Department of Stomatology, China-Japan Union Hospital of Jilin University, Changchun 130033, Jilin, China.
Department of Pharmacy, China-Japan Union Hospital of Jilin University, Changchun 130033, Jilin, China.
Brain Res Bull. 2020 Dec;165:228-237. doi: 10.1016/j.brainresbull.2020.09.025. Epub 2020 Oct 10.
Neuropathic pain is caused by damage to the nervous system. Increasing studies have confirmed that jagged 1 (JAG1) plays a significant role in nervous system diseases. However, the regulatory mechanisms of JAG1 in neuropathic pain remain vague. In this study, a chronic constriction injury (CCI) rat model was performed. JAG1 was found to be upregulated in CCI rats. The recombinant lentiviruses containing sh-JAG1 were injected to the CCI rats for knockdown of JAG1 in rats. JAG1 knockdown improved the mechanical allodynia and thermal hyperalgesia in CCI rats, and decreased the concentrations and mRNA expression of inflammatory cytokines (IL-6, TNF-α and IL-1β) in spinal cord dorsal horn of CCI rats, suggesting that JAG1 knockdown attenuated neuropathic pain. In addition, we explored for the upstream mechanism of JAG1. Through RNA pull down assay and luciferase reporter assay, we confirmed that miR-124-3p and miR-141-3p bound with JAG1. Long non-coding RNA (lncRNA) small nucleolar RNA host gene 6 (SNHG16) was verified to be the upstream molecule of miR-124-3p and miR-141-3p to negatively regulate miR-124-3p and miR-141-3p. SNHG16 positively regulated JAG1 expression through competitively binding with miR-124-3p and miR-141-3p. Moreover, SNHG16 was found to be upregulated in CCI rats. SNHG16 knockdown improved the mechanical allodynia and thermal hyperalgesia as well as reduced the concentrations and mRNA expression of inflammatory cytokines in CCI rats. Finally, SNHG16 was confirmed to aggravate neuropathic pain in CCI rats via upregulating JAG1. In conclusion, this study verified that SNHG16 aggravated neuropathic pain in CCI rats via binding with miR-124-3p and miR-141-3p to upregulate JAG1, which may provide new insights into the development of gene therapy for neuropathic pain.
神经病理性疼痛是由神经系统损伤引起的。越来越多的研究证实锯齿 1（JAG1）在神经系统疾病中发挥着重要作用。然而，JAG1 在神经病理性疼痛中的调控机制尚不清楚。本研究构建慢性压迫损伤（CCI）大鼠模型，发现 JAG1 在 CCI 大鼠中上调。将含有 sh-JAG1 的重组慢病毒注射到 CCI 大鼠中，以敲低大鼠 JAG1。JAG1 敲低改善了 CCI 大鼠的机械性痛觉过敏和热痛觉过敏，并降低了 CCI 大鼠脊髓背角中炎症细胞因子（IL-6、TNF-α 和 IL-1β）的浓度和 mRNA 表达，表明 JAG1 敲低减轻了神经病理性疼痛。此外，我们还探讨了 JAG1 的上游机制。通过 RNA 下拉实验和荧光素酶报告基因实验，我们证实了 miR-124-3p 和 miR-141-3p 与 JAG1 结合。长链非编码 RNA（lncRNA）小核仁 RNA 宿主基因 6（SNHG16）被证实是 miR-124-3p 和 miR-141-3p 的上游分子，可负调控 miR-124-3p 和 miR-141-3p。SNHG16 通过与 miR-124-3p 和 miR-141-3p 竞争性结合来正向调节 JAG1 的表达。此外，我们还发现 SNHG16 在 CCI 大鼠中上调。SNHG16 敲低改善了 CCI 大鼠的机械性痛觉过敏和热痛觉过敏，并降低了 CCI 大鼠中炎症细胞因子的浓度和 mRNA 表达。最后，我们证实 SNHG16 通过上调 JAG1 加重 CCI 大鼠的神经病理性疼痛。综上所述，本研究证实 SNHG16 通过与 miR-124-3p 和 miR-141-3p 结合来上调 JAG1，从而加重 CCI 大鼠的神经病理性疼痛，这可能为神经病理性疼痛的基因治疗提供新的思路。
