Wang Q, Wang J, Gao D, Li J
Tumor Center, The First Hospital of Jilin University, Changchun, Jilin, China.
Department of Oto¬rhinolaryngology, The First Hospital of Jilin University, Changchun, Jilin, China.
J Biol Regul Homeost Agents. 2017 Oct-Dec;31(4):977-983.
Bortezomib (BTZ) is generally used as a chemotherapeutic agent for the treatment of multiple myeloma; however, one of the significant limiting complications of BTZ is painful peripheral neuropathy observed during BTZ therapy. There is a lack of drugs which can prevent and/or treat the painful symptoms induced by BTZ, as the underlying molecular mechanism leading to neuropathic pain remains largely unclear. In the present study, we examined engagement of proteinase-activated receptor 2 (PAR2) and transient receptor potential ankyrin 1 (TRPA1) in neuropathic pain induced by BTZ in rats. Our results demonstrated that systemic injection of BTZ increased mechanical pain and cold sensitivity as compared with control animals (P less than 0.05 vs control rats). Our data further showed that blocking respective PAR2 and TRPA1 attenuated mechanical pain and cold sensitivity observed in control rats and BTZ rats (P less than 0.05 vs vehicle control). Notably, the attenuating effect of blocking PAR2 and TRPA1 on mechanical pain and cold sensitivity was significantly less in BTZ rats than that in control rats. In addition, protein expression of PAR2 and TRPA1 was upregulated in the lumbar dorsal root ganglion of BTZ rats, and inhibition of PAR2 decreased the levels of TRPA1 and attenuated its downstream pathways (namely, PKCɛ and PKA). Overall, we revealed specific signaling pathways leading to neuropathic pain induced by chemotherapeutic BTZ and that blocking PAR2 and TRPA1 in sensory nerves is beneficial to improve neuropathic pain during BTZ intervention.
硼替佐米（BTZ）通常用作治疗多发性骨髓瘤的化疗药物；然而，BTZ的一个重大局限性并发症是在BTZ治疗期间观察到的疼痛性周围神经病变。由于导致神经性疼痛的潜在分子机制在很大程度上仍不清楚，因此缺乏能够预防和/或治疗由BTZ引起的疼痛症状的药物。在本研究中，我们研究了蛋白酶激活受体2（PAR2）和瞬时受体电位锚蛋白1（TRPA1）在BTZ诱导的大鼠神经性疼痛中的作用。我们的结果表明，与对照动物相比，全身注射BTZ会增加机械性疼痛和冷敏感性（与对照大鼠相比，P小于0.05）。我们的数据进一步表明，阻断各自的PAR2和TRPA1可减轻对照大鼠和BTZ大鼠中观察到的机械性疼痛和冷敏感性（与溶剂对照相比，P小于0.05）。值得注意的是，阻断PAR2和TRPA1对机械性疼痛和冷敏感性的减弱作用在BTZ大鼠中明显小于对照大鼠。此外，PAR2和TRPA1的蛋白表达在BTZ大鼠的腰段背根神经节中上调，抑制PAR2可降低TRPA1的水平并减弱其下游通路（即PKCɛ和PKA）。总体而言，我们揭示了化疗药物BTZ诱导神经性疼痛的特定信号通路，并且阻断感觉神经中的PAR2和TRPA1有利于改善BTZ干预期间的神经性疼痛。
