Tian Liujun, Fan Tianren, Zhou Nan, Guo Hui, Zhang Weijie
Department of Pain Medicine Weifang People's Hospital Weifang City, Shandong Province 261041, China.
Transl Neurosci. 2015 Mar 18;6(1):111-116. doi: 10.1515/tnsci-2015-0010. eCollection 2015.
Oxaliplatin (OXL) is a third-generation chemotherapeutic agent commonly used to treat metastatic digestive tumors; however, one of the main limiting complications of OXL is neuropathic pain. In this study, the underlying mechanisms responsible for OXL evoked-neuropathic pain were examined. Using a rat model, the results demonstrated that intraperitoneal (i.p.) injection of OXL significantly increased mechanical pain and cold sensitivity as compared with control animals ( < 0.05 control rats). Blocking proteinase-activated receptor 2 (PAR2) significantly attenuated mechanical pain and cold sensitivity observed in control rats and OXL rats ( < 0.05 vehicle control). The attenuating effect of PAR2 on mechanical pain and cold sensitivity were significantly smaller in OXL-rats than in control rats. The role played by PAR2 downstream signaling pathways [namely, transient receptor potential ankyrin 1 (TRPA1)] in regulating OXL evoked-neuropathic pain was also examined. The data shows that TRPA1 expression was upregulated in the lumbar dorsal root ganglion (DRG) of OXL rats and blocking TRPA1 inhibited mechanical pain and heightened cold sensitivity ( < 0.05 control rats). Blocking PAR2 also significantly decreased TRPA1 expression in the DRG. Findings in this study show that OXL intervention amplifies mechanical hyperalgesia and cold hypersensitivity and PAR2 plays an important role in regulating OXL-induced neuropathic pain via TRPA1 pathways.
奥沙利铂（OXL）是一种常用于治疗转移性消化肿瘤的第三代化疗药物；然而，奥沙利铂的主要限制性并发症之一是神经性疼痛。在本研究中，对奥沙利铂诱发神经性疼痛的潜在机制进行了研究。使用大鼠模型，结果表明，与对照动物相比，腹腔注射奥沙利铂显著增加了机械性疼痛和冷敏感性（与对照大鼠相比，P<0.05）。阻断蛋白酶激活受体2（PAR2）可显著减轻对照大鼠和奥沙利铂处理大鼠的机械性疼痛和冷敏感性（与溶剂对照相比，P<0.05）。PAR2对机械性疼痛和冷敏感性的减轻作用在奥沙利铂处理大鼠中比在对照大鼠中显著更小。还研究了PAR2下游信号通路[即瞬时受体电位锚蛋白1（TRPA1）]在调节奥沙利铂诱发神经性疼痛中的作用。数据显示，TRPA1表达在奥沙利铂处理大鼠的腰段背根神经节（DRG）中上调，阻断TRPA1可抑制机械性疼痛并加剧冷敏感性（与对照大鼠相比，P<0.05）。阻断PAR2也显著降低了DRG中TRPA1的表达。本研究结果表明，奥沙利铂干预会放大机械性痛觉过敏和冷超敏反应，PAR2在通过TRPA1途径调节奥沙利铂诱导的神经性疼痛中起重要作用。
