Department of Human Anatomy, School of Basic Medicine, Zhengzhou University, Zhengzhou 450001, China; Institute of Neuroscience, Zhengzhou University, Zhengzhou 450052, China.
Department of Human Anatomy, School of Basic Medicine, Zhengzhou University, Zhengzhou 450001, China; Institute of Neuroscience, Zhengzhou University, Zhengzhou 450052, China.
Life Sci. 2021 Sep 15;281:119804. doi: 10.1016/j.lfs.2021.119804. Epub 2021 Jul 3.
Oxaliplatin is an effective anti-cancer platinum-based chemotherapy drug which can cause severe chronic neuropathy, but the molecular mechanism underlying this adverse effect is still unclear. Opa interacting protein 5 (OIP5) is a member of the cancer/testis antigen (CTA) family and is involved in a variety of cancers. Studies have shown that Raf1, which is a serine/threonine-protein kinase, can directly combine with OIP5 to promote its expression. Whether Raf1 and OIP5 can participate in oxaliplatin-induced neuropathic pain has not been reported.
In this study, the oxaliplatin-induced neuropathic pain model was prepared by intraperitoneal injection of oxaliplatin. OIP5 and Raf1 were knocked down by intrathecal injection of siRNA against Raf1 and OIP5 (siRaf1, siOIP5). Von Frey fiber and acetone were used to detect pain behavior, and western blot was used to detect the protein expression changes of OIP5 and Raf1 in the dorsal root ganglion (DRG).
The expression levels of p-Raf1 and OIP5 were increased in DRGs of oxaliplatin-induced neuropathic pain rats. Intrathecal administration of siOIP5 to inhibit the expression of OIP5 not only effectively alleviated oxaliplatin-induced mechanical allodynia and cold hyperalgesia, but also decreased the protein expression of Raf1. Intrathecal administration of siRaf1 inhibited the expression of OIP5 and attenuated oxaliplatin-induced neuropathic pain.
This study confirmed that Raf1 interacts with OIP5 to participate in oxaliplatin-induced neuropathic pain. The restricted expression of OIP5 in normal tissues may make it an ideal drug target for the treatment of oxaliplatin-induced neuropathic pain.
奥沙利铂是一种有效的抗癌铂类化疗药物，可引起严重的慢性周围神经病，但这种不良反应的分子机制尚不清楚。Opa 相互作用蛋白 5（OIP5）是癌症/睾丸抗原（CTA）家族的成员，参与多种癌症。研究表明，丝氨酸/苏氨酸蛋白激酶 Raf1 可直接与 OIP5 结合，促进其表达。Raf1 和 OIP5 是否参与奥沙利铂诱导的神经病理性疼痛尚未报道。
本研究通过腹腔注射奥沙利铂制备奥沙利铂诱导的神经病理性疼痛模型。通过鞘内注射 Raf1 和 OIP5 的 siRNA（siRaf1、siOIP5）敲低 OIP5 和 Raf1。使用 Von Frey 纤维和丙酮检测疼痛行为，Western blot 检测背根神经节（DRG）中 OIP5 和 Raf1 蛋白表达变化。
奥沙利铂诱导的神经病理性疼痛大鼠 DRG 中 p-Raf1 和 OIP5 的表达水平升高。鞘内给予 siOIP5 抑制 OIP5 的表达不仅能有效缓解奥沙利铂诱导的机械性痛觉过敏和冷超敏反应，还能降低 Raf1 的蛋白表达。鞘内给予 siRaf1 抑制 OIP5 的表达并减轻奥沙利铂诱导的神经病理性疼痛。
本研究证实 Raf1 与 OIP5 相互作用参与奥沙利铂诱导的神经病理性疼痛。OIP5 在正常组织中的受限表达可能使其成为治疗奥沙利铂诱导的神经病理性疼痛的理想药物靶点。
