The endocannabinoid signaling system in acute and chronic pancreatitis

The endocannabinoid system (ECS) is a ubiquitous lipid signaling network that regulates tissue homeostasis. Increasing evidence indicates that the ECS undergoes profound remodeling during pancreatic injury and may influence key pathological processes underlying acute pancreatitis (AP) and chronic pancreatitis (CP). Interest in this field has grown in parallel with increasing cannabis use among individuals with pancreatic disorders and the urgent need for alternatives to opioid-based pain management. Components of the ECS, including cannabinoid receptors, the endogenous ligands, and enzymes that mobilize such ligands, are widely expressed throughout both the exocrine and endocrine pancreas, where they contribute to the regulation of pancreatic function under physiological and pathological conditions. Studies demonstrate that AP and CP are associated with distinct alterations in cannabinoid receptor expression and endocannabinoid levels, yet the functional significance of these changes remains incompletely understood. Clinical evidence, however, remains limited and often conflicting. In this narrative review, we summarize current knowledge of ECS organization and function in the pancreas, examine how endocannabinoid signaling is altered during pancreatitis, and critically evaluate the therapeutic opportunities and challenges associated with targeting ECS pathways. We discuss an emerging hypothesis in which adaptive endocannabinoid signaling may contribute to resilience following pancreatic injury and propose that progressive disruption of this response could contribute to the transition from AP to CP.