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.