The Pathogenesis of Chronic Pancreatitis

  • Jakob Lykke Poulsen
  • Søren Schou Olesen
  • Asbjørn Mohr DrewesEmail author
  • Bo Ye
  • Wei-Qin LiEmail author
  • Ali A. Aghdassi
  • Matthias Sendler
  • Julia Mayerle
  • Markus M. LerchEmail author


Chronic abdominal pain remains a major clinical challenge in chronic pancreatitis (CP) and is present in up to 90% of the patients. It is associated with a poor life quality, an increased health resource utilization and is the primary cause of hospitalization Lieb et al. (Aliment Pharmacol Ther 29:706–19, 2009). The etiologies of pain in CP are increasingly better understood and likely involve multiple mechanisms. The focus of this chapter is to provide an overview of the mechanisms involved in chronic pancreatic pain. First, the traditional view of pain in CP is discussed where pain is thought to arise due to mechanical problems such as obstruction of the pancreatic gland. Although this theory is widely accepted and forms the theoretical background for invasive treatments of pain it is largely undocumented and has been challenged by recent research where no uniform associations between morphological changes and pain exist. The next section provides an overview of a novel neurobiological understanding of pain in CP, which is shifting the focus of pain from mechanical problems towards changes in peripheral and central pain processing. This has substantial consequences for treatment and may result in a paradigm shift of pain management of CP in a foreseeable future. Finally, we briefly discuss extra-pancreatic causes of pain in associated with CP, which are important to diagnose, as they are often easy to treat.


  1. Acioli JM, Isobe M, Kawasaki S. Early complement system activation and neutrophil priming in acute pancreatitis: participation of trypsin. Surgery. 1997;122(5):909–17.PubMedCrossRefGoogle Scholar
  2. Addadi L, Weiner S. Interaction between acidic proteins and crystals: stereochemical requirements in biomineralization. PNAS. 1985;82:4110–4.PubMedPubMedCentralCrossRefGoogle Scholar
  3. Aghdassi A, Mayerle J, Kraft M, Sielenkämper AW, Heidecke C-DD, Lerch MM. Diagnosis and treatment of pancreatic pseudocysts in chronic pancreatitis. Pancreas. 2008;36:105–12.PubMedCrossRefGoogle Scholar
  4. Aghdassi AA, Mayerle J, Christochowitz S, Weiss FU, Sendler M, Lerch MM. Animal models for investigating chronic pancreatitis. Fibrogenesis Tissue Repair. 2011;4(1):26. doi: 10.1186/1755-1536-4-26.PubMedPubMedCentralCrossRefGoogle Scholar
  5. Aghdassi AA, Weiss FU, Mayerle J, Lerch MM, Simon P. Genetic susceptibility factors for alcohol-induced chronic pancreatitis. Pancreatology. 2015;15(4 Suppl):S23–31. doi: 10.1016/j.pan.2015.05.476.PubMedCrossRefGoogle Scholar
  6. Allan J, White TT. An alternate mechanism for the formation of protein plugs in chronic calcifying pancreatitis. Digestion. 1974;11:428–31.PubMedCrossRefGoogle Scholar
  7. Ammann RW, Akovbiantz A, Largiader F, Schueler G. Course and outcome of chronic pancreatitis. Longitudinal study of a mixed medical-surgical series of 245 patients. Gastroenterology. 1984;86:820–8.PubMedGoogle Scholar
  8. Ammann RW, Muellhaupt B, Meyenberger C, Heitz PU. Alcoholic nonprogressive chronic pancreatitis: prospective long-term study of a large cohort with alcoholic acute pancreatitis (1976-1992). Pancreas. 1994;9(3):365–73.PubMedCrossRefGoogle Scholar
  9. Ammann RW, Heitz PU, Kloppel G. Course of alcoholic chronic pancreatitis: a prospective clinicomorphological long-term study. Gastroenterology. 1996;111(1):224–31.PubMedCrossRefGoogle Scholar
  10. Anand P, Aziz Q, Willert R, van Oudenhove L. Peripheral and central mechanisms of visceral sensitization in man. Neurogastroenterol Motil. 2007;19:29–46.PubMedCrossRefGoogle Scholar
  11. Anaparthy R, Pasricha PJ. Pain and chronic pancreatitis: is it the plumbing or the wiring? Curr Gastroenterol Rep. 2008;10:101–6.PubMedCrossRefGoogle Scholar
  12. Anderson MA, Akshintala V, Albers KM, et al. Mechanism, assessment and management of pain in chronic pancreatitis: recommendations of a multidisciplinary study group. Pancreatology. 2015;16:83–94.PubMedPubMedCentralCrossRefGoogle Scholar
  13. Andrén-Sandberg A, Dervenis C. Pancreatic pseudocysts in the 21st century. Part I: classification, pathophysiology, anatomic considerations and treatment. JOP. 2004;5:8–24.PubMedGoogle Scholar
  14. Andrews BS, Eisenberg RA, Theofilopoulos AN, et al. Spontaneous murine lupus-like syndromes. Clinical and immunopathological manifestations in several strains. J Exp Med. 1978;148(5):1198–215.PubMedCrossRefGoogle Scholar
  15. Apkarian AV, Hashmi JA, Baliki MN. Pain and the brain: specificity and plasticity of the brain in clinical chronic pain. Pain. 2011;152:S49–64.PubMedCrossRefGoogle Scholar
  16. Apte MV, Haber PS, Darby SJ, et al. Pancreatic stellate cells are activated by proinflammatory cytokines: implications for pancreatic fibrogenesis. Gut. 1999;44(4):534–41.PubMedPubMedCentralCrossRefGoogle Scholar
  17. Apte MV, Phillips PA, Fahmy RG, et al. Does alcohol directly stimulate pancreatic fibrogenesis? Studies with rat pancreatic stellate cells. Gastroenterology. 2000;118(4):780–94.PubMedCrossRefGoogle Scholar
  18. Archer H, Jura N, Keller J, Jacobson M, Bar-Sagi D. A mouse model of hereditary pancreatitis generated by transgenic expression of R122H trypsinogen. Gastroenterology. 2006;131(6):1844–55. doi: 10.1053/j.gastro.2006.09.049.PubMedCrossRefGoogle Scholar
  19. Backonja M, Wallace MS, Blonsky ER, Cutler BJ, Malan P Jr, Rauck R, Tobias J. NGX-4010, a high-concentration capsaicin patch, for the treatment of postherpetic neuralgia: a randomised, double-blind study. Lancet Neurol. 2008;7:1106–12.PubMedCrossRefGoogle Scholar
  20. Balci NC, Perman WH, Saglam S, Akisik F, Fattahi R, Bilgin M. Diffusion-weighted magnetic resonance imaging of the pancreas. Top Magn Reson Imaging. 2009;20:43–7.PubMedCrossRefGoogle Scholar
