Li Yan, Adamek Pavel, Zhang Haijun, Tatsui Claudio Esteves, Rhines Laurence D, Mrozkova Petra, Li Qin, Kosturakis Alyssa K, Cassidy Ryan M, Harrison Daniel S, Cata Juan P, Sapire Kenneth, Zhang Hongmei, Kennamer-Chapman Ross M, Jawad Abdul Basit, Ghetti Andre, Yan Jiusheng, Palecek Jiri, Dougherty Patrick M
Departments of Anesthesia and Pain Medicine.
Department of Functional Morphology, Institute of Physiology, Academy of Sciences Czech Republic, 14220 Prague, Czech Republic.
J Neurosci. 2015 Sep 30;35(39):13487-500. doi: 10.1523/JNEUROSCI.1956-15.2015.
Peripheral neuropathy is dose limiting in paclitaxel cancer chemotherapy and can result in both acute pain during treatment and chronic persistent pain in cancer survivors. The hypothesis tested was that paclitaxel produces these adverse effects at least in part by sensitizing transient receptor potential vanilloid subtype 1 (TRPV1) through Toll-like receptor 4 (TLR4) signaling. The data show that paclitaxel-induced behavioral hypersensitivity is prevented and reversed by spinal administration of a TRPV1 antagonist. The number of TRPV1(+) neurons is increased in the dorsal root ganglia (DRG) in paclitaxel-treated rats and is colocalized with TLR4 in rat and human DRG neurons. Cotreatment of rats with lipopolysaccharide from the photosynthetic bacterium Rhodobacter sphaeroides (LPS-RS), a TLR4 inhibitor, prevents the increase in numbers of TRPV1(+) neurons by paclitaxel treatment. Perfusion of paclitaxel or the archetypal TLR4 agonist LPS activated both rat DRG and spinal neurons directly and produced acute sensitization of TRPV1 in both groups of cells via a TLR4-mediated mechanism. Paclitaxel and LPS sensitize TRPV1 in HEK293 cells stably expressing human TLR4 and transiently expressing human TRPV1. These physiological effects also are prevented by LPS-RS. Finally, paclitaxel activates and sensitizes TRPV1 responses directly in dissociated human DRG neurons. In summary, TLR4 was activated by paclitaxel and led to sensitization of TRPV1. This mechanism could contribute to paclitaxel-induced acute pain and chronic painful neuropathy. Significance statement: In this original work, it is shown for the first time that paclitaxel activates peripheral sensory and spinal neurons directly and sensitizes these cells to transient receptor potential vanilloid subtype 1 (TRPV1)-mediated capsaicin responses via Toll-like receptor 4 (TLR4) in multiple species. A direct functional interaction between TLR4 and TRPV1 is shown in rat and human dorsal root ganglion neurons, TLR4/TRPV1-coexpressing HEK293 cells, and in both rat and mouse spinal cord slices. Moreover, this is the first study to show that this interaction plays an important role in the generation of behavioral hypersensitivity in paclitaxel-related neuropathy. The key translational implications are that TLR4 and TRPV1 antagonists may be useful in the prevention and treatment of chemotherapy-induced peripheral neuropathy in humans.
外周神经病变是紫杉醇癌症化疗中的剂量限制因素，可导致治疗期间的急性疼痛以及癌症幸存者的慢性持续性疼痛。所检验的假设是，紫杉醇产生这些不良反应至少部分是通过Toll样受体4（TLR4）信号通路使瞬时受体电位香草酸亚型1（TRPV1）敏感化。数据表明，脊髓给予TRPV1拮抗剂可预防并逆转紫杉醇诱导的行为超敏反应。在紫杉醇处理的大鼠中，背根神经节（DRG）中TRPV1（+）神经元的数量增加，并且在大鼠和人类DRG神经元中与TLR4共定位。用光合细菌球形红杆菌的脂多糖（LPS-RS，一种TLR4抑制剂）对大鼠进行联合处理，可防止紫杉醇处理导致的TRPV1（+）神经元数量增加。灌注紫杉醇或典型的TLR4激动剂LPS可直接激活大鼠DRG和脊髓神经元，并通过TLR4介导的机制使两组细胞中的TRPV1产生急性敏感化。紫杉醇和LPS可使稳定表达人TLR4并瞬时表达人TRPV1的HEK293细胞中的TRPV1敏感化。这些生理效应也可被LPS-RS阻止。最后，紫杉醇可直接激活解离的人DRG神经元并使其TRPV1反应敏感化。总之，紫杉醇激活TLR4并导致TRPV1敏感化。这一机制可能导致紫杉醇诱导的急性疼痛和慢性疼痛性神经病变。意义声明：在这项原创工作中，首次表明紫杉醇可直接激活外周感觉神经元和脊髓神经元，并通过Toll样受体4（TLR4）使这些细胞对瞬时受体电位香草酸亚型1（TRPV1）介导的辣椒素反应敏感化，这在多个物种中均有体现。在大鼠和人类背根神经节神经元、共表达TLR4/TRPV1的HEK293细胞以及大鼠和小鼠脊髓切片中均显示了TLR4与TRPV1之间的直接功能相互作用。此外，这是第一项表明这种相互作用在紫杉醇相关神经病变的行为超敏反应产生中起重要作用的研究。关键的转化意义在于，TLR4和TRPV1拮抗剂可能有助于预防和治疗人类化疗引起的外周神经病变。
