Hama Aldric, Natsume Takahiro, Ogawa Shin'ya, Higo Noriyuki, Hayashi Ikuo, Takamatsu Hiroyuki
Hamamatsu Pharma Research, Inc., Hamamatsu, Shizuoka 431-2103, Japan.
Human Informatics Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki 305-8568, Japan.
Pain Res Manag. 2018 May 2;2018:1630709. doi: 10.1155/2018/1630709. eCollection 2018.
The antineoplastic agent oxaliplatin induces an acute hypersensitivity evoked by cold that has been suggested to be due to sensitized central and peripheral neurons. Rodent-based preclinical studies have suggested numerous treatments for the alleviation of oxaliplatin-induced neuropathic pain, but few have demonstrated robust clinical efficacy. One issue is that current understanding of the pathophysiology of oxaliplatin-induced neuropathic pain is primarily based on rodent models, which might not entirely recapitulate the clinical pathophysiology. In addition, there is currently no objective physiological marker for pain that could be utilized to objectively indicate treatment efficacy. Nonhuman primates are phylogenetically and neuroanatomically similar to humans; thus, disease mechanism in nonhuman primates could reflect that of clinical oxaliplatin-induced neuropathy. Cold-activated pain-related brain areas in oxaliplatin-treated macaques were attenuated with duloxetine, the only drug that has demonstrated clinical efficacy for chemotherapy-induced neuropathic pain. By contrast, drugs that have not demonstrated clinical efficacy in oxaliplatin-induced neuropathic pain did not reduce brain activation. Thus, a nonhuman primate model could greatly enhance understanding of clinical pathophysiology beyond what has been obtained with rodent models and, furthermore, brain activation could serve as an objective marker of pain and therapeutic efficacy.
抗肿瘤药物奥沙利铂会引发由寒冷诱发的急性超敏反应，这种反应被认为是由致敏的中枢和外周神经元引起的。基于啮齿动物的临床前研究提出了多种缓解奥沙利铂诱导的神经性疼痛的治疗方法，但很少有方法显示出强大的临床疗效。一个问题是，目前对奥沙利铂诱导的神经性疼痛病理生理学的理解主要基于啮齿动物模型，而这些模型可能无法完全重现临床病理生理学。此外，目前还没有可用于客观指示治疗效果的疼痛客观生理标志物。非人灵长类动物在系统发育和神经解剖学上与人类相似；因此，非人灵长类动物的疾病机制可能反映临床奥沙利铂诱导的神经病变机制。在接受奥沙利铂治疗的猕猴中，与冷激活疼痛相关的脑区在使用度洛西汀后减弱，度洛西汀是唯一一种已证明对化疗诱导的神经性疼痛具有临床疗效的药物。相比之下，在奥沙利铂诱导的神经性疼痛中未显示出临床疗效的药物并未减少脑激活。因此，非人灵长类动物模型可以极大地增进对临床病理生理学的理解，这是啮齿动物模型所无法做到的，此外，脑激活可以作为疼痛和治疗效果的客观标志物。