  21. Bertelli E, Bendayan M. Intermediate endocrine-acinar pancreatic cells in duct ligation conditions. Am J Phys. 1997;273(5 Pt 1):C1641–9.Google Scholar
  22. Bimmler D, Graf R, Scheele GA, et al. Pancreatic stone protein (lithostathine), a physiologically relevant pancreatic calcium carbonate crystal inhibitor? J Biol Chem. 1997;272:3073–82.PubMedCrossRefGoogle Scholar
  23. Bockman DE, Kennedy RH, Multigner L, et al. Fine structure of the organic matrix of human pancreatic stones. Pancreas. 1986;1:204–10.PubMedCrossRefGoogle Scholar
  24. Bockman DE, Buchler M, Malfertheiner P, Beger HG. Analysis of nerves in chronic pancreatitis. Gastroenterology. 1988;94:1459–69.PubMedCrossRefGoogle Scholar
  25. Boerma D, Obertop H, Gouma DJ. Pancreatic pseudocysts in chronic pancreatitis. Surgical or interventional drainage? Ann Ital Chir. 2000;71:43–50.PubMedGoogle Scholar
  26. Bornman PC, Marks IN, Girdwood AH, Clain JE, Narunsky L, Clain DJ, Wright JP. Is pancreatic duct obstruction or stricture a major cause of pain in calcific pancreatitis? Br J Surg. 1980;67:425–8.PubMedCrossRefGoogle Scholar
  27. Bourdi M, Davies JS, Pohl LR. Mispairing C57BL/6 substrains of genetically engineered mice and wild-type controls can lead to confounding results as it did in studies of JNK2 in acetaminophen and concanavalin A liver injury. Chem Res Toxicol. 2011;24(6):794–6. doi: 10.1021/tx200143x.PubMedPubMedCentralCrossRefGoogle Scholar
  28. Bouwense SA, Buscher HC, van Goor H, Wilder-Smith OH. S-ketamine modulates hyperalgesia in patients with chronic pancreatitis pain. Reg Anesth Pain Med. 2011a;36:303–7.PubMedCrossRefGoogle Scholar
  29. Bouwense SA, Buscher HC, van Goor H, Wilder-Smith OH. Has central sensitization become independent of nociceptive input in chronic pancreatitis patients who fail thoracoscopic splanchnicectomy? Reg Anesth Pain Med. 2011b;36:531–6.PubMedCrossRefGoogle Scholar
  30. Bouwense SA, Olesen SS, Drewes AM, Frøkjær JB, van Goor H, Wilder-Smith OH. Is altered central pain processing related to disease stage in chronic pancreatitis patients with pain? An exploratory study. PLoS One. 2013;8:e55460.PubMedPubMedCentralCrossRefGoogle Scholar
  31. Brock C, Olesen SS, Olesen AE, Frokjaer JB, Andresen T, Drewes AM, Frøkjaer JB, Andresen T, Drewes AM. Opioid-induced bowel dysfunction: pathophysiology and management. Drugs. 2012;72:1847–65.PubMedCrossRefGoogle Scholar
  32. Brock C, Nielsen LM, Lelic D, Drewes AM. Pathophysiology of chronic pancreatitis. World J Gastroenterol. 2013;19(42):7231–40. doi: 10.3748/wjg.v19.i42.7231.PubMedPubMedCentralCrossRefGoogle Scholar
  33. Büchler M, Weihe E, Friess H, Malfertheiner P, Bockman E, Müller S, Nohr D, Beger HG. Changes in peptidergic innervation in chronic pancreatitis. Pancreas. 1992;7:183–92.PubMedCrossRefGoogle Scholar
  34. Buscher HC, Wilder-Smith OH, van Goor H. Chronic pancreatitis patients show hyperalgesia of central origin: a pilot study. Eur J Pain. 2006;10:363–70.PubMedCrossRefGoogle Scholar
  35. Cano DA, Sekine S, Hebrok M. Primary cilia deletion in pancreatic epithelial cells results in cyst formation and pancreatitis. Gastroenterology. 2006;131(6):1856–69. doi: 10.1053/j.gastro.2006.10.050.PubMedCrossRefGoogle Scholar
  36. Casellas F, Guarner L, Vaquero E, Antolin M, de Gracia X, Malagelada JR. Hydrogen breath test with glucose in exocrine pancreatic insufficiency. Pancreas. 1998;16:481–6.PubMedCrossRefGoogle Scholar
  37. Ceyhan GO, Deucker S, Demir IE, et al. Neural fractalkine expression is closely linked to pain and pancreatic neuritis in human chronic pancreatitis. Lab Invest. 2009a;89:347–61.PubMedCrossRefGoogle Scholar
  38. Ceyhan GO, Demir IE, Rauch U, Bergmann F, Müller MW, Büchler MW, Friess H, Schäfer K-H. Pancreatic neuropathy results in “neural remodeling” and altered pancreatic innervation in chronic pancreatitis and pancreatic cancer. Am J Gastroenterol. 2009b;104:2555–65.PubMedCrossRefGoogle Scholar
  39. Ceyhan GO, Bergmann F, Kadihasanoglu M, et al. Pancreatic neuropathy and neuropathic pain—a comprehensive pathomorphological study of 546 cases. Gastroenterology. 2009c;136:177–186.e1.PubMedCrossRefGoogle Scholar
  40. Chebli JM, de Souza AF, Gaburri PD, Bastos KV, Ribeiro TC, Filho RJ, Chebli LA, Castro Ferreira LE. Prevalence and pathogenesis of duodenal ulcer in chronic alcoholic pancreatitis. J Clin Gastroenterol. 2002;35:71–4.PubMedCrossRefGoogle Scholar
  41. Chen JM, Ferec C. Genetics and pathogenesis of chronic pancreatitis: the 2012 update. Clin Res Hepatol Gastroenterol. 2012;36(4):334–40. doi: 10.1016/j.clinre.2012.05.003.PubMedCrossRefGoogle Scholar
  42. Churg A, Richter WR. Early changes in the exocrine pancreas of the dog and rat after ligation of the pancreatic duct. A light and electron microscopic study. Am J Pathol. 1971;63(3):521–46.PubMedPubMedCentralGoogle Scholar
  43. Cohn JA, Friedman KJ, Noone PG, Knowles MR, Silverman LM, Jowell PS. Relation between mutations of the cystic fibrosis gene and idiopathic pancreatitis. N Engl J Med. 1998;339(10):653–8. doi: 10.1056/NEJM199809033391002.PubMedCrossRefGoogle Scholar
  44. Colomer V, Lal K, Hoops TC, et al. Exocrine granule specific packaging signals are present in the polypeptide moiety of the pancreatic granule membrane protein GP2 and in amylase: implications for protein targeting to secretory granules. EMBO J. 1994;13(16):3711–9.PubMedPubMedCentralGoogle Scholar
  45. Criddle DN. The role of fat and alcohol in acute pancreatitis: a dangerous liaison. Pancreatology. 2015;15(4 Suppl):S6–12. doi: 10.1016/j.pan.2015.02.009.PubMedCrossRefGoogle Scholar
  46. Criddle DN, Murphy J, Fistetto G, et al. Fatty acid ethyl esters cause pancreatic calcium toxicity via inositol trisphosphate receptors and loss of ATP synthesis. Gastroenterology. 2006;130(3):781–93. doi: 10.1053/j.gastro.2005.12.031.PubMedCrossRefGoogle Scholar
