Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
Department of Anesthesiology, Shaanxi Provincial Cancer Hospital, Xi'an, Shaanxi 71061, China.
Aging (Albany NY). 2020 May 4;12(9):7945-7962. doi: 10.18632/aging.103114.
There are many reports about natural products relieving neuralgia. Osthole is the main component of , a natural product that treats rheumatism through the elimination of inflammation and the alleviation of pain that has a long history in the clinic. The analgesic mechanism of osthole is complicated and confusing. Astrocytes have attracted increasing attention from pain researchers. Inhibitors targeting astrocytes are thought to be promising treatments for neuropathic pain. Whether osthole can alleviate neuropathic pain through astrocytes has not been elucidated in detail. In this study, CCI surgery was used to establish the neuropathic pain model in mice. The CCI mice were treated with osthole (5, 10, or 20 mg/kg/day) for 14 days . Mechanical allodynia and heat hyperalgesia were measured to evaluate the therapeutic effect of osthole. In mechanism research, the activation of astrocytes; the protein expression of P2YR and p-JNK in astrocytes; the release of inflammatory factors; the variations in mEPSPs and eEPSPs; and the levels of GluA1, GluN2B, p-ERK, p-CREB and c-Fos in neurons were observed. The P2YR inhibitor MRS2179 and the p-JNK inhibitor SP600125 were used to demonstrate how osthole works in neuropathic pain. In addition, astrocytes and neurons were used to estimate the direct effect of osthole on astrocyte-neuron interactions and signal transmission . Our findings suggest that osthole treatment obviously relieved mechanical allodynia and heat hyperalgesia in CCI mice. P2YR is involved in CCI-induced pain hypersensitivity, and P2YR is required for osthole-induced p-JNK downregulation in the spinal cord. Osthole inhibited astrocyte activation and reduced inflammatory factor expression. After osthole treatment, mEPSP frequency and eEPSP amplitude were decreased in spinal lamina I-II neurons. Downstream signaling molecules such as pGluA1, pGluN2B, p-ERK, p-CREB and c-Fos were also reduced very quickly in osthole-treated neuralgic mice. Our conclusion is that osthole alleviates neuropathic pain in mice via the P2Y-receptor-dependent JNK signaling pathway in spinal astrocytes, and osthole could be considered a potential pharmacotherapy to alleviate neuropathic pain.
有许多关于天然产物缓解神经痛的报道。蛇床子素是一种天然产物的主要成分，该天然产物通过消除炎症和缓解疼痛来治疗风湿，在临床上已有很长的历史。蛇床子素的镇痛机制复杂而混乱。星形胶质细胞越来越受到疼痛研究人员的关注。靶向星形胶质细胞的抑制剂被认为是治疗神经病理性疼痛的有希望的治疗方法。蛇床子素是否可以通过星形胶质细胞缓解神经病理性疼痛尚未详细阐明。在这项研究中，使用 CCI 手术在小鼠中建立神经病理性疼痛模型。CCI 小鼠用蛇床子素（5、10 或 20mg/kg/天）治疗 14 天。测量机械性痛觉过敏和热痛觉过敏，以评估蛇床子素的治疗效果。在机制研究中，观察星形胶质细胞的激活；星形胶质细胞中 P2YR 和 p-JNK 的蛋白表达；炎症因子的释放；mEPSPs 和 eEPSPs 的变化；神经元中 GluA1、GluN2B、p-ERK、p-CREB 和 c-Fos 的水平。使用 P2YR 抑制剂 MRS2179 和 p-JNK 抑制剂 SP600125 来证明蛇床子素在神经病理性疼痛中的作用方式。此外，使用星形胶质细胞和神经元来估计蛇床子素对星形胶质细胞-神经元相互作用和信号转导的直接影响。我们的研究结果表明，蛇床子素治疗明显缓解了 CCI 小鼠的机械性痛觉过敏和热痛觉过敏。P2YR 参与 CCI 诱导的疼痛过敏，P2YR 是蛇床子素诱导脊髓中 p-JNK 下调所必需的。蛇床子素抑制星形胶质细胞激活并降低炎症因子表达。蛇床子素治疗后，脊髓 I-II 层神经元的 mEPSP 频率和 eEPSP 幅度降低。下游信号分子如 pGluA1、pGluN2B、p-ERK、p-CREB 和 c-Fos 在蛇床子素治疗的神经痛小鼠中也很快降低。我们的结论是，蛇床子素通过脊髓星形胶质细胞中的 P2Y 受体依赖性 JNK 信号通路缓解小鼠的神经病理性疼痛，蛇床子素可以被认为是一种潜在的缓解神经病理性疼痛的药物治疗方法。
