Pancreatic Neuropathy Results in “Neural Remodeling” and Altered Pancreatic Innervation in Chronic Pancreatitis and Pancreatic Cancer

OBJECTIVES: Chronic pancreatitis (CP) and pancreatic cancer (PCa) are characterized by intrapancreatic neuropathic alterations, including increased neural density and hypertrophy, pancreatic neuritis and neural invasion (NI) by cancer cells in PCa. The aim of this study was to identify the influence of these neuropathic changes on the quality of pancreatic innervation, intrapancreatic glia, and visceral pain. METHODS: Pancreatic nerve fiber qualities were characterized by immunohistochemical visualization of various markers, including those for sympathetic (tyrosine hydroxylase, TH) and cholinergic innervation (choline acetyltransferase, ChAT), as well as the glial transcription factor, Sox10, and the neuroepithelial progenitor cell marker, Nestin, in normal pancreas (NP, n=16), CP (n=20), and PCa (n=20) patients. The neural immunoreactivity scores of these markers were correlated with the severity of intrapancreatic neuropathic changes and with abdominal pain sensation of patients. RESULTS: Pancreatic sympathetic innervation was significantly reduced in CP and PCa, whereas parasympathetic innervation did not show major changes. Nestin neuro-immunoreactivity was stronger, and Sox10-immunoreactivity was weaker in CP and PCa than in NP. Pancreatic sympathetic and cholinergic innervation was noticeably decreased in patients with severe pancreatic neuritis, NI by cancer cells, or abdominal pain. Moreover, the neural immunoreactivity for Sox10 and Nestin also varied with intrapancreatic neuropathic alterations and abdominal pain. CONCLUSIONS: The quality of intrapancreatic nerve fibers and the activation state of intrapancreatic glia in CP and PCa are strikingly different from those in normal pancreas. This novel phenomenon of "neural remodeling" shows how pancreatic neuropathic pain and "visceral neuropathy" are associated with altered pancreatic innervation in CP and PCa.