  47. De Caro A, Lohse J, Sarles H. Characterization of a protein isolated from pancreatic calculi of men suffering from chronic calcifying pancreatitis. Biochem Biophys Res Commun. 1979;87:1176–82.PubMedCrossRefGoogle Scholar
  48. De Reggi M, Gharib B, Patard L, et al. Lithostathine, the presumed pancreatic stone inhibitor, does not interact specifically with calcium carbonate crystals. J Biol Chem. 1998;273:4967–71.PubMedCrossRefGoogle Scholar
  49. Demir IE, Friess H, Ceyhan GO. Neural plasticity in pancreatitis and pancreatic cancer. Nat Rev Gastroenterol Hepatol. 2015;12:649–59.PubMedCrossRefGoogle Scholar
  50. Deng X, Wang L, Elm MS, et al. Chronic alcohol consumption accelerates fibrosis in response to cerulein-induced pancreatitis in rats. Am J Pathol. 2005;166(1):93–106. doi: 10.1016/S0002-9440(10)62235-3.PubMedPubMedCentralCrossRefGoogle Scholar
  51. Derikx MH, Kovacs P, Scholz M, et al. Polymorphisms at PRSS1-PRSS2 and CLDN2-MORC4 loci associate with alcoholic and non-alcoholic chronic pancreatitis in a European replication study. Gut. 2015;64(9):1426–33. doi: 10.1136/gutjnl-2014-307453.PubMedCrossRefGoogle Scholar
  52. Detlefsen S, Sipos B, Feyerabend B, Kloppel G. Fibrogenesis in alcoholic chronic pancreatitis: the role of tissue necrosis, macrophages, myofibroblasts and cytokines. Mod Pathol. 2006;19(8):1019–26. doi: 10.1038/modpathol.3800613.PubMedCrossRefGoogle Scholar
  53. Di Sebastiano P, Fink T, Weihe E, Friess H, Innocenti P, Beger HG, Büchler MW. Immune cell infiltration and growth-associated protein 43 expression correlate with pain in chronic pancreatitis. Gastroenterology. 1997;112:1648–55.PubMedCrossRefGoogle Scholar
  54. Dimagno MJ, Lee SH, Hao Y, Zhou SY, McKenna BJ, Owyang C. A proinflammatory, antiapoptotic phenotype underlies the susceptibility to acute pancreatitis in cystic fibrosis transmembrane regulator (-/-) mice. Gastroenterology. 2005;129(2):665–81. doi: 10.1016/j.gastro.2005.05.059.PubMedCrossRefGoogle Scholar
  55. Dimcevski G, Sami SA, Funch-Jensen P, Le Pera D, Valeriani M, Arendt-Nielsen L, Drewes AM. Pain in chronic pancreatitis: the role of reorganization in the central nervous system. Gastroenterology. 2007;132:1546–56.PubMedCrossRefGoogle Scholar
  56. Drewes A-M. Is the pain in chronic pancreatitis of neuropathic origin? Support from EEG studies during experimental pain. World J Gastroenterol. 2008;14:4020.PubMedPubMedCentralCrossRefGoogle Scholar
  57. Durie PR, Kent G, Phillips MJ, Ackerley CA. Characteristic multiorgan pathology of cystic fibrosis in a long-living cystic fibrosis transmembrane regulator knockout murine model. Am J Pathol. 2004;164(4):1481–93. doi: 10.1016/S0002-9440(10)63234-8.PubMedPubMedCentralCrossRefGoogle Scholar
  58. Ebbehøj N, Svendsen LB, Madsen P. Pancreatic tissue pressure: techniques and pathophysiological aspects. Scand J Gastroenterol. 1984;19:1066–8.PubMedGoogle Scholar
  59. Ebbehøj N, Borly L, Bülow J, Rasmussen SG, Madsen P, Matzen P, Owre A. Pancreatic tissue fluid pressure in chronic pancreatitis. Relation to pain, morphology, and function. Scand J Gastroenterol. 1990a;25:1046–51.PubMedCrossRefGoogle Scholar
  60. Ebbehøj N, Borly L, Bülow J, Rasmussen SG, Madsen P. Evaluation of pancreatic tissue fluid pressure and pain in chronic pancreatitis. A longitudinal study. Scand J Gastroenterol. 1990b;25:462–6.PubMedCrossRefGoogle Scholar
  61. Elsasser HP, Haake T, Grimmig M, Adler G, Kern HF. Repetitive cerulein-induced pancreatitis and pancreatic fibrosis in the rat. Pancreas. 1992;7(3):385–90.PubMedCrossRefGoogle Scholar
  62. Esposito I, Friess H, Kappeler A, Shrikhande S, Kleeff J, Ramesh H, Zimmermann A, Büchler MW. Mast cell distribution and activation in chronic pancreatitis. Hum Pathol. 2001;32:1174–83.PubMedCrossRefGoogle Scholar
  63. Farnbacher MJ, Voll RE, Faissner R, et al. Composition of clogging material in pancreatic endoprostheses. Gastrointest Endosc. 2005;61:862–6.PubMedCrossRefGoogle Scholar
  64. Fasanella KE, Davis B, Lyons J, Chen Z, Lee KK, Slivka A, Whitcomb DC. Pain in chronic pancreatitis and pancreatic cancer. Gastroenterol Clin North Am. 2007;36:335–64, ix.PubMedCrossRefGoogle Scholar
  65. Flor H, Elbert T, Knecht S, Wienbruch C, Pantev C, Birbaumer N, Larbig W, Taub E. Phantom-limb pain as a perceptual correlate of cortical reorganization following arm amputation. Nature. 1995;375:482–4.PubMedCrossRefGoogle Scholar
  66. Flor H, Nikolajsen L, Jensen TS. Phantom limb pain: a case of maladaptive CNS plasticity? Nat Rev Neurosci. 2006;7:873–81.PubMedCrossRefGoogle Scholar
  67. Freedman SD, Kern HF, Scheele GA. Apical membrane trafficking during regulated pancreatic exocrine secretion—role of alkaline pH in the acinar lumen and enzymatic cleavage of GP2, a GPI-linked protein. Eur J Cell Biol. 1994;65:354–65.PubMedGoogle Scholar
  68. Freedman SD, Kern HF, Scheele GA. Pancreatic acinar cell dysfunction in CFTR(-/-) mice is associated with impairments in luminal pH and endocytosis. Gastroenterology. 2001;121(4):950–7.PubMedCrossRefGoogle Scholar
  69. Friess H, Shrikhande S, Shrikhande M, Martignoni M, Kulli C, Zimmermann A, Kappeler A, Ramesh H, Büchler M. Neural alterations in surgical stage chronic pancreatitis are independent of the underlying aetiology. Gut. 2002;50:682–6.PubMedPubMedCentralCrossRefGoogle Scholar
  70. Frokjaer JB, Drewes AM, Olesen SS, Frøkjær JB, Olesen SS, Drewes AM. Fibrosis, atrophy, and ductal pathology in chronic pancreatitis are associated with pancreatic function but independent of symptoms. Pancreas. 2013;42:1182–7.PubMedCrossRefGoogle Scholar
  71. Frøkjær JB, Olesen SS, Gram M, Yavarian Y, Bouwense SA, Wilder-Smith OH, Drewes AM. Altered brain microstructure assessed by diffusion tensor imaging in patients with chronic pancreatitis. Gut. 2011;60:1554–62.PubMedCrossRefGoogle Scholar
