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Microglia play a critical role in neuropathic pain. Since upregulated Foxp3 in microglia enhances tissue repair by resolving neuroinflammation in excitotoxin-induced neuronal death, it may attenuate neuropathic pain in a similar manner. Therefore, this study tests whether Foxp3 introduced with poly (D, L-lactic-co-glycolic acid) (PLGA) nanoparticles (Foxp3 NPs) can alleviate neuropathic pain by inhibiting microglia activity. The prepared Foxp3 NPs had an anti-inflammatory effect on lipopolysaccharide-stimulated BV2 cells in vitro , and localized to spinal microglia in vivo. Further, the Foxp3 NPs significantly attenuated pain behavior induced by spinal nerve ligation in rats for 7 days by suppressing microglial activity, followed by the downregulation of pro-nociceptive genes and the upregulation of anti-nociceptive genes in the spinal dorsal horn. Collectively, these data suggest that Foxp3 NPs effectively relieve neuropathic pain in animals by reducing microglia activity and subsequent modulation of neuroinflammation, and may be of therapeutic value in the treatment of neuropathic pain. Neuropathic pain was induced by lumbar 5 spinal nerve ligation in rats. NC or Foxp3 plasmids-encapsulated PLGA nanoparticles (NC NPs or Foxp3 NPs) were then administered intrathecally into the spinal subarachnoid space of rats with neuropathic pain. Pain behavior in von Frey filaments tests was significantly attenuated in rats with the Foxp3 NPs compared with the NC NPs. Unlabelled Image [ABSTRACT FROM AUTHOR]

Targeting microglial activation is emerging as a clinically promising drug target for neuropathic pain treatment. Fexofenadine, a histamine receptor 1 antagonist, is a clinical drug for the management of allergic reactions as well as pain and inflammation. However, the effect of fexofenadine on microglial activation and pain behaviors remains elucidated. Here, we investigated nanomedicinal approach that targets more preferentially microglia and long-term analgesics. Fexofenadine significantly abolished histamine-induced microglial activation. The fexofenadine-encapsulated poly(lactic-co-glycolic acid) nanoparticles (Fexo NPs) injection reduced the pain sensitivity of spinal nerve ligation rats in a dose-dependent manner. This alleviation was sustained for 4 days, whereas the effective period by direct fexofenadine injection was 3 h. Moreover, Fexo NPs inhibited microglial activation, inflammatory signaling, cytokine release, and a macrophage phenotype shift towards the alternative activated state in the spinal cord. These results show that Fexo NPs exhibit drug repositioning promise as a long-term treatment modality for neuropathic pain. Fexofenadine-encapsulated PLGA nanoparticles (Fexo NPs) and negative control nanoparticles (NC NPs) were generated by sonication with the typical double emulsion (W/O/W) method. As a neuropathic pain model, lumbar 5 spinal nerve ligated rats were administered intrathecally into the spinal subarachnoid space with/without fexofenadine alone, NC NPs, and Fexo NPs. Then, the thermal hyperalgesia was assessed as paw withdrawal latency (PWL) by using Hargreaves Apparatus. The results highlighted that fexofenadine-loaded nanoparticles prolong pain relief in SNL rats. Fexo NPs also reduced M1/M2 macrophage ratio and inhibited cytokine release. [Display omitted] [ABSTRACT FROM AUTHOR]