Signal transduction at sensory neurons occurs via transmembrane flux of cations, which is largely governed by the transient receptor potential (TRP) family of ion channels. It is unknown whether TRP channel activation contributes to the pain that accompanies radiation-induced oral mucositis. This study sought to characterize changes in TRP channel expression and function that occur in the locally irradiated tissues and afferent neurons of mice. Female CD-1 mice received single high-dose (27 Gy) tongue irradiation, or sham irradiation. Animals were euthanized either before overt glossitis developed (days 1 and 5 postirradiation), when glossitis was severe (day 11), or after mice had recovered (days 21 and 45). Tongue irradiation caused upregulation of the Trpv1 gene in trigeminal ganglia (TG) neurons. Other TRP genes (Trpv2, Trpv4, Trpa1, Trpm8) and Gfrα3 (which acts upstream of several TRP channels) were also upregulated in TGs and/or tongue tissue, in response to radiation. Ex vivo calcium imaging experiments demonstrated that the proportions of TG neurons responding to histamine (an activator of TRPV1, TRPV4 and TRPA1), TNF-α (an activator of TRPV1, TRPV2 and TRPV4), and capsaicin (a TRPV1 agonist), were increased as early as one day after tongue irradiation; these changes persisted for at least 21 days. In a subsequent experiment, we found that genetic deletion of TRPV1 mitigated weight loss (a surrogate marker of pain severity) in mice with severe glossitis. The results intimate that various TRP channels, and TRPV1 in particular, should be explored as analgesic targets for patients experiencing pain after oral irradiation.

感觉神经元的信号转导通过阳离子的跨膜通量发生，这在很大程度上受到离子通道的瞬时受体电位（TRP）家族的控制。目前尚不清楚 TRP 通道激活是否会导致放射性口腔粘膜炎伴随的疼痛。本研究试图表征小鼠局部受辐射组织和传入神经元中 TRP 通道表达和功能的变化。雌性 CD-1 小鼠接受单次高剂量 (27 Gy) 舌头照射，或假照射。在出现明显舌炎之前（照射后第1天和第5天）、舌炎严重时（第11天）或小鼠康复后（第21天和45天）对动物实施安乐死。舌头照射引起三叉神经节 (TG) 神经元中Trpv1基因的上调。其他 TRP 基因（ Trpv2 、 Trpv4 、 Trpa1 、 Trpm8 ）和Gfr α 3 （作用于多个 TRP 通道的上游）在 TG 和/或舌组织中也因辐射而上调。离体钙成像实验表明，TG 神经元对组胺（TRPV1、TRPV4 和 TRPA1 的激活剂）、TNF-α（TRPV1、TRPV2 和 TRPV4 的激活剂）和辣椒素（TRPV1 激动剂）做出反应的比例增加最早在舌头照射后一天；这些变化至少持续了 21 天。在随后的实验中，我们发现 TRPV1 基因缺失可以减轻患有严重舌炎的小鼠的体重减轻（疼痛严重程度的替代标志）。结果表明，应探索各种 TRP 通道，特别是 TRPV1，作为口腔照射后疼痛患者的镇痛靶点。