Chemotherapy-induced peripheral neuropathic pain (CIPNP) often occurs in cancer patients treated with antineoplastic drugs. Therapeutic management of CIPNP is very limited, at least in part due to the largely unknown mechanisms that underlie CIPNP genesis. Here, we showed that systemic administration of the chemotherapeutic drug paclitaxel significantly and time-dependently increased the levels of cyclic AMP response element-binding protein (CREB) in dorsal root ganglion (DRG) neurons. Blocking this increase through DRG microinjection of Creb siRNA attenuated paclitaxel-induced mechanical, heat, and cold nociceptive hypersensitivities. Mimicking this increase through DRG microinjection of the adeno-associated virus 5 expressing full-length Creb mRNA led to enhanced responses to basal mechanical, heat, and cold stimuli in mice in absence of paclitaxel treatment. Mechanically, paclitaxel-induced increase of DRG CREB protein augmented Dnmt3a promoter activity and participated in the paclitaxel-induced upregulation of DNMT3a protein in the DRG. CREB overexpression also elevated the expression of DNMT3a in in vivo and in vitro DRG neurons of naïve mice. Given that DNMT3a is an endogenous instigator of CIPNP and that CREB co-expresses with DNMT3a in DRG neurons, CREB may be a key player in CIPNP through transcriptional activation of the Dnmt3a gene in primary sensory neurons. CREB is thus a likely potential target for the therapeutic management of this disorder.

化疗引起的周围神经性疼痛（CIPNP）经常发生在接受抗肿瘤药物治疗的癌症患者中。 CIPNP 的治疗管理非常有限，至少部分是由于 CIPNP 发生机制很大程度上未知。在这里，我们发现化疗药物紫杉醇的全身给药显着且时间依赖性地增加了背根神经节（DRG）神经元中环AMP反应元件结合蛋白（CREB）的水平。通过 DRG 显微注射Creb siRNA 阻断这种增加，可减轻紫杉醇诱导的机械、热和冷伤害性超敏反应。通过 DRG 显微注射表达全长Creb mRNA 的腺相关病毒 5 来模拟这种增加，导致在没有紫杉醇治疗的小鼠中对基础机械、热和冷刺激的反应增强。从机械角度来看，紫杉醇诱导的 DRG CREB ​​蛋白增加增强了Dnmt3a启动子活性，并参与了紫杉醇诱导的 DRG 中 DNMT3a 蛋白的上调。 CREB ​​过表达还提高了幼鼠体内和体外DRG 神经元中 DNMT3a 的表达。鉴于 DNMT3a 是 CIPNP 的内源性刺激物，并且 CREB ​​与 DRG 神经元中的 DNMT3a 共表达，CREB ​​可能通过初级感觉神经元中Dnmt3a基因的转录激活而在 CIPNP 中发挥关键作用。因此，CREB ​​可能是治疗这种疾病的潜在目标。