Trypsin-protease activated receptor-2 signaling contributes to pancreatic cancer pain

// Jiao Zhu 1, * , Xue-Rong Miao 1, * , Kun-Ming Tao 1, * , Hai Zhu 2 , Zhi-Yun Liu 1 , Da-Wei Yu 3 , Qian-Bo Chen 1 , Hai-Bo Qiu 1 and Zhi-Jie Lu 1 1 Department of Anesthesiology and Intensive Care Medicine, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200433, China 2 Department of Anesthesiology, Maternity and Infant Health Hospital of Putuo District, Shanghai 200062, China 3 Department of Anesthesiology, No.101 hospital of PLA, Wuxi 214000, China * These authors have contributed equally to this work Correspondence to: Zhi-Jie Lu, email: lzjwxyz@163.com Keywords: pancreatic cancer, pain, trypsin, protease activated receptor-2, pancreatic cancer pain model Received: December 12, 2016     Accepted: May 05, 2017     Published: June 27, 2017 ABSTRACT Pain treatment is a critical aspect of pancreatic cancer patient clinical care. This study investigated the role of trypsin-protease activated receptor-2 (PAR-2) in pancreatic cancer pain. Pancreatic tissue samples were collected from pancreatic cancer (n=22) and control patients (n=22). Immunofluorescence analyses confirmed colocalization of PAR-2 and neuronal markers in pancreatic cancer tissues. Trypsin levels and protease activities were higher in pancreatic cancer tissue specimens than in the controls. Supernatants from cultured human pancreatic cancer tissues (PC supernatants) induced substance P and calcitonin gene-related peptide release in dorsal root ganglia (DRG) neurons, and FS-NH 2 , a selective PAR-2 antagonist, inhibited this effect. A BALB/c nude mouse orthotopic tumor model was used to confirm the role of PAR-2 signaling in pancreatic cancer visceral pain, and male Sprague-Dawley rats were used to assess ambulatory pain. FS-NH 2 treatment decreased hunch scores, mechanical hyperalgesia, and visceromotor reflex responses in tumor-bearing mice. In rats, subcutaneous injection of PC supernatant induced pain behavior, which was alleviated by treatment with FS-NH 2 or FUT-175, a broad-spectrum serine protease inhibitor. Our findings suggest that trypsin-PAR-2 signaling contributes to pancreatic cancer pain in vivo . Treatment strategies targeting PAR-2 or its downstream signaling molecules might effectively relieve pancreatic cancer pain.