Capsaicin vanilloid receptor-1 mediates substance P release in experimental pancreatitis

We examined whether the capsaicin vanilloid receptor-1 (VR1) mediates subst ance P (SP) release from primary sensory neurons in experimental pancreatit is. Pancreatitis was achieved by 12 hourly injections of caerulein (50 mug/ kg ip) in mice. One group received capsazepine (100 mu mol/kg sc), a compet itive VR1 antagonist, at 4-h intervals. Neurokinin-1 receptor (NK1R) intern alization in acinar cells, used as an index of endogenous SP release, was a ssessed by immunocytochemical quantification of NK1R endocytosis. The sever ity of pancreatitis was assessed by measurements of serum amylase, pancreat ic myeloperoxidase (MPO) activity, and histological grading. Caerulein admi nistration caused significant elevations in serum amylase and pancreatic MP O activity, produced histological evidence of pancreatitis, and caused a dr amatic increase in NK1R endocytosis. Capsazepine treatment significantly re duced the level of NK1R endocytosis, and this was associated with similar r eductions in pancreatic MPO activity and histological severity of pancreati tis. These results demonstrate that repeated caerulein stimulation causes e xperimental pancreatitis that is mediated in part by stimulation of VR1 on primary sensory neurons, resulting in endogenous SP release.