  72. Frøkjær JB, Bouwense SA, Olesen SS, Lundager FH, Eskildsen SF, van Goor H, Wilder-Smith OH, Drewes AM. Reduced cortical thickness of brain areas involved in pain processing in patients with chronic pancreatitis. Clin Gastroenterol Hepatol. 2012;10:434–8.e1.PubMedCrossRefGoogle Scholar
  73. Frulloni L, Gabbrielli A, Pezzilli R, et al. Chronic pancreatitis: report from a multicenter Italian survey (PanCroInfAISP) on 893 patients. Dig Liver Dis. 2009;41(4):311–7. doi: 10.1016/j.dld.2008.07.316.PubMedCrossRefGoogle Scholar
  74. Gebhart GF. Visceral pain-peripheral sensitisation. Gut. 2000;47(Suppl 4):iv54–5, discussion iv58.PubMedPubMedCentralGoogle Scholar
  75. Gebhart GF. Descending modulation of pain. Neurosci Biobehav Rev. 2004;27:729–37.PubMedCrossRefGoogle Scholar
  76. Gebhart GF. It’s chickens and eggs all over again: is central reorganization the result or cause of persistent visceral pain? Gastroenterology. 2007;132:1618–20.PubMedCrossRefGoogle Scholar
  77. Geider S, Baronnet A, Cerini C, et al. Pancreatic lithostathine as a calcite habit modifier. J Biol Chem. 1996;271:26302–6.PubMedCrossRefGoogle Scholar
  78. Gerasimenko JV, Lur G, Sherwood MW, et al. Pancreatic protease activation by alcohol metabolite depends on Ca2+ release via acid store IP3 receptors. Proc Natl Acad Sci U S A. 2009;106(26):10758–63. doi: 10.1073/pnas.0904818106.PubMedPubMedCentralCrossRefGoogle Scholar
  79. Goto M, Nakano I, Kimura T, Miyahara T, Kinjo M, Nawata H. New chronic pancreatitis model with diabetes induced by cerulein plus stress in rats. Dig Dis Sci. 1995;40(11):2356–63.PubMedCrossRefGoogle Scholar
  80. Gouyon B, Lévy P, Ruszniewski P, Zins M, Hammel P, Vilgrain V, Sauvanet A, Belghiti J, Bernades P. Predictive factors in the outcome of pseudocysts complicating alcoholic chronic pancreatitis. Gut. 1997;41:821–5.PubMedPubMedCentralCrossRefGoogle Scholar
  81. Graversen C, Olesen SS, Olesen AE, Steimle K, Farina D, Wilder-Smith OHG, Bouwense SAW, van Goor H, Drewes AM. The analgesic effect of pregabalin in patients with chronic pain is reflected by changes in pharmaco-EEG spectral indices. Br J Clin Pharmacol. 2012;73:363–72.PubMedCrossRefGoogle Scholar
  82. Gress T, Muller-Pillasch F, Elsasser HP, et al. Enhancement of transforming growth factor beta 1 expression in the rat pancreas during regeneration from caerulein-induced pancreatitis. Eur J Clin Investig. 1994;24(10):679–85.CrossRefGoogle Scholar
  83. Grippo PJ, Venkatasubramanian PN, Knop RH, et al. Visualization of mouse pancreas architecture using MR microscopy. Am J Pathol. 2011;179(2):610–8. doi: 10.1016/j.ajpath.2011.04.007.PubMedPubMedCentralCrossRefGoogle Scholar
  84. Gross J, Carlson RI, Brauer AW, et al. Isolation, characterization, and distribution of an unusual pancreatic human secretory protein. J Clin Invest. 1985;76:2115–26.PubMedPubMedCentralCrossRefGoogle Scholar
  85. Gukovskaya AS, Mareninova OA, Odinokova IV, et al. Cell death in pancreatitis: effects of alcohol. J Gastroenterol Hepatol. 2006;21(Suppl 3):S10–3. doi: 10.1111/j.1440-1746.2006.04571.x.PubMedCrossRefGoogle Scholar
  86. Gukovsky I, Lugea A, Shahsahebi M, et al. A rat model reproducing key pathological responses of alcoholic chronic pancreatitis. Am J Physiol Gastrointest Liver Physiol. 2008;294(1):G68–79. doi: 10.1152/ajpgi.00006.2007.PubMedCrossRefGoogle Scholar
  87. Gupte AR, Forsmark CE. Chronic pancreatitis. Curr Opin Gastroenterol. 2014;30(5):500–5. doi: 10.1097/MOG.0000000000000094.PubMedCrossRefGoogle Scholar
  88. Halangk W, Lerch MM, Brandt-Nedelev B, et al. Role of cathepsin B in intracellular trypsinogen activation and the onset of acute pancreatitis. J Clin Invest. 2000;106(6):773–81. doi: 10.1172/JCI9411.PubMedPubMedCentralCrossRefGoogle Scholar
  89. Harada H, Ueda O, Kochi F, Kobayashi T, Komazawa M. Comparative studies on viscosity and concentration of protein and hexosamine in pure pancreatic juice. Gastroenterol Jpn. 1981;16(6):623–6.PubMedGoogle Scholar
  90. Harding HP, Zeng H, Zhang Y, et al. Diabetes mellitus and exocrine pancreatic dysfunction in perk-/- mice reveals a role for translational control in secretory cell survival. Mol Cell. 2001;7(6):1153–63.PubMedCrossRefGoogle Scholar
  91. Haroutounian S, Nikolajsen L, Bendtsen TF, Finnerup NB, Kristensen AD, Hasselstrom JB, Jensen TS. Primary afferent input critical for maintaining spontaneous pain in peripheral neuropathy. Pain. 2014;155:1272–9.PubMedCrossRefGoogle Scholar
  92. Hartel M, di Mola FF, Selvaggi F, et al. Vanilloids in pancreatic cancer: potential for chemotherapy and pain management. Gut. 2006;55:519–28.PubMedPubMedCentralCrossRefGoogle Scholar
  93. Hayakawa T, Harada H, Noda A, et al. Lactoferrin in pure pancreatic juice in chronic pancreatitis. Am J Gastroenterol. 1983;78(4):222.PubMedGoogle Scholar
  94. Hayakawa T, Kondo T, Shibata T, et al. Trypsin(ogen) content of pancreatic calculi in chronic calcified pancreatitis in man. Dig Dis Sci. 1994;39:1345–50.PubMedCrossRefGoogle Scholar
  95. Heinricher MM, Tavares I, Leith JL, Lumb BM. Descending control of nociception: specificity, recruitment and plasticity. Brain Res Rev. 2009;60:214–25.PubMedCrossRefGoogle Scholar
  96. Hillebrandt S, Wasmuth HE, Weiskirchen R, et al. Complement factor 5 is a quantitative trait gene that modifies liver fibrogenesis in mice and humans. Nat Genet. 2005;37(8):835–43. doi: 10.1038/ng1599.PubMedCrossRefGoogle Scholar
  97. Hingorani SR, Wang L, Multani AS, et al. Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell. 2005;7(5):469–83. doi: 10.1016/j.ccr.2005.04.023.PubMedCrossRefGoogle Scholar
  98. Hoogerwerf WA, Gondesen K, Xiao S-Y, Winston JH, Willis WD, Pasricha PJ. The role of mast cells in the pathogenesis of pain in chronic pancreatitis. BMC Gastroenterol. 2005;5:8.PubMedPubMedCentralCrossRefGoogle Scholar
  99. Huang W, Booth DM, Cane MC, et al. Fatty acid ethyl ester synthase inhibition ameliorates ethanol-induced Ca2+-dependent mitochondrial dysfunction and acute pancreatitis. Gut. 2014;63(8):1313–24. doi: 10.1136/gutjnl-2012-304058.PubMedCrossRefGoogle Scholar
