Gauchan Punam, Andoh Tsugunobu, Kato Atsushi, Kuraishi Yasushi
Department of Applied Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
Neurosci Lett. 2009 Jul 17;458(2):93-5. doi: 10.1016/j.neulet.2009.04.029. Epub 2009 Apr 16.
Oxaliplatin is a chemotherapy drug and induces peripheral neuropathy which is aggravated by exposure to cold, the mechanism of which is unclear. In the present study, we investigated in mice whether transient receptor potential melastatin 8 (TRPM8), which is activated by cooling temperature, would be involved in cold allodynia induced by oxaliplatin. Mice were given an intraperitoneal injection of oxaliplatin. Acetone was applied to hind paw for cooling stimulation, and the time spent for licking to the hind paw was measured. The expression of TRPM8 mRNA in dorsal root ganglion was determined by the RT-PCR method. An injection of oxaliplatin induced cold allodynia, which peaked on day 3 after injection and did not disappear even on day 25. Peak cold allodynia was inhibited by capsazepine, a blocker of both TRPM8 and heat-activated TRPV1, but not by 5'-iodoresiniferatoxin, a TRPV1 blocker. Oxaliplatin increased wet-dog shake and jumping behaviors evoked by the TRPM8 agonist icilin. An injection of oxaliplatin increased the expression level of TRPM8 mRNA at day 3 after injection and the expression was decreased to the near-normal level on days 10 and 25. These results suggest that cold allodynia induced by oxaliplatin is at least partly due to the increased expression of TRPM8 in the primary afferents.
奥沙利铂是一种化疗药物，可诱发周围神经病变，且暴露于寒冷环境会使其加重，其机制尚不清楚。在本研究中，我们在小鼠中研究了由低温激活的瞬时受体电位香草酸亚型8（TRPM8）是否参与奥沙利铂诱导的冷痛觉过敏。给小鼠腹腔注射奥沙利铂。将丙酮涂抹于后爪进行冷刺激，并测量舔后爪的时间。采用逆转录聚合酶链反应（RT-PCR）法测定背根神经节中TRPM8 mRNA的表达。注射奥沙利铂可诱发冷痛觉过敏，在注射后第3天达到峰值，甚至在第25天仍未消失。TRPM8和热激活的TRPV1的阻断剂辣椒素可抑制冷痛觉过敏的峰值，但TRPV1阻断剂5'-碘树脂毒素则不能。奥沙利铂增加了TRPM8激动剂依西利定诱发的湿狗抖身和跳跃行为。注射奥沙利铂后第3天，TRPM8 mRNA的表达水平升高，在第10天和第25天表达降至接近正常水平。这些结果表明，奥沙利铂诱导的冷痛觉过敏至少部分是由于初级传入神经元中TRPM8表达增加所致。
