The proteinase inhibitor camostat mesilate suppresses pancreatic pain in rodents.
Camostat mesilate, an orally available proteinase inhibitor, is clinically used for treatment of pancreatitis. Given recent evidence that pancreatic proteinases including trypsin and/or proteinase-activated receptor-2 (PAR2) might be involved in pancreatic pain, we examined if camostat mesilate could suppress spinal Fos expression, a marker for neuronal activation, following specific application of trypsin to the pancreas, and pancreatitis-related referred allodynia. Trypsin, administered into the pancreatic duct, caused delayed expression of Fos proteins in the superficial layer of the bilateral T8 and T9 spinal dorsal horns in rats. The trypsin-induced spinal Fos expression was completely abolished by oral pre-administration of camostat mesilate at 300 mg/kg. After hourly repeated (6 times in total) administration of caerulein, mice showed typical symptoms of pancreatitis, accompanied by mechanical allodynia in the upper abdomen (i.e., referred hyperalgesia/allodynia), as assessed by use of von Frey filaments. Camostat mesilate at 100-300 mg/kg, given orally twice before the 1st and 4th doses of caerulein, abolished the pancreatitis-related abdominal allodynia, while it partially prevented the inflammatory signs. The same doses of camostat mesilate, when administered once after the final dose of caerulein, also revealed significant anti-allodynic effect. These data suggest that camostat mesilate prevents and/or depresses pancreatitis-induced pain and/or referred hyperalgesia/allodynia, in which proteinases including trypsin would play a critical role.
Ishikura
Hiroyasu
H
Division of Endocrinology, Clinical Research Institute for Endocrine and Metabolic Diseases, National Hospital Organization, Kyoto Medical Center, 1-1 Fukakusa, Fushimiku 612-8555, Japan.
Nishimura
Sachiyo
S
Matsunami
Maho
M
Tsujiuchi
Toshifumi
T
Ishiki
Tsuyoshi
T
Sekiguchi
Fumiko
F
Naruse
Mitsuhide
M
Nakatani
Toshio
T
Kamanaka
Yoshihisa
Y
Kawabata
Atsufumi
A
D015746:Abdominal Pain / Q000188:drug therapy* / Q000209:etiology; D000818:Animals; D002108:Ceruletide / Q000008:administration & dosage / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004952:Esters; D016670:Gabexate / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D006146:Guanidines; D008297:Male; D053591:Referred Pain / Q000188:drug therapy* / Q000209:etiology; D010195:Pancreatitis / Q000139:chemically induced / Q000150:complications*; D010812:Physical Stimulation; D020671:Posterior Horn Cells / Q000187:drug effects / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014357:Trypsin / Q000008:administration & dosage / Q000633:toxicity
D004952:Esters; D006146:Guanidines; D011480:Protease Inhibitors; D016760:Proto-Oncogene Proteins c-fos; C034532:camostat; D016670:Gabexate; D002108:Ceruletide; D014357:Trypsin