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...
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Elsevier
2025-12-01
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| Series: | IBRO Neuroscience Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2667242125000958 |
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| author | Zhiyun Liu Jiao Zhu Qianbo Chen Kunming Tao Kai Wei Xiaodan Wu Haibo Qiu Zhijie Lu |
| author_facet | Zhiyun Liu Jiao Zhu Qianbo Chen Kunming Tao Kai Wei Xiaodan Wu Haibo Qiu Zhijie Lu |
| author_sort | Zhiyun Liu |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-8f16c7bf4ad34ce49287056ae32ad478 |
| institution | Kabale University |
| issn | 2667-2421 |
| language | English |
| publishDate | 2025-12-01 |
| publisher | Elsevier |
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| series | IBRO Neuroscience Reports |
| spelling | doaj-art-8f16c7bf4ad34ce49287056ae32ad4782025-08-20T03:30:15ZengElsevierIBRO Neuroscience Reports2667-24212025-12-011923524410.1016/j.ibneur.2025.06.012Synergistic effects of PAR2 and TrkA exacerbate visceral hypersensitivity induced by chronic pancreatitis in ratsZhiyun Liu0Jiao Zhu1Qianbo Chen2Kunming Tao3Kai Wei4Xiaodan Wu5Haibo Qiu6Zhijie Lu7Department of Anesthesiology and Intensive Care, Third Affiliated Hospital of Second Military Medical University, Shanghai, China; Department of Anesthesiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, ChinaDepartment of Anesthesiology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China; Department of Anesthesiology and Intensive Care, Third Affiliated Hospital of Second Military Medical University, Shanghai, ChinaDepartment of Anesthesiology and Intensive Care, Third Affiliated Hospital of Second Military Medical University, Shanghai, ChinaDepartment of Anesthesiology and Intensive Care, Third Affiliated Hospital of Second Military Medical University, Shanghai, ChinaDepartment of Anesthesiology and Intensive Care, Third Affiliated Hospital of Second Military Medical University, Shanghai, ChinaDepartment of Anesthesiology, Fujian Provincial Hospital, Fujian Provincial Clinical Medical College, Fujian Medical University, Fuzhou, Fujian, ChinaDepartment of Anesthesiology and Intensive Care, Third Affiliated Hospital of Second Military Medical University, Shanghai, ChinaDepartment of Anesthesiology, Minhang Hospital, Fudan University, Shanghai 201199, China; Corresponding author.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.http://www.sciencedirect.com/science/article/pii/S2667242125000958Chronic pancreatitisPainTrkAPAR2TRPV1 |
| spellingShingle | Zhiyun Liu Jiao Zhu Qianbo Chen Kunming Tao Kai Wei Xiaodan Wu Haibo Qiu Zhijie Lu Synergistic effects of PAR2 and TrkA exacerbate visceral hypersensitivity induced by chronic pancreatitis in rats IBRO Neuroscience Reports Chronic pancreatitis Pain TrkA PAR2 TRPV1 |
| title | Synergistic effects of PAR2 and TrkA exacerbate visceral hypersensitivity induced by chronic pancreatitis in rats |
| title_full | Synergistic effects of PAR2 and TrkA exacerbate visceral hypersensitivity induced by chronic pancreatitis in rats |
| title_fullStr | Synergistic effects of PAR2 and TrkA exacerbate visceral hypersensitivity induced by chronic pancreatitis in rats |
| title_full_unstemmed | Synergistic effects of PAR2 and TrkA exacerbate visceral hypersensitivity induced by chronic pancreatitis in rats |
| title_short | Synergistic effects of PAR2 and TrkA exacerbate visceral hypersensitivity induced by chronic pancreatitis in rats |
| title_sort | synergistic effects of par2 and trka exacerbate visceral hypersensitivity induced by chronic pancreatitis in rats |
| topic | Chronic pancreatitis Pain TrkA PAR2 TRPV1 |
| url | http://www.sciencedirect.com/science/article/pii/S2667242125000958 |
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