Division of Urology, Department of Surgery, Children's National Hospital, Washington, DC, USA.
Biomedical Research Institute, Rockville, MD, USA.
Mol Pain. 2020 Jan-Dec;16:1744806920970099. doi: 10.1177/1744806920970099.
The transient receptor potential cation channel subfamily V member 1 (TRPV1) receptor is an important mediator of nociception and its expression is enriched in nociceptive neurons. TRPV1 signaling has been implicated in bladder pain and is a potential analgesic target. Resiniferatoxin is the most potent known agonist of TRPV1. Acute exposure of the rat bladder to resiniferatoxin has been demonstrated to result in pain-related freezing and licking behaviors that are alleviated by virally encoded IL-4. The interleukin-4-inducing principle of eggs (IPSE) is a powerful inducer of IL-4 secretion, and is also known to alter host cell transcription through a nuclear localization sequence-based mechanism. We previously reported that IPSE ameliorates ifosfamide-induced bladder pain in an IL-4- and nuclear localization sequence-dependent manner. We hypothesized that pre-administration of IPSE to resiniferatoxin-challenged mice would dampen pain-related behaviors. IPSE indeed lessened resiniferatoxin-triggered freezing behaviors in mice. This was a nuclear localization sequence-dependent phenomenon, since administration of a nuclear localization sequence mutant version of IPSE abrogated IPSE's analgesic effect. In contrast, IPSE's analgesic effect did not seem IL-4-dependent, since use of anti-IL-4 antibody in mice given both IPSE and resiniferatoxin did not significantly affect freezing behaviors. RNA-Seq analysis of resiniferatoxin- and IPSE-exposed bladders revealed differential expression of TNF/NF-κb-related signaling pathway genes. testing of IPSE uptake by urothelial cells and TRPV1-expressing neuronal cells showed uptake by both cell types. Thus, IPSE's nuclear localization sequence-dependent therapeutic effects on TRPV1-mediated bladder pain may act on TRPV1-expressing neurons and/or may rely upon urothelial mechanisms.
瞬时受体电位阳离子通道亚家族 V 成员 1（TRPV1）受体是伤害感受的重要介质，其表达丰富于伤害感受神经元。TRPV1 信号转导与膀胱疼痛有关，是一种潜在的镇痛靶点。树脂毒素是已知最有效的 TRPV1 激动剂。已经证明，急性暴露于大鼠膀胱的树脂毒素会导致与疼痛相关的冻结和舔舐行为，而病毒编码的 IL-4 可减轻这些行为。卵中的白细胞介素-4 诱导因子（IPSE）是 IL-4 分泌的强大诱导剂，并且通过核定位序列为基础的机制也已知改变宿主细胞转录。我们之前报道 IPSE 以 IL-4 和核定位序列依赖性方式改善异环磷酰胺诱导的膀胱疼痛。我们假设在树脂毒素挑战的小鼠中预先给予 IPSE 会减轻与疼痛相关的行为。IPSE 确实减轻了树脂毒素引发的小鼠冻结行为。这是一种核定位序列依赖性现象，因为给予 IPSE 的核定位序列突变体版本消除了 IPSE 的镇痛作用。相比之下，IPSE 的镇痛作用似乎不依赖于 IL-4，因为在给予 IPSE 和树脂毒素的小鼠中使用抗 IL-4 抗体并没有显著影响冻结行为。对树脂毒素和 IPSE 暴露的膀胱进行 RNA-Seq 分析显示 TNF/NF-κb 相关信号通路基因的差异表达。测试 IPSE 对尿路上皮细胞和 TRPV1 表达神经元细胞的摄取显示两种细胞类型均摄取 IPSE。因此，IPSE 的核定位序列依赖性治疗 TRPV1 介导的膀胱疼痛的作用可能作用于 TRPV1 表达神经元和/或可能依赖于尿路上皮机制。
