The Affiliated Taian City Centeral Hospital of Qingdao University, Taian, China.
Shandong Provincial Maternal and Child Health Care Hospital Affiliated to Qingdao University, Jinan, China.
Mol Pain. 2024 Jan-Dec;20:17448069241232349. doi: 10.1177/17448069241232349.
. Neuro-inflammatory response promotes the initiation and sustenance of lumbar disc herniation (LDH). Protectin D1 (PD1), as a new type of specialized pro-resolving mediator (SPM), can improve the prognosis of various inflammatory diseases. Recent studies have shown that over representation of calcitonin gene-related peptides (CGRP) may activate nociceptive signaling following nerve injury. Silent information regulator 1 (SIRT1) is ubiquitously expressed in the dorsal horn of the spinal cord and plays a role in the pathogenesis of LDH. In this study, we investigated the analgesic effects of PD1 and elucidated the impact of neurogenic inflammation in the pathogenesis of neuropathic pain induced by non-compressive lumbar disc herniation (NCLDH) in a rat model. . NCLDH models were established by applying protruding autologous nucleus pulposus to the L5 Dorsal root ganglion (DRG). PD1, SIRT1 antagonist or agonist, CGRP or antagonist were administered as daily intrathecal injections for three consecutive days postoperatively. Behavioral tests were conducted to assess mechanical and thermal hyperalgesia. The ipsilateral lumbar (L4-6) segment of the spinal dorsal horn was isolated for further analysis. Alterations in the release of SIRT1 and CGRP were explored using western blot and immunofluorescence. . Application of protruded nucleus (NP) materials to the DRG induced mechanical and thermal allodynia symptoms, and deregulated the expression of pro-inflammatory and anti-inflammatory cytokines in rats. Intrathecal delivery of PD1 significantly reversed the NCLDH-induced imbalance in neuro-inflammatory response and alleviated the symptoms of mechanical and thermal hyperalgesia. In addition, NP application to the DGRs resulted the spinal upregulation of CGRP and SIRT1 expression, which was almost restored by intrathecal injection of PD1 in a dose-dependent manner. SIRT1 antagonist or agonist and CGRP or antagonist treatment further confirmed the result. . Our findings indicate PD1 has a potent analgesic effect, and can modulate neuro-inflammation by regulating SIRT1-mediated CGRP signaling in NCLDH.
神经炎症反应促进了腰椎间盘突出症（LDH）的发生和持续。保护素 D1（PD1）作为一种新型的特异性促解决介质（SPM），可以改善各种炎症性疾病的预后。最近的研究表明，降钙素基因相关肽（CGRP）的过度表达可能会在神经损伤后激活伤害性信号。沉默信息调节因子 1（SIRT1）在脊髓背角中广泛表达，在 LDH 的发病机制中发挥作用。在这项研究中，我们研究了 PD1 的镇痛作用，并阐明了神经源性炎症在非压迫性腰椎间盘突出症（NCLDH）诱导的神经病理性疼痛发病机制中的作用。通过将自体突出的髓核应用于 L5 背根神经节（DRG）来建立 NCLDH 模型。术后连续 3 天每天鞘内注射 PD1、SIRT1 拮抗剂或激动剂、CGRP 或拮抗剂。进行行为测试以评估机械性和热痛觉过敏。分离同侧腰椎（L4-6）节段的脊髓背角进行进一步分析。使用 Western blot 和免疫荧光法研究 SIRT1 和 CGRP 释放的变化。将突出的核（NP）物质应用于 DRG 会引起机械性和热感觉过敏症状，并使大鼠中促炎和抗炎细胞因子的表达失调。鞘内给予 PD1 可显著逆转 NCLDH 诱导的神经炎症反应失衡，并缓解机械性和热痛觉过敏症状。此外，NP 应用于 DGRs 导致脊髓中 CGRP 和 SIRT1 表达上调，PD1 鞘内注射以剂量依赖性方式几乎恢复了这一上调。SIRT1 拮抗剂或激动剂和 CGRP 或拮抗剂治疗进一步证实了这一结果。我们的研究结果表明，PD1 具有强大的镇痛作用，通过调节 SIRT1 介导的 CGRP 信号通路，可调节 NCLDH 中的神经炎症。
