Lnc-NR-001567通过调控AMPK/GR通路参与硼替佐米诱导痛觉过敏的作用及机制

化疗药硼替佐米诱导的痛觉过敏严重影响肿瘤患者的治疗进程和生活质量。我们前期研究发现：脊髓背角丙酮醛上调，通过RAGE/STAT3通路介导硼替佐米诱导痛觉过敏，然而丙酮醛上调的机制不清。我们预实验发现：腹腔注射硼替佐米后，大鼠脊髓背角lnc-NR-001567（lnc-NR）表达水平显著升高；鞘内注射lnc-NR shRNA显著抑制硼替佐米诱导的痛觉过敏及谷胱甘肽还原酶（GR，丙酮醛代谢限速酶）的降低，提示硼替佐米可能通过上调lnc-NR抑制GR蛋白的表达，介导痛觉过敏。研究显示：AMPK可通过影响转录因子ATF1活性，介导多种生物学功能。预实验还发现：硼替佐米可增强lnc-NR和AMPK的结合，并显著下调了p-AMPK和ATF1的表达。据此我们推测：上调的lnc-NR通过影响AMPK/ATF1，表观遗传调控GR蛋白表达，介导痛觉过敏的发生。本项目将为阐明硼替佐米诱导痛觉过敏提供全新的证据。

Allodynia caused by bortezomib is an important trouble during chemotherapy, but the mechanism remains unknown. Our preliminary study showed that accumulation of methylglyoxal may activate the RAGE/STAT3 signaling pathway in dorsal horn, and contributes to the spinal central sensitization and persistent pain induced by bortezomib treatment. But the mechanism of methylglyoxal accumulation remained unclear. Our prior experiment showed that the level of lnc-NR-001567(lnc-NR) induced following downregulation of glutathione reductase (GR, a methylglyoxal metabolic rate-limiting enzyme) in spinal dorsal horn after bortezomib treated. Intrathecal injection of lnc-NR shRNA significantly reduced allodynia and GR level induced by bortezomib. These results indicated that bortezomib may upregulate lnc-NR that caused downregulation of GR protein expression, which further induced allodynia. Study shows that AMPK can mediate many biological functions by affecting the activity of transcription factor ATF1. Our prior experiment further showed that upregulated lnc-NR mediates allodynia by affecting AMPK/ATF1 and epigenetic regulation of GR protein expression. This project will provide new evidence to elucidate bortezomib-induced allodynia.