  100. Hughes MS, Shenoy M, Liu L, Colak T, Mehta K, Pasricha PJ. Brain-derived neurotrophic factor is upregulated in rats with chronic pancreatitis and mediates pain behavior. Pancreas. 2011;40:551–6.PubMedPubMedCentralCrossRefGoogle Scholar
  101. Iimuro Y, Frankenberg MV, Arteel GE, Bradford BU, Wall CA, Thurman RG. Female rats exhibit greater susceptibility to early alcohol-induced liver injury than males. Am J Phys. 1997;272(5 Pt 1):G1186–94.Google Scholar
  102. Irving HM, Samokhvalov AV, Rehm J. Alcohol as a risk factor for pancreatitis. A systematic review and meta-analysis. JOP. 2009;10(4):387–92.PubMedPubMedCentralGoogle Scholar
  103. Isaksson G, Lundquist I, Ihse I. Effects on the exocrine and endocrine pancreas of duct occlusion with two different tissue glues in the rat. Eur Surg Res. 1983;15(3):136–44.PubMedCrossRefGoogle Scholar
  104. Jensen AR, Matzen P, Malchow-Møller A, Christoffersen I. Pattern of pain, duct morphology, and pancreatic function in chronic pancreatitis. A comparative study. Scand J Gastroenterol. 1984;19:334–8.PubMedGoogle Scholar
  105. Jin CX, Naruse S, Kitagawa M, et al. Pancreatic stone protein of pancreatic calculi in chronic calcified pancreatitis in man. JOP. 2002;3:54–61.PubMedGoogle Scholar
  106. Juel J, Olesen SS, Olesen AE, Poulsen JL, Dahan A, Wilder-Smith O, Madzak A, Frøkjær JB, Drewes AM. Study protocol for a randomised, double-blinded, placebo-controlled, clinical trial of S-ketamine for pain treatment in patients with chronic pancreatitis (RESET trial). BMJ Open. 2015;5:e007087.PubMedPubMedCentralCrossRefGoogle Scholar
  107. Kahl S, Zimmermann S, Genz I, Schmidt U, Pross M, Schulz HU, Malfertheiner P. Biliary strictures are not the cause of pain in patients with chronic pancreatitis. Pancreas. 2004;28:387–90.PubMedCrossRefGoogle Scholar
  108. Kalvaria I, Bornman PC, Marks IN, Girdwood AH, Bank L, Kottler RE. The spectrum and natural history of common bile duct stenosis in chronic alcohol-induced pancreatitis. Ann Surg. 1989;210:608–13.PubMedPubMedCentralCrossRefGoogle Scholar
  109. Kanno H, Nose M, Itoh J, Taniguchi Y, Kyogoku M. Spontaneous development of pancreatitis in the MRL/Mp strain of mice in autoimmune mechanism. Clin Exp Immunol. 1992;89(1):68–73.PubMedPubMedCentralCrossRefGoogle Scholar
  110. Kara ME. The anatomical study on the rat pancreas and its ducts with emphasis on the surgical approach. Ann Anat. 2005;187(2):105–12. doi: 10.1016/j.aanat.2004.10.004.PubMedCrossRefGoogle Scholar
  111. Keith RG, Keshavjee SH, Kerenyi NR. Neuropathology of chronic pancreatitis in humans. Can J surgery. 1985;28:207–11.Google Scholar
  112. Keller J, Aghdassi AA, Lerch MM, Mayerle JV, Layer P. Tests of pancreatic exocrine function—clinical significance in pancreatic and non-pancreatic disorders. Best Pract Res Clin Gastroenterol. 2009;23(3):425–39. doi: 10.1016/j.bpg.2009.02.013.PubMedCrossRefGoogle Scholar
  113. Kimura Y, Torimura T, Ueno T, Inuzuka S, Tanikawa K. Transforming growth factor beta 1, extracellular matrix, and inflammatory cells in wound repair using a closed duodenal loop pancreatitis model rat. Immunohistochemical study. Scand J Gastroenterol. 1995;30(7):707–14.PubMedCrossRefGoogle Scholar
  114. Kishi S, Takeyama Y, Ueda T, et al. Pancreatic duct obstruction itself induces expression of alpha smooth muscle actin in pancreatic stellate cells. J Surg Res. 2003;114(1):6–14.PubMedCrossRefGoogle Scholar
  115. Klöppel G. Chronic pancreatitis, pseudotumors and other tumor-like lesions. Mod Pathol. 2007;20(Suppl 1):S113–31. doi: 10.1038/modpathol.3800690.PubMedCrossRefGoogle Scholar
  116. Klöppel G. Histopathologie der chronischen Pankreatitis. In: Beger HG, Büchler MW, Dralle H, Lerch MM, Malfertheiner P, Mössner J, Riemann JF, editors. Erkrankungen des Pankreas. Berlin: Springer; 2013. p. 86–91.CrossRefGoogle Scholar
  117. Kloppel G, Detlefsen S, Feyerabend B. Fibrosis of the pancreas: the initial tissue damage and the resulting pattern. Virchows Arch. 2004;445(1):1–8. doi: 10.1007/s00428-004-1021-5.PubMedCrossRefGoogle Scholar
  118. Kohl J. Anaphylatoxins and infectious and non-infectious inflammatory diseases. Mol Immunol. 2001;38(2–3):175–87.PubMedCrossRefGoogle Scholar
  119. Kono H, Nakagami M, Rusyn I, et al. Development of an animal model of chronic alcohol-induced pancreatitis in the rat. Am J Physiol Gastrointest Liver Physiol. 2001;280(6):G1178–86.PubMedGoogle Scholar
  120. Lampel M, Kern HF. Acute interstitial pancreatitis in the rat induced by excessive doses of a pancreatic secretagogue. Virchows Arch A Pathol Anat Histol. 1977;373(2):97–117.PubMedCrossRefGoogle Scholar
  121. Lankisch PG, Löhr-Happe A, Otto J, Creutzfeldt W. Natural course in chronic pancreatitis. Pain, exocrine and endocrine pancreatic insufficiency and prognosis of the disease. Digestion. 1993;54:148–55.PubMedCrossRefGoogle Scholar
  122. Lankisch PG, Breuer N, Bruns A, Weber-Dany B, Lowenfels AB, Maisonneuve P. Natural history of acute pancreatitis: a long-term population-based study. Am J Gastroenterol. 2009;104(11):2797–2805.;, quiz 2806. doi: 10.1038/ajg.2009.405.PubMedCrossRefGoogle Scholar
  123. Latremoliere A, Woolf CJ. Central sensitization: a generator of pain hypersensitivity by central neural plasticity. J Pain. 2009;10:895–926.PubMedPubMedCentralCrossRefGoogle Scholar
  124. Laugier R. Dynamic endoscopic manometry of the response to secretin in patients with chronic pancreatitis. Endoscopy. 1994;26:222–7.PubMedCrossRefGoogle Scholar
  125. Layer PH. Motor cycles and other cycles in chronic pancreatitis. Gastroenterology. 1995;109:316–9.PubMedCrossRefGoogle Scholar
  126. Lelic D, Olesen SS, Hansen TM, Valeriani M, Drewes AM. Functional reorganization of brain networks in patients with painful chronic pancreatitis. Eur J Pain. 2014; doi: 10.1002/j.1532-2149.2013.00442.x.
