Pancreatic Pain Across the Neural Axis: Organ-Specific Drivers and Shared Mechanisms of Visceral Pain

Visceral pain shares several mechanisms across organs, including nociceptor activation, peripheral sensitization, neuroimmune signaling, and central sensitization. Pancreatic pain, however, can be severe, difficult to treat, and particularly complex because these shared pathways coexist with distinct forms of local tissue and neural injury. Toxic, metabolic, inflammatory, mechanical, and malignant processes may overlap within the pancreas. Their effects are shaped by neural, immune, and stromal signaling, while possible neuroendocrine contributions remain an important area for investigation.Pancreatic injury does more than damage tissue. It can sensitize nociceptors and alter the structure and function of pancreatic nerves, leading to peripheral sensitization, perineural inflammation, nerve hypertrophy, and broader neural remodeling. In pancreatic cancer, tumor cells can infiltrate perineural spaces and spread along nerves, a process known as perineural invasion. This can cause neural injury and contribute to pain, while bidirectional signaling between tumor cells and nerves may also promote disease progression. Clinically, pancreatic pain is often diffuse, difficult to localize, and referred to the back. In chronic pancreatitis, its severity may correlate poorly with the extent of inflammation, fibrosis, or structural change. Pain may persist after the initial injury has subsided or an obstruction has been treated, while some patients with substantial pancreatic disease report little or no pain.This mismatch suggests that pain does not simply reflect the extent of tissue damage. Its pattern, persistence, and response to treatment may help distinguish pain driven mainly by active pancreatic pathology from pain sustained by peripheral sensitization, neural injury, or altered spinal and brain processing. At the heart of this Research Topic is a clear question: What can pain tell us about the nature of pancreatic injury, and how can that knowledge guide treatment? The collection will trace pancreatic pain from tissue injury and nociceptor activation to neural remodeling, central sensitization, and treatment response.Themes central to the collection: 1. Organ-Specific Injury and Pain InitiationAlcohol-related, drug-induced, toxic, and metabolic pancreatic injuryAcinar and ductal cell injury, oxidative stress, ischemia, and inflammationFibrosis, ductal obstruction, pressure, and other mechanical driversPancreatic nociceptors, ion channels, and sensory receptorsNeural, immune, stromal, and potential neuroendocrine contributions to painComparative mechanisms of nociception across visceral organs2. Peripheral Sensitization and Neural RemodelingPeripheral nociceptor sensitization and neurogenic inflammationPancreatic neuritis, nerve hypertrophy, altered nerve density, and neuropathic remodelingAxonal injury and regenerationInteractions among Schwann cells, immune cells, stromal cells, and neuronsPerineural inflammation and fibrosisTumor cell invasion of perineural spaces and bidirectional tumor-nerve signalingOrgan-specific patterns of visceral neural plasticity3. From Pancreatic Signals to Central Pain ProcessingNeuroimmune signaling and glial activationSpinal cord sensitization and descending pain modulationBrain network changes associated with pancreatic painReferred abdominal and back painViscero-visceral convergence and cross-organ sensitizationProgression from episodic to persistent painNeuropathic and nociplastic features of pancreatic painShared and distinct central pathways across visceral pain conditions4. Mechanism-Based Phenotyping and TreatmentNociceptive, neuropathic, and nociplastic pain featuresQuantitative sensory testing, neurophysiology, and patient-reported outcomesStructural, functional, and molecular imagingBiomarkers of pain persistence and treatment responseNonopioid pharmacologic targetsNeuromodulation and nerve-directed interventionsMechanistic evaluation of endoscopic and surgical treatmentsOpioid-induced hyperalgesia and opioid-sparing strategiesTransferable therapeutic targets across visceral organsPrecision analgesia based on dominant pain mechanismsScope noteThe primary focus is pain associated with acute, recurrent acute, and chronic pancreatitis; pancreatic cancer; and pancreatic procedures or interventions. Comparative studies involving the stomach, intestine, liver, biliary system, or other visceral organs may be included when they clarify a pancreatic mechanism, identify a shared pathway, or provide a meaningful comparison.This scope keeps the pancreas at the center while opening the collection to pain neuroscientists and researchers working across visceral systems. It will help distinguish the mechanisms shared across visceral pain conditions from those shaped by the distinctive biology and innervation of the pancreas. Topic editors: Stephen J Pandol, Yi Jiang, Alex Mabou Tagne Source: https://www.frontiersin.org/research-topics/81892/pancreatic-pain-across-the-neural-axis-organ-specific-drivers-and-shared-mechanisms-of-visceral-pain