Inhibition of Mast Cell Degranulation Relieves Visceral Hypersensitivity Induced by Pancreatic Carcinoma in Mice

Dawei Yu,Mei Zhu,Zhijie Lu,Qianbo Chen,Xiaodan Wu,Kai Wei,Xuerong Miao,Jiao Zhu

doi:10.1007/s12031-019-01352-6

Abstract

Cancer pain induced by pancreatic carcinoma is one of the most common symptoms and is difficult to endure, especially in the advanced stage. Evidence suggests that mast cells are recruited and degranulate in enteric disease-related visceral hypersensitivity. However, whether mast cells promote the visceral pain induced by pancreatic carcinoma remains unclear. Here, using toluidine blue staining and western blotting, we observed that mast cells were dramatically recruited to tissues surrounding pancreatic carcinoma, but not inside the carcinoma in patients with severe visceral pain. The levels of mast cell degranulation products, including tryptase, histamine, and nerve growth factor, were significantly increased in pericarcinoma tissues relative to their levels in normal controls, as evidenced by enzyme-linked immunosorbent assay. We determined that systemic administration of mast cell secretagogue compound 48/80 exacerbated pancreatic carcinoma-induced visceral hypersensitivity in a male BALB/c nude mouse model as assessed by measuring the hunching behavior scores and mechanical withdrawal response frequency evoked by von Frey stimulation. In contrast, the mast cell stabilizer ketotifen dose-dependently alleviated pancreatic cancer pain. In addition, we observed incomplete development of abdominal mechanical hyperalgesia and hunching behavior in mast cell–deficient mice with pancreatic carcinoma. However, ketotifen did not further attenuate visceral hypersensitivity in mast cell–deficient mice with carcinoma. Finally, we confirmed that intraplantar injection of pericarcinoma supernatants from BALB/c nude mice but not mast cell–deficient mice caused acute somatic nociception. In conclusion, our findings suggest that mast cells contribute to pancreatic carcinoma-induced visceral hypersensitivity through enrichment and degranulation in pericarcinoma tissues. The inhibition of mast cell degranulation may be a potential strategy for the therapeutic treatment of pancreatic carcinoma-induced chronic visceral pain.

Highlights

Pancreatic cancer is a kind of malignant carcinoma of the digestive system with poor prognosis
Pancreatic carcinoma caused by orthotopic inoculation of SW1990 cells leads to long-term spontaneous nociception visualized as hunching behavior and epigastric mechanical hyperalgesia in a mouse model, which mimics progressive visceral pain in pancreatic carcinoma patients
Recent studies have shown that the genesis and development of visceral pain may be related to the increase in local nerve fibers accompanied by the growth of pancreatic carcinoma (Ceyhan et al 2009)

Summary

Introduction

Pancreatic cancer is a kind of malignant carcinoma of the digestive system with poor prognosis. Pain is usually one of the first symptoms in patients with pancreatic cancer. In the advanced stage of pancreatic cancer, patient suffering involves physical and social, psychological, and spiritual aspects. Some patients are more fearful of cancer pain than of death. Relieving cancer pain has become an indispensable part of pancreatic cancer treatment. It is believed that a variety of factors are involved in the generation of pancreatic cancer pain, but the exact mechanisms are unclear. It is considered that pancreatic cancer pain is a kind of distinct pain that manifests as chronic visceral pain and is induced by the progressive growth and invasion of pancreatic tumor cells (Bapat et al 2011). Previous evidence suggests that mast cells can be recruited by chemokines, including adrenomedullin, C-C chemokine ligand 2, and

Methods

Results

Conclusion