Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
School of Behavioral and Brain Sciences and Center for Advanced Pain Studies, University of Texas at Dallas, Richardson, TX 75080, USA.
Sci Transl Med. 2021 May 26;13(595). doi: 10.1126/scitranslmed.abd7702.
Tactile and spontaneous pains are poorly managed symptoms of inflammatory and neuropathic injury. Here, we found that transient receptor potential canonical 5 (TRPC5) is a chief contributor to both of these sensations in multiple rodent pain models. Use of TRPC5 knockout mice and inhibitors revealed that TRPC5 selectively contributes to the mechanical hypersensitivity associated with CFA injection, skin incision, chemotherapy induced peripheral neuropathy, sickle cell disease, and migraine, all of which were characterized by elevated concentrations of lysophosphatidylcholine (LPC). Accordingly, exogenous application of LPC induced TRPC5-dependent behavioral mechanical allodynia, neuronal mechanical hypersensitivity, and spontaneous pain in naïve mice. Lastly, we found that 75% of human sensory neurons express , the activity of which is directly modulated by LPC. On the basis of these results, TRPC5 inhibitors might effectively treat spontaneous and tactile pain in conditions characterized by elevated LPC.
触觉和自发性疼痛是炎症和神经病理性损伤的症状，治疗效果不佳。在这里，我们发现瞬时受体电位经典型 5（TRPC5）是多种啮齿动物疼痛模型中这两种感觉的主要贡献者。使用 TRPC5 敲除小鼠和抑制剂发现，TRPC5 选择性地导致与 CFA 注射、皮肤切口、化疗诱导的周围神经病、镰状细胞病和偏头痛相关的机械性超敏反应，所有这些疾病都表现出溶血磷脂酰胆碱（LPC）浓度升高。因此，外源性应用 LPC 会在未处理的小鼠中引起 TRPC5 依赖性行为机械性痛觉过敏、神经元机械性超敏反应和自发性疼痛。最后，我们发现 75%的人类感觉神经元表达 ，其活性可被 LPC 直接调节。基于这些结果，TRPC5 抑制剂可能有效地治疗由 LPC 升高引起的自发性和触觉性疼痛。
