From Inflammation to Neuroplasticity: Molecular Mechanisms of Pain in Acute, Recurrent and Chronic Pancreatitis.

Pain is the most significant and debilitating symptom throughout all stages of pancreatitis, yet the precise mechanisms responsible for it remain only partially understood, and current pain relief methods often prove insufficient. To gain a clearer understanding, it is crucial to consider pancreatitis not as a singular condition but as comprising three distinct clinical types: acute pancreatitis (AP), recurrent acute pancreatitis (RAP), and chronic pancreatitis (CP), each of which may involve different pathways for pain perception. Notably, RAP has historically been overlooked as a distinct entity, resulting in a paucity of phenotype-specific data regarding its pain mechanisms. At the molecular level, pain in pancreatitis involves peripheral and central sensitization, neuroinflammatory signaling, and structural neural remodeling, processes driven by mediators such as substance P, CGRP, NGF, TRP channels, and pro-inflammatory cytokines. However, these mechanisms have been studied largely in isolation and within single phenotypes, leaving a critical gap in our understanding of how they evolve and interact across the full disease spectrum. This review aims to establish a comprehensive framework detailing the molecular mechanisms responsible for pain in all three pancreatitis phenotypes, with a particular focus on RAP as a less-studied clinical condition and to identify phenotype-specific targets for therapeutic development.