PAR2和TrkA的协同作用加重了大鼠慢性胰腺炎引起的内脏过敏

IF 2.9 Q3 NEUROSCIENCES

IBRO Neuroscience Reports Pub Date : 2025-06-19 DOI:10.1016/j.ibneur.2025.06.012

Zhiyun Liu , Jiao Zhu , Qianbo Chen , Kunming Tao , Kai Wei , Xiaodan Wu , Haibo Qiu , Zhijie Lu

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引用次数: 0

摘要

背景：腹痛是慢性胰腺炎最严重的症状。然而，迄今为止，关于慢性胰腺炎疼痛机制的研究还很少。先前的研究报告称，肥大细胞在神经纤维周围富集，与内脏疼痛有关。在这项研究中，我们旨在探讨蛋白酶激活受体2 （PAR2）和原肌球蛋白受体激酶A （TrkA）加重慢性胰腺炎疼痛的分子机制。方法采用Wistar大鼠尾静脉注射二氯化二丁基锡建立慢性胰腺炎动物模型。采用von Frey法评价大鼠的疼痛行为。通过苏木素和伊红染色、免疫印迹、免疫荧光组织化学、逆行标记、背根神经节（DRG）神经元培养和全细胞膜片钳记录来阐明其机制。结果慢性胰腺炎胰腺组织结构破坏，包括炎症细胞浸润和腺泡萎缩，肥大细胞大量聚集到胰腺组织。全身给予肥大细胞稳定剂酮替芬减轻Wistar大鼠慢性胰腺炎诱导的内脏过敏。相反，肥大细胞促分泌化合物48/80剂量依赖性加重慢性胰腺炎疼痛。慢性胰腺炎模型大鼠和正常大鼠注射Dil染色后，DRG神经元投射到胰腺的数量明显增加。PAR2和TrkA的共表达仅在含有瞬时受体电位香草样蛋白1通道的小直径DRG神经元中观察到，且显著高于正常大鼠。最后，我们通过全细胞膜片钳记录证明了PAR2和TrkA之间的功能相互作用。结论ast细胞通过富集和脱颗粒参与慢性胰腺炎疼痛的发生。PAR2和TrkA的相互作用加剧了慢性胰腺炎疼痛，这可能是治疗慢性胰腺炎引起的内脏疼痛的潜在策略。

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Synergistic effects of PAR2 and TrkA exacerbate visceral hypersensitivity induced by chronic pancreatitis in rats

Background

Abdominal pain is the most severe symptom of chronic pancreatitis. However, till date, there are only a few studies on the mechanism of pain in chronic pancreatitis. Previous research has reported that mast cells are enriched around nerve fibers and are associated with visceral pain. In this study, we aimed to investigate the molecular mechanisms by which protease-activated receptor 2 (PAR2) and tropomyosin receptor kinase A (TrkA) exacerbate pain in chronic pancreatitis.

Methods

A chronic pancreatitis animal model was established by injecting dibutyltin dichloride into the tail vein of Wistar rats. The von Frey test was performed to evaluate pain behavior in the rats. Hematoxylin and eosin staining, western blotting, immunofluorescence histochemistry, retrograde labeling, culture of dorsal root ganglion (DRG) neurons, and whole-cell patch clamp recordings were performed to illustrate the mechanisms.

Results

The pancreatic structures were destroyed, including inflammatory cell infiltration and acinar atrophy, and mast cells were dramatically recruited to the pancreatic tissue in chronic pancreatitis. Systemic administration of the mast cell stabilizer ketotifen alleviated chronic pancreatitis-induced visceral hypersensitivity in the Wistar rat model. In contrast, the mast cell secretagogue compound 48/80 dose-dependently exacerbated chronic pancreatitis pain. Furthermore, the number of DRG neurons projected into the pancreas was significantly increased by injecting Dil stain in chronic pancreatitis rat models and normal rats. The co-expression of PAR2 and TrkA was only observed in small-diameter DRG neurons containing transient receptor potential vanilloid 1 channel and was significantly higher than those in normal rats. Finally, we demonstrated the functional interaction between PAR2 and TrkA by whole-cell patch clamp recordings.

Conclusions

Mast cells contribute to chronic pancreatitis pain through enrichment and degranulation. The interaction of PAR2 and TrkA exacerbates chronic pancreatitis pain, which may be a potential strategy for the treatment of chronic pancreatitis -induced visceral pain.

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