensitivity and microglial proliferation. Finally, inhibiting NFAT1 and c‐MYC by intrathecal injection of inhibitor or siRNA alleviates SNL‐induced neuropathic pain. Collectively, NFAT1 is a hub transcription factor that regulates microglial proliferation via c‐MYC and guides the expression of the activated microglia genome. Thus, NFAT1 may be an effective target for treating neuropathic pain. [ABSTRACT FROM AUTHOR]

Ligustilide ( LIG) is a major component of Radix Angelica Sinensis, and reportedly has neuroprotective and anti-inflammatory effects. Recent studies have demonstrated that spinal astrocyte-mediated neuroinflammation plays an important role in the pathogenesis of chronic pain. Here we investigated the anti-nociceptive effect of systemic treatment with LIG on chronic inflammatory pain and explored possible mechanisms. Unilateral hindpaw injection of complete Freund's adjuvant ( CFA) induced persistent pain hypersensitivity. Repeated daily intravenous treatment with LIG, either before or after CFA injection, attenuated CFA-induced thermal hyperalgesia and mechanical allodynia. The same treatment also inhibited CFA-induced keratinocyte-derived chemokine ( KC) and monocyte chemoattractant protein-1 ( MCP-1) mRNA and protein increases in astrocytes of the spinal cord. In vitro study showed LIG dose-dependently reduced lipopolysaccharide ( LPS)-induced upregulation of KC and MCP-1 mRNA in astrocyte cultures. Interestingly, LIG treatment did not affect CFA- or LPS-induced glial fibrillary acidic protein upregulation, but did inhibit CFA-induced phosphorylated nuclear factor-κB (p- NFκ B) upregulation in spinal astrocytes. Furthermore, intrathecal injection of NFκ B inhibitor attenuated CFA-induced pain hypersensitivity and upregulation of KC and MCP-1 in the spinal cord. Finally, single intravenous injection of LIG attenuated intrathecal injection of LPS-induced mechanical allodynia. The same treatment also decreased LPS-induced NFκ B activation and KC and MCP-1 upregulation in the spinal cord. These data indicate that LIG attenuates chronic inflammatory pain potentially via inhibiting NFκ B-mediated chemokines production in spinal astrocytes. These results provide direct evidence of the anti-nociceptive and anti-inflammatory effects of LIG, suggesting a new application of LIG for the treatment of chronic inflammatory pain. [ABSTRACT FROM AUTHOR]