  127. Lerch MM, Gorelick FS. Models of acute and chronic pancreatitis. Gastroenterology. 2013;144(6):1180–93. doi: 10.1053/j.gastro.2012.12.043.PubMedCrossRefGoogle Scholar
  128. Levy P, Dominguez-Munoz E, Imrie C, Lohr M, Maisonneuve P. Epidemiology of chronic pancreatitis: burden of the disease and consequences. United European Gastroenterol J. 2014;2(5):345–54. doi: 10.1177/2050640614548208.PubMedPubMedCentralCrossRefGoogle Scholar
  129. Li J, Guo M, Hu B, Liu R, Wang R, Tang C. Does chronic ethanol intake cause chronic pancreatitis?: evidence and mechanism. Pancreas. 2008;37(2):189–95. doi: 10.1097/MPA.0b013e31816459b7.PubMedCrossRefGoogle Scholar
  130. Lieb JG II, Forsmark CE, Lieb JG, Forsmark CE. Review article: pain and chronic pancreatitis. Aliment Pharmacol Ther. 2009;29:706–19.PubMedCrossRefGoogle Scholar
  131. Lieber CS, DeCarli LM. Liquid diet technique of ethanol administration: 1989 update. Alcohol Alcohol. 1989;24(3):197–211.Google Scholar
  132. Lieber CS, Jones DP, Decarli LM. Effects of prolonged ethanol intake: production of fatty liver despite adequate diets. J Clin Invest. 1965;44:1009–21. doi: 10.1172/JCI105200.PubMedPubMedCentralCrossRefGoogle Scholar
  133. Liu L, Shenoy M, Pasricha PJ. Substance P and calcitonin gene related peptide mediate pain in chronic pancreatitis and their expression is driven by nerve growth factor. JOP. 2011;12:389–94.PubMedPubMedCentralGoogle Scholar
  134. Lohse J, Kraemer R. Calcium binding to the“stone protein” isolated from pancreatic stones of patients with chronic calcified pancreatitis. Hoppe Seylers Z Physiol Chem. 1984;365:549–54.PubMedCrossRefGoogle Scholar
  135. Lohse J, Vérnie HJ, Sarles H. Studies on pancreatic stones. I. In vitro dissolution. Digestion. 1981;21:125–32.PubMedCrossRefGoogle Scholar
  136. Lugea A, Gukovsky I, Gukovskaya AS, Pandol SJ. Nonoxidative ethanol metabolites alter extracellular matrix protein content in rat pancreas. Gastroenterology. 2003;125(6):1845–59.PubMedCrossRefGoogle Scholar
  137. Lugea A, Gong J, Nguyen J, Nieto J, French SW, Pandol SJ. Cholinergic mediation of alcohol-induced experimental pancreatitis. Alcohol Clin Exp Res. 2010;34(10):1768–81. doi: 10.1111/j.1530-0277.2010.01264.x.PubMedPubMedCentralCrossRefGoogle Scholar
  138. Malfertheiner P, Büchler M, Stanescu A, Ditschuneit H. Pancreatic morphology and function in relationship to pain in chronic pancreatitis. Int J Pancreatol. 1987;2:59–66.PubMedGoogle Scholar
  139. Manes G, Büchler M, Pieramico O, Di Sebastiano P, Malfertheiner P. Is increased pancreatic pressure related to pain in chronic pancreatitis? Int J Pancreatol. 1994;15:113–7.PubMedGoogle Scholar
  140. Mariani A, Bernard JP, Provansal-Cheylan M, et al. Differences of pancreatic stone morphology and content in patients with pancreatic lithiasis. Dig Dis Sci. 1991;36:1509–16.PubMedCrossRefGoogle Scholar
  141. Marrache F, Tu SP, Bhagat G, et al. Overexpression of interleukin-1beta in the murine pancreas results in chronic pancreatitis. Gastroenterology. 2008;135(4):1277–87. doi: 10.1053/j.gastro.2008.06.078.PubMedPubMedCentralCrossRefGoogle Scholar
  142. McIlwrath SL, Westlund KN. Pharmacological attenuation of chronic alcoholic pancreatitis induced hypersensitivity in rats. World J Gastroenterol. 2015;21(3):836–53. doi: 10.3748/wjg.v21.i3.836.PubMedPubMedCentralCrossRefGoogle Scholar
  143. Meier T, Wasner G, Faust M, Kuntzer T, Ochsner F, Hueppe M, Bogousslavsky J, Baron R. Efficacy of lidocaine patch 5% in the treatment of focal peripheral neuropathic pain syndromes: a randomized, double- blind, placebo-controlled study. Pain. 2003;106:151–8.PubMedCrossRefGoogle Scholar
  144. Menke A, Yamaguchi H, Gress TM, Adler G. Extracellular matrix is reduced by inhibition of transforming growth factor beta1 in pancreatitis in the rat. Gastroenterology. 1997;113(1):295–303.PubMedCrossRefGoogle Scholar
  145. Miyahara T, Kawabuchi M, Goto M, Nakano I, Nada O, Nawata H. Morphological study of pancreatic endocrine in an experimental chronic pancreatitis with diabetes induced by stress and cerulein. Ultrastruct Pathol. 1999;23(3):171–80.PubMedCrossRefGoogle Scholar
  146. Miyauchi M, Suda K, Kuwayama C, Abe H, Kakinuma C. Role of fibrosis-related genes and pancreatic duct obstruction in rat pancreatitis models: implications for chronic pancreatitis. Histol Histopathol. 2007;22(10):1119–27.PubMedGoogle Scholar
  147. Moran RA, James T, Pasricha PJ. Pancreatic pain. Curr Opin Gastroenterol. 2015;31:407–15.PubMedCrossRefGoogle Scholar
  148. Mori M, Fu X, Chen L, Zhang G, Higuchi K. Hereditary pancreatitis model WBN/Kob rat strain has a unique haplotype in the Pdwk1 region on chromosome 7. Exp Anim. 2009;58(4):409–13.PubMedCrossRefGoogle Scholar
  149. Mullady DK, Yadav D, Amann ST, et al. Type of pain, pain-associated complications, quality of life, disability and resource utilisation in chronic pancreatitis: a prospective cohort study. Gut. 2011;60:77–84.PubMedCrossRefGoogle Scholar
  150. Multigner L, Daudon M, Montalto G, et al. Radiolucent pancreatic stones. New Engl J Med. 1986;314:248.PubMedGoogle Scholar
  151. Muniraj T, Aslanian HR, Farrell J, Jamidar PA. Chronic pancreatitis, a comprehensive review and update. Part I: epidemiology, etiology, risk factors, genetics, pathophysiology, and clinical features. Dis Mon. 2014;60(12):530–50. doi: 10.1016/j.disamonth.2014.11.002.PubMedCrossRefGoogle Scholar
  152. Nagai H, Ohtsubo K. Pancreatic lithiasis in the aged. Its clinicopathology and pathogenesis. Gastroenterology. 1984;86:331–8.PubMedGoogle Scholar
  153. Nakamura M, Oka M, Iizuka N, et al. Osteopontin expression in chronic pancreatitis. Pancreas. 2002;25:182–7.PubMedCrossRefGoogle Scholar
  154. Nakayama S, Nishio A, Yamashina M, et al. Acquired immunity plays an important role in the development of murine experimental pancreatitis induced by alcohol and lipopolysaccharide. Pancreas. 2014;43(1):28–36. doi: 10.1097/MPA.0b013e3182a7c76b.PubMedCrossRefGoogle Scholar
  155. Neuschwander-Tetri BA, Bridle KR, Wells LD, Marcu M, Ramm GA. Repetitive acute pancreatic injury in the mouse induces procollagen alpha1(I) expression colocalized to pancreatic stellate cells. Lab Investig. 2000a;80(2):143–50.PubMedCrossRefGoogle Scholar
  156. Neuschwander-Tetri BA, Burton FR, Presti ME, et al. Repetitive self-limited acute pancreatitis induces pancreatic fibrogenesis in the mouse. Dig Dis Sci. 2000b;45(4):665–74.PubMedCrossRefGoogle Scholar
