The effect of CP96,345 on the expression of tachykinins and neurokinin receptors in acute pancreatitis


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Abstract

Acute pancreatitis (AP) is a life-threatening condition that involves an acute inflammatory process in the pancreas. The involvement of tachykinins and neurokinin receptors in acute pancreatitis has been described only recently, despite their long-established role in inflammatory conditions. Among these, substance P (SP) is believed to play a central role in exacerbating the inflammatory process by acting through neurokinin-1 receptor (NK1R). Treatment with the NK1R antagonist, CP96,345, results in protection against caerulein-induced acute pancreatitis in mice. However, the mechanism by which NK1R and SP worsen the condition is still unclear. In the present study, we have investigated the effect of NK1R blockage on the expression of preprotachykinin genes and neurokinin receptors in acute pancreatitis. In the pancreas, CP96,345 treatment resulted in suppression of the elevation of SP concentration, preprotachykinin-A gene (PPT-A) mRNA expression, andNK1RmRNA and protein expression. In the lungs, the antagonist was found to suppress the increase in SP concentration,PPT-AmRNA expression and preprotachykinin-C gene (PPT-C) mRNA expression. However, the antagonist treatment further promoted the accumulation of pulmonaryNK1RmRNA and protein expression. Neurokinin-2 receptor (NK2R) mRNA expression was not detected in normal pancreas. However, up-regulated expression of the mRNA for this receptor was observed during acute pancreatitis and treatment with CP96,345 further increased this expression. PulmonaryNK2RmRNA expression was found to be reduced during acute pancreatitis and CP96,345 treatment normalized this reduction. Neurokinin-3 receptor (NK3R) mRNA expression was absent in both pancreas and lung. These data have provided valuable information regarding the regulation of tachykinins and neurokinin receptors during acute pancreatitis. Copyright © 2005 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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