State Key Laboratory of Natural Medicines, Department of Physiology, China Pharmaceutical University, Nanjing 210009, PR China.
Department of Pharmacy, Children's Hospital of Nanjing Medical University, Nanjing, 210004, PR China.
Neuropharmacology. 2018 Jun;135:34-47. doi: 10.1016/j.neuropharm.2018.03.004. Epub 2018 Mar 5.
Vincristine is a commonly used chemotherapeutic drug that can produce painful peripheral neuropathy. The chemokine (C-X-C motif) ligand 1 (CXCL1) and its receptor chemokine (C-X-C motif) receptor 2 (CXCR2) may mediate the resolution of this inflammation. In this study, we investigated whether and how CXCL1 contributes to vincristine-induced pain and the underlying mechanisms of levo-corydalmine (l-CDL, a tetrahydroprotoberberine). Oxycodone hydrochloride (a semisynthetic opioid analgesic) was used as positive control in vivo experiments. The results revealed that both l-CDL and oxycodone attenuated vincristine-induced persistent pain hypersensitivity and proinflammatory factors release in mice. CXCL1 and CXCR2 were increased from 6 to 14 days after vincristine administration in the spinal cord. In addition, vincristine injection induced the phosphorylation of NFκB by activating p65/RelA. To confirm these results, we demonstrated that l-CDL controlled astrocytic-released CXCL1 by inhibiting p65/RelA activation, thus acting on the CXCR2 receptor in the spinal cord. In cultured astrocytes, TNF-α elicited marked release of the chemokine CXCL1; moreover, the release was blocked by NFκB p65 small interfering RNA, NFκB inhibitor, and was dose-dependently decreased by l-CDL. However, l-CDL had no effect on CXCL1 in response to NFκB p65-silenced. In primary neurons, l-CDL indirectly reduced an increase in CXCR2 by astrocyte-conditioned medium but did not act directly on the CXCR2 site. Taken together, our data first demonstrate that an NFκB-dependent CXCL1/CXCR2 signaling pathway is involved in vincristine-induced neuropathic pain. In addition, the present findings suggest that l-CDL likely attenuates this inflammation through down-regulation of this signaling pathway.
长春新碱是一种常用的化疗药物，可产生疼痛性周围神经病。趋化因子（C-X-C 基序）配体 1（CXCL1）及其受体趋化因子（C-X-C 基序）受体 2（CXCR2）可能介导这种炎症的消退。在这项研究中，我们研究了 CXCL1 是否以及如何参与长春新碱诱导的疼痛，以及左旋考地姆（l-CDL，一种四氢原小檗碱）的潜在机制。盐酸羟考酮（一种半合成阿片类镇痛药）在体内实验中用作阳性对照。结果表明，l-CDL 和羟考酮均能减轻长春新碱诱导的小鼠持续性疼痛过敏和促炎因子释放。长春新碱给药后 6 至 14 天，脊髓中 CXCL1 和 CXCR2 增加。此外，长春新碱注射通过激活 p65/RelA 诱导 NFκB 的磷酸化。为了证实这些结果，我们表明 l-CDL 通过抑制 p65/RelA 激活来控制星形胶质细胞释放的 CXCL1，从而作用于脊髓中的 CXCR2 受体。在培养的星形胶质细胞中，TNF-α引起趋化因子 CXCL1 的明显释放；此外，NFκB p65 小干扰 RNA、NFκB 抑制剂阻断了释放，l-CDL 呈剂量依赖性降低释放。然而，l-CDL 对 NFκB p65 沉默后的 CXCL1 没有影响。在原代神经元中，l-CDL 通过星形胶质细胞条件培养基间接降低 CXCR2 的增加，但不直接作用于 CXCR2 位点。总之，我们的数据首次表明，NFκB 依赖性 CXCL1/CXCR2 信号通路参与长春新碱诱导的神经病理性疼痛。此外，本研究结果表明，l-CDL 可能通过下调该信号通路来减轻这种炎症。