  157. Noda A, Hayakawa T, Kondo T, et al. Pancreatic stones dissolution with dimethadione (DMO). I. In vitro dissolution. Jpn J Gastroenterol. 1984;81:101–7.Google Scholar
  158. Noda A, Ibuki E, Murayama H, Hase S. Bromhexine hydrochloride eliminates protein plugs and relieves attacks of pancreatitis. Pancreas. 1997;15:209–11.PubMedCrossRefGoogle Scholar
  159. Novis BH, Bornman PC, Girdwood AW, Marks IN. Endoscopic manometry of the pancreatic duct and sphincter zone in patients with chronic pancreatitis. Dig Dis Sci. 1985;30:225–8.PubMedCrossRefGoogle Scholar
  160. Ohashi K, Kim JH, Hara H, Aso R, Akimoto T, Nakama K. WBN/Kob rats. A new spontaneously occurring model of chronic pancreatitis. Int J Pancreatol. 1990;6(4):231–47.PubMedGoogle Scholar
  161. Ohashi S, Nishio A, Nakamura H, et al. Overexpression of redox-active protein thioredoxin-1 prevents development of chronic pancreatitis in mice. Antioxid Redox Signal. 2006;8(9–10):1835–45. doi: 10.1089/ars.2006.8.1835.PubMedCrossRefGoogle Scholar
  162. Okazaki K, Yamamoto Y, Ito K. Endoscopic measurement of papillary sphincter zone and pancreatic main ductal pressure in patients with chronic pancreatitis. Gastroenterology. 1986;91:409–18.PubMedCrossRefGoogle Scholar
  163. Olesen SS, Brock C, Krarup AL, Funch-Jensen P, Arendt-Nielsen L, Wilder-Smith OH, Drewes AM. Descending inhibitory pain modulation is impaired in patients with chronic pancreatitis. Clin Gastroenterol Hepatol. 2010a;8:724–30.PubMedCrossRefGoogle Scholar
  164. Olesen SS, Frøkjær JB, Lelic D, Valeriani M, Drewes AM. Pain-associated adaptive cortical reorganisation in chronic pancreatitis. Pancreatology. 2010b;10:742–51.PubMedCrossRefGoogle Scholar
  165. Olesen SS, Hansen TM, Graversen C, Steimle K, Wilder-Smith OHG, Drewes AM. Slowed EEG rhythmicity in patients with chronic pancreatitis: evidence of abnormal cerebral pain processing? Eur J Gastroenterol Hepatol. 2011;23:418–24.PubMedCrossRefGoogle Scholar
  166. Olesen SS, Graversen C, Bouwense SA, van Goor H, Wilder-Smith OH, Drewes AM. Quantitative sensory testing predicts pregabalin efficacy in painful chronic pancreatitis. PLoS One. 2013a;8:e57963.PubMedPubMedCentralCrossRefGoogle Scholar
  167. Olesen SS, Hansen TM, Graversen C, Valeriani M, Drewes AM. Cerebral excitability is abnormal in patients with painful chronic pancreatitis. Eur J Pain. 2013b;17:46–54.PubMedCrossRefGoogle Scholar
  168. Pandol SJ, Lugea A, Mareninova OA, et al. Investigating the pathobiology of alcoholic pancreatitis. Alcohol Clin Exp Res. 2011;35(5):830–7. doi: 10.1111/j.1530-0277.2010.01408.x.PubMedPubMedCentralCrossRefGoogle Scholar
  169. Patel AG, Toyama MT, Alvarez C, Nguyen TN, Reber PU, Ashley SW, Reber HA. Pancreatic interstitial pH in human and feline chronic pancreatitis. Gastroenterology. 1995;109:1639–45.PubMedCrossRefGoogle Scholar
  170. Perides G, Tao X, West N, Sharma A, Steer ML. A mouse model of ethanol dependent pancreatic fibrosis. Gut. 2005;54(10):1461–7. doi: 10.1136/gut.2004.062919.PubMedPubMedCentralCrossRefGoogle Scholar
  171. Perkins PS, Rutherford RE, Pandol SJ. Effect of chronic ethanol feeding on digestive enzyme synthesis and mRNA content in rat pancreas. Pancreas. 1995;10(1):14–21.PubMedCrossRefGoogle Scholar
  172. Pfutzer RH, Tadic SD, Li HS, et al. Pancreatic cholesterol esterase, ES-10, and fatty acid ethyl ester synthase III gene expression are increased in the pancreas and liver but not in the brain or heart with long-term ethanol feeding in rats. Pancreas. 2002;25(1):101–6.PubMedCrossRefGoogle Scholar
  173. Pitchumoni CS. Special problems of tropical pancreatitis. Clin Gastroenterol. 1984;13(3):941–59.PubMedGoogle Scholar
  174. Pitchumoni CS, Viswanathan KV, Gee Varghese PJ, et al. Ultrastructure and elemental composition of human pancreatic calculi. Pancreas. 1987;2:152–8.PubMedCrossRefGoogle Scholar
  175. Piubello W, Vantini I, Scuro LA, Novelli P, Benini L, Brocco G, Cavallini G. Gastric secretion, gastroduodenal histological changes, and serum gastrin in chronic alcoholic pancreatitis. Am J Gastroenterol. 1982;77:105–10.PubMedGoogle Scholar
  176. Prinz RA, Aranha GV, Greenlee HB. Combined pancreatic duct and upper gastrointestinal and biliary tract drainage in chronic pancreatitis. Arch Surg. 1985;120:361–6.PubMedCrossRefGoogle Scholar
  177. Puig-Divi V, Molero X, Salas A, Guarner F, Guarner L, Malagelada JR. Induction of chronic pancreatic disease by trinitrobenzene sulfonic acid infusion into rat pancreatic ducts. Pancreas. 1996;13(4):417–24.PubMedCrossRefGoogle Scholar
  178. Puig-Divi V, Molero X, Vaquero E, Salas A, Guarner F, Malagelada J. Ethanol feeding aggravates morphological and biochemical parameters in experimental chronic pancreatitis. Digestion. 1999;60(2):166–74.PubMedCrossRefGoogle Scholar
  179. Renner IG, Rinderknecht H, Valenzuela JE, et al. Studies of pure pancreatic secretion in chronic alcoholic subjects without pancreatic insufficiency. Scand J Gastroenterol. 1980;15:241–4.PubMedCrossRefGoogle Scholar
  180. Renou C, Grandval P, Ville E, Laugier R. Endoscopic treatment of the main pancreatic duct: correlations among morphology, manometry, and clinical follow-up. Int J Pancreatol. 2000;27:143–9.PubMedCrossRefGoogle Scholar
  181. Rolny P, Arlebäck A, Järnerot G, Andersson T. Endoscopic manometry of the sphincter of Oddi and pancreatic duct in chronic pancreatitis. Scand J Gastroenterol. 1986;21:415–20.PubMedCrossRefGoogle Scholar
  182. Sarles H, Bernard JP. Lithostathine and pancreatic lithogenesis. Gastroenterol Int Ed Int. 1991;4:130–4.Google Scholar
  183. Sarles H, Lebreuil G, Tasso F, et al. A comparison of alcoholic pancreatitis in rat and man. Gut. 1971;12(5):377–88.PubMedPubMedCentralCrossRefGoogle Scholar
  184. Sarnthein J, Stern J, Aufenberg C, Rousson V, Jeanmonod D. Increased EEG power and slowed dominant frequency in patients with neurogenic pain. Brain. 2006;129:55–64.PubMedCrossRefGoogle Scholar
  185. Sato T, Miyashita E, Yamauchi H, Matsuno S. The role of surgical treatment for chronic pancreatitis. Ann Surg. 1986;203:266–71.PubMedPubMedCentralCrossRefGoogle Scholar
  186. Saunders JH, Cargill JM, Wormsley KG. Gastric secretion of acid in patients with pancreatic disease. Digestion. 1978;17:365–9.PubMedCrossRefGoogle Scholar
  187. Schneider L, Pietschmann M, Hartwig W, et al. Alcohol pretreatment increases hepatic and pulmonary injury in experimental pancreatitis. Pancreatology. 2009;9(3):258–66. doi: 10.1159/000181176.PubMedCrossRefGoogle Scholar
