Background: Endoplasmic reticulum (ER) stress leads to the accumulation of misfolded proteins in the ER lumen and initiates the unfolded protein response (UPR). Components of the UPR important in pancreatic development and recent studies have indicated that the UPR is activated in the arginine model of acute pancreatitis. However, the effects of secretagogues on UPR components in the pancreas are unknown. The current study aimed to examine the effects of different types and concentrations of secretagogues on acinar cell function and specific components of the UPR. Materials and Methods: Rat pancreatic acini were stimulated with cholecystokinin analogs, CCK8 (10 pM-10 nM) or JMV-180 (10 nm-10 µM), or with bombesin (1-100 nM). Components of the UPR, including BiP expression, PERK phosphorylation, XBP1 splicing, and CHOP expression, were measured, as were effects on amylase secretion and intracellular trypsin activation. Results: CCK8 generated a biphasic secretion dose-response curve, and high concentrations increased intracellular active trypsin levels. In contrast, JMV-180 and bombesin secretion dose-response curves were monophasic, and high concentrations did not increase intracellular trypsin activity. All three secretagogues increased BiP levels and XBP1 splicing. However, only supraphysiologic levels of CCK8 associated with inhibited amylase secretion and trypsin activation stimulated PERK phosphorylation and expression of CHOP. The effects of CCK8 on UPR components were rapid, occurring within 5-20 minutes. Conclusions: ER stress response mechanisms appear to be involved in both pancreatic physiology and pathophysiology.