Cerulein

Cerulein binds CCK1 receptors (also called CCKA receptors) on pancreatic acinar cells and gallbladder smooth muscle with high affinity, and CCK2 receptors (CCKB) on gastric ECL cells and brain. CCK1 receptor activation in acinar cells couples through Gq/G11 proteins to activate PLC, generating IP3 and DAG, releasing Ca2+ from the ER and activating PKC. This triggers enzyme-containing zymogen granule exocytosis, releasing amylase, lipase, trypsinogen, and other digestive enzymes. At physiological doses, this mirrors the normal postprandial response.

At supraphysiological doses (50-75 mcg/kg SC x 7-12 hourly injections in rodents), cerulein causes acinar cell overstimulation. Excessive Ca2+ signaling leads to premature intracellular trypsinogen activation, co-localization of digestive enzyme compartments with lysosomes, and auto-digestion of acinar cells. This triggers an inflammatory cascade: NF-kB activation, cytokine release (TNF-alpha, IL-6, IL-1beta), neutrophil recruitment, and eventually systemic inflammatory response. The cerulein-induced pancreatitis model closely mimics human acute pancreatitis.

Like CCK, cerulein stimulates gallbladder contraction (releasing bile for fat digestion), relaxes the sphincter of Oddi, and stimulates intestinal motility. At low doses, cerulein promotes satiety by activating CCK1 receptors on vagal afferents, which transmit fullness signals to the brainstem. These actions make cerulein useful for studying the gut-brain satiety axis, GI motility, and hepatobiliary function in research settings.

The cerulein pancreatitis model (7-12 hourly SC injections of 50 mcg/kg in mice/rats) is the most widely used experimental pancreatitis model, generating thousands of publications on pancreatitis pathophysiology, inflammation mechanisms, and therapeutic candidates (including BPC-157, which shows benefit in this model). It produces reproducible acute pancreatitis with histological changes (acinar vacuolization, edema, neutrophil infiltration) and elevated serum amylase/lipase.

Cerulein infusion (75 ng/kg/h IV) was used in the secretin-cerulein test for exocrine pancreatic insufficiency diagnosis in Europe, stimulating maximal pancreatic enzyme output for collection via duodenal tube. This provided a gold standard for diagnosing chronic pancreatitis and pancreatic insufficiency, though pancreatic function tests have largely been replaced by fecal elastase-1 measurement in clinical practice.

Low-dose cerulein (0.1-8 mcg/kg IP) dose-dependently reduces food intake in rodents, an effect blocked by CCK1 receptor antagonists and vagotomy. This model has been used to study postprandial satiety mechanisms, the gut-brain axis, CCK-dependent food intake regulation, and to develop CCK-based satiety therapeutics. Cerulein remains a valuable tool for interrogating cholecystokinin-dependent feeding circuits.