Substance P (SP) acting at the NK-1 neurokinin receptor has a well-documented role in the transmission and maintenance of nociceptive information. SP is found in the majority of fibers innervating the pancreas, and it is up-regulated after pancreatic inflammation. The aim of this study was to investigate the role of the NK-1 receptors in the maintenance of pancreatic nociception. Using a newly developed rat model of acute pancreatic nociception that persists for 1 week, the NK-1 receptor expression in the spinal cord and pancreas was examined using immunohistochemistry and Western blotting procedures. The effects of a specific NK-1 antagonist, CP99,994, on the behavioral manifestations of pancreatic nociception were determined. The antagonist was administered intraperitoneally and intrathecally to differentiate peripheral and central effects. Injection of CP-100,263, the inactive enantiomer of CP-99,994 was used as a control for nonspecific effects of the antagonist. Immunohistochemistry and Western blotting analysis revealed an up-regulation of the NK-1 receptor occurs in the pancreas but not at the spinal cord level. The NK-1 antagonist was able to attenuate the nociceptive behaviors in rats with pancreatitis when applied intraperitoneally with a short duration of effectiveness. Intrathecal application of the antagonist was ineffective. These results suggest the involvement of pancreatic NK-1 receptors in the maintenance of nociception during pancreatic inflammation.