Acute pancreatitis carries significant morbidity and mortality. The cellular mechanisms that underlie the inflammatory process are poorly understood, and effective treatment of acute pancreatitis is unavailable. Neurogenic inflammation has been implicated in the evolution of acute pancreatitis. In other inflammatory diseases, substance P is released from primary sensory nerve endings by activation of the capsaicin receptor, vanilloid receptor subtype 1 (VR1), and triggers neurogenic inflammation by acting via the neurokinin-1 (NK-1) receptor on target cells. The severity of experimental pancreatitis is markedly reduced in NK-1 receptor-deficient mice, suggesting a proinflammatory role for the NK-1 receptor in acute pancreatitis. The hypothesis to be tested is that neurogenic inflammation contributes to the evolution of acute pancreatitis and is mediated by substance P release from primary sensory nerve endings. The following specific aims will be addressed in caerulein-induced experimental pancreatitis: (1) to demonstrate that the proinflammatory role of NK-1 receptors results from binding of substance P, (2) to determine by pharmacological and by surgical manipulations whether primary sensory afferent neurons are the source of substance P release, (3) to determine whether substance P release is mediated by activation of VR1. The severity of pancreatitis will be assessed by biochemical assays and histological examination following pretreatment with an NK-1 receptor antagonist, with capsaicin, and with a VR-l antagonist, and following dorsal rhizotomy. NK-1 receptor immunolocalization will be performed to assess binding of substance P. Elucidation of the mechanisms of neurogenic inflammation in acute pancreatitis may result in improved treatment modalities for this disease.
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