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

Ceyhan, Güralp Onur, MD1,2,5; Demir, Ihsan Ekin, MD1,2,5; Rauch, Ulrich, PhD3; Bergmann, Frank, MD4; Müller, Michael W., MD1; Büchler, Markus W., MD2; Friess, Helmut, MD1; Schäfer, Karl-Herbert, MD3

American Journal of Gastroenterology: October 2009 - Volume 104 - Issue 10 - p 2555–2565

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.

SUPPLEMENTARY MATERIAL is linked to the online version of the paper at

Am J Gastroenterol 2009; 104:2555-2565; doi:10.1038/ajg.2009.380; published online 30 June 2009

1Department of Surgery, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany; 2Department of General Surgery, University of Heidelberg, Heidelberg, Germany; 3Department of Biotechnology, University of Applied Sciences Kaiserslautern/Zweibrücken, Germany; 4Institute of Pathology, University of Heidelberg, Heidelberg, Germany. 5These authors contributed equally to this work. Correspondence: Güralp Onur Ceyhan, MD, Department of Surgery, Klinikum Rechts der Isar, Technische Universität München, Ismaningerstr. 22, München, D-81675, Germany. E-mail:

Received 21 January 2009; accepted 21 May 2009

© The American College of Gastroenterology 2009. All Rights Reserved.
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