PDF(Pubmed)
Abstract：
Paclitaxel, a microtubule-stabilizing chemotherapy drug, can cause severe paclitaxel-induced peripheral neuropathic pain (PIPNP). The roles of transient receptor potential (TRP) ion channel vanilloid 1 (TRPV1, a nociceptor and heat sensor) and melastatin 8 (TRPM8, a cold sensor) in PIPNP remain controversial. In this study, Western blotting, immunofluorescence staining, and calcium imaging revealed that the expression and functional activity of TRPV1 were upregulated in rat dorsal root ganglion (DRG) neurons in PIPNP. Behavioral assessments using the von Frey and brush tests demonstrated that mechanical hyperalgesia in PIPNP was significantly inhibited by intraperitoneal or intrathecal administration of the TRPV1 antagonist capsazepine, indicating that TRPV1 played a key role in PIPNP. Conversely, the expression of TRPM8 protein decreased and its channel activity was reduced in DRG neurons. Furthermore, activation of TRPM8 via topical application of menthol or intrathecal injection of WS-12 attenuated the mechanical pain. Mechanistically, the TRPV1 activity triggered by capsaicin (a TRPV1 agonist) was reduced after menthol application in cultured DRG neurons, especially in the paclitaxel-treated group. These findings showed that upregulation of TRPV1 and inhibition of TRPM8 are involved in the generation of PIPNP, and they suggested that inhibition of TRPV1 function in DRG neurons via activation of TRPM8 might underlie the analgesic effects of menthol.
摘要：
紫杉醇,一种稳定微管的化疗药物，可引起严重的紫杉醇诱导的外周神经性疼痛(PIPNP)。瞬时受体电位（TRP）离子通道香草酸1（TRPV1，一种伤害感受器和热传感器）和美司他丁8（TRPM8，一种冷传感器）在PIPNP中的作用仍存在争议。在这项研究中,西方印迹,免疫荧光染色，钙成像显示，TRPV1在PIPNP大鼠背根神经节（DRG）神经元中的表达和功能活性上调。使用vonFrey和刷检进行的行为评估表明，腹膜内或鞘内施用TRPV1拮抗剂卡萨西平可显着抑制PIPNP中的机械性痛觉过敏，表明TRPV1在PIPNP中起关键作用。相反，DRG神经元中TRPM8蛋白的表达降低，其通道活性降低。此外，通过局部应用薄荷醇或鞘内注射WS-12激活TRPM8减轻了机械性疼痛。机械上,在培养的DRG神经元中施用薄荷醇后，辣椒素（TRPV1激动剂）引发的TRPV1活性降低，尤其是紫杉醇治疗组。这些发现表明TRPV1的上调和TRPM8的抑制参与了PIPNP的产生,他们认为，通过激活TRPM8抑制DRG神经元中的TRPV1功能可能是薄荷醇镇痛作用的基础。
