Noda Kazuko, Akita Hisanao, Ogata Masanori, Saji Makoto
Department of Physiology, School of Allied Health Sciences, Kitasato University, Sagamihara, Japan.
Department of Physiology, School of Allied Health Sciences, Kitasato University, Sagamihara, Japan; Division of Brain Science, Graduate School of Medical Sciences, Kitasato University, Sagamihara, Japan.
Neurosci Res. 2014 Mar;80:32-7. doi: 10.1016/j.neures.2014.01.002. Epub 2014 Jan 17.
Paclitaxel, one of the chemotherapeutic agents clinically used to treat several types of cancer, produces side effects such as peripheral neuropathy, sensory abnormalities, and hyperalgesia. Since hyperalgesia remains after cessation of paclitaxel therapy and becomes chronic, we hypothesize that alteration in memory and the cognitive process of pain underlies hyperalgesia. To test this hypothesis, we examined whether drug-induced hyperalgesia alters the affective component of pain and the NMDA-NR1 and mGluR1 receptors as a mediator for signal transmission and memory of pain. Mechanical sensitivity was measured by von Frey filament test after intraperitoneal injection of paclitaxel in rats. Paclitaxel-induced hyperalgesia was confirmed over almost the entire 14-day period of observation after the treatment. The effect of paclitaxel-induced hyperalgesia on the affective component of pain was assessed using pain-induced place aversion. The formalin-induced conditioned place aversion was completely abolished in the paclitaxel-treated rats. Immunoblot analysis of NR1 and mGluR1 protein levels in various brain regions was performed after paclitaxel treatment. Treatment reduced only the NR1 expression within the frontal cortex. These results suggest that the hypofunction of memory processes with the reduced NMDA receptors in the frontal cortex might be involved in the expression of abnormal emotional behaviors accompanied by hyperalgesia.
紫杉醇是临床上用于治疗多种癌症的化疗药物之一，会产生外周神经病变、感觉异常和痛觉过敏等副作用。由于在紫杉醇治疗停止后痛觉过敏仍然存在并变为慢性，我们推测疼痛记忆和认知过程的改变是痛觉过敏的基础。为了验证这一假设，我们研究了药物诱导的痛觉过敏是否会改变疼痛的情感成分以及作为疼痛信号传递和记忆介质的NMDA-NR1和mGluR1受体。在大鼠腹腔注射紫杉醇后，通过von Frey细丝试验测量机械敏感性。在治疗后的几乎整个14天观察期内，均证实了紫杉醇诱导的痛觉过敏。使用疼痛诱导的位置厌恶来评估紫杉醇诱导的痛觉过敏对疼痛情感成分的影响。在紫杉醇治疗的大鼠中，福尔马林诱导的条件性位置厌恶被完全消除。在紫杉醇治疗后，对各个脑区的NR1和mGluR1蛋白水平进行免疫印迹分析。治疗仅降低了额叶皮质内的NR1表达。这些结果表明，额叶皮质中NMDA受体减少导致的记忆过程功能减退可能与伴有痛觉过敏的异常情绪行为表现有关。