  188. Schulze S, Thorsgaard Pedersen N, Jørgensen MJ, Møllmann KM, Rune SJ. Association between duodenal bulb ulceration and reduced exocrine pancreatic function. Gut. 1983;24:781–3.PubMedPubMedCentralCrossRefGoogle Scholar
  189. Schütte K, Waldthaler A, Malfertheiner P. Klinik der chronischen Pankreatitis. In: Beger HG, Büchler MW, Dralle H, Lerch MM, Malfertheiner P, Mössner J, Riemann JF, editors. Erkrankungen des Pankreas. Berlin: Springer; 2013. p. 92–4.CrossRefGoogle Scholar
  190. Schwaiger T, van den Brandt C, Fitzner B, et al. Autoimmune pancreatitis in MRL/Mp mice is a T cell-mediated disease responsive to cyclosporine A and rapamycin treatment. Gut. 2014;63(3):494–505. doi: 10.1136/gutjnl-2012-303635.PubMedCrossRefGoogle Scholar
  191. Schwartz ES, La JH, Scheff NN, Davis BM, Albers KM, Gebhart GF. TRPV1 and TRPA1 antagonists prevent the transition of acute to chronic inflammation and pain in chronic pancreatitis. J Neurosci. 2013;33:5603–11.PubMedPubMedCentralCrossRefGoogle Scholar
  192. Scoggins CR, Meszoely IM, Wada M, Means AL, Yang L, Leach SD. p53-dependent acinar cell apoptosis triggers epithelial proliferation in duct-ligated murine pancreas. Am J Physiol Gastrointest Liver Physiol. 2000;279(4):G827–36.PubMedGoogle Scholar
  193. Seleznik GM, Reding T, Romrig F, et al. Lymphotoxin beta receptor signaling promotes development of autoimmune pancreatitis. Gastroenterology. 2012;143(5):1361–74. doi: 10.1053/j.gastro.2012.07.112.PubMedCrossRefGoogle Scholar
  194. Sendler M, Dummer A, Weiss FU, et al. Tumour necrosis factor alpha secretion induces protease activation and acinar cell necrosis in acute experimental pancreatitis in mice. Gut. 2013;62(3):430–9. doi: 10.1136/gutjnl-2011-300771.PubMedCrossRefGoogle Scholar
  195. Sendler M, Beyer G, Mahajan UM, et al. Complement component 5 mediates development of fibrosis, via activation of stellate cells, in 2 mouse models of chronic pancreatitis. Gastroenterology. 2015;149(3):765–76.e10. doi: 10.1053/j.gastro.2015.05.012.PubMedPubMedCentralCrossRefGoogle Scholar
  196. Sharer N, Schwarz M, Malone G, et al. Mutations of the cystic fibrosis gene in patients with chronic pancreatitis. N Engl J Med. 1998;339(10):645–52. doi: 10.1056/NEJM199809033391001.PubMedCrossRefGoogle Scholar
  197. Snouwaert JN, Brigman KK, Latour AM, et al. An animal model for cystic fibrosis made by gene targeting. Science. 1992;257(5073):1083–8.PubMedCrossRefGoogle Scholar
  198. Steele CW, Karim SA, Foth M, et al. CXCR2 inhibition suppresses acute and chronic pancreatic inflammation. J Pathol. 2015;237(1):85–97. doi: 10.1002/path.4555.PubMedPubMedCentralCrossRefGoogle Scholar
  199. Steinberg AD, Roths JB, Murphy ED, Steinberg RT, Raveche ES. Effects of thymectomy or androgen administration upon the autoimmune disease of MRL/Mp-lpr/lpr mice. J Immunol. 1980;125(2):871–3.PubMedGoogle Scholar
  200. Stewart TA. The human reg gene encodes pancreatic stone protein. Biochem J. 1989;260:622–3.PubMedPubMedCentralCrossRefGoogle Scholar
  201. Tanaka T, Ichiba Y, Fujii Y, Itoh H, Kodama O, Dohi K. New canine model of chronic pancreatitis due to chronic ischemia with incomplete pancreatic duct obstruction. Digestion. 1988;41(3):149–55.PubMedCrossRefGoogle Scholar
  202. Tanaka T, Miura Y, Matsugu Y, Ichiba Y, Ito H, Dohi K. Pancreatic duct obstruction is an aggravating factor in the canine model of chronic alcoholic pancreatitis. Gastroenterology. 1998;115(5):1248–53.PubMedCrossRefGoogle Scholar
  203. Tatsumi Y, Lichtenberger LM. Molecular association of trinitrobenzenesulfonic acid and surface phospholipids in the development of colitis in rats. Gastroenterology. 1996;110(3):780–9.PubMedCrossRefGoogle Scholar
  204. Toma H, Winston J, Micci MA, Shenoy M, Pasricha PJ. Nerve growth factor expression is up-regulated in the rat model of L-arginine-induced acute pancreatitis. Gastroenterology. 2000;119:1373–81.PubMedCrossRefGoogle Scholar
  205. Treuting PM, Dintzis SM, Liggitt D, Charles W. Pancreas. In: Treuting PM, Dintzis SM, Montine KS, editors. Comparative anatomy and histology: a mouse and human atlas. New York: Elsevier; 2012. p. 203–9.Google Scholar
  206. Tsujimoto T, Tsuruzono T, Hoppo K, Matsumura Y, Yamao J, Fukui H. Effect of bromhexine hydrochloride therapy for alcoholic chronic pancreatitis. Alcohol Clin Exp Res. 2005;29(suppl 12):272S–6S.PubMedCrossRefGoogle Scholar
  207. Tsukamoto H, Towner SJ, Yu GS, French SW. Potentiation of ethanol-induced pancreatic injury by dietary fat. Induction of chronic pancreatitis by alcohol in rats. Am J Pathol. 1988;131(2):246–57.PubMedPubMedCentralGoogle Scholar
  208. Tuteja AK, Biskupiak J, Stoddard GJ, Lipman AG. Opioid-induced bowel disorders and narcotic bowel syndrome in patients with chronic non-cancer pain. Neurogastroenterol Motil. 2010;22:424–30, e96.PubMedCrossRefGoogle Scholar
  209. Tuveson DA, Hingorani SR. Ductal pancreatic cancer in humans and mice. Cold Spring Harb Symp Quant Biol. 2005;70:65–72. doi: 10.1101/sqb.2005.70.040.PubMedCrossRefGoogle Scholar
  210. Tympner F. Selectively aspirated pure pancreatic secretion. Viscosity, trypsin activity, protein concentration and lactoferrin content of pancreatic juice in chronic pancreatitis. Hepatogastroenterology. 1981;28:169–72.PubMedGoogle Scholar
  211. Ugljesić M, Bulajić M, Milosavljević T, Stimec B. Endoscopic manometry of the sphincter of Oddi and pancreatic duct in patients with chronic pancreatitis. Int J Pancreatol. 1996;19:191–5.PubMedGoogle Scholar
  212. Ulmasov B, Oshima K, Rodriguez MG, Cox RD, Neuschwander-Tetri BA. Differences in the degree of cerulein-induced chronic pancreatitis in C57BL/6 mouse substrains lead to new insights in identification of potential risk factors in the development of chronic pancreatitis. Am J Pathol. 2013;183(3):692–708. doi: 10.1016/j.ajpath.2013.05.020.PubMedPubMedCentralCrossRefGoogle Scholar
  213. Unal E, Atalay S, Tolan HK, et al. Biliopancreatic duct injection of ethanol as an experimental model of acute and chronic pancreatitis in rats. Int J Clin Exp Med. 2015;8(1):304–10.PubMedPubMedCentralGoogle Scholar
  214. Van Laethem JL, Robberecht P, Resibois A, Deviere J. Transforming growth factor beta promotes development of fibrosis after repeated courses of acute pancreatitis in mice. Gastroenterology. 1996;110(2):576–82.PubMedCrossRefGoogle Scholar
  215. Vaquero E, Molero X, Tian X, Salas A, Malagelada JR. Myofibroblast proliferation, fibrosis, and defective pancreatic repair induced by cyclosporin in rats. Gut. 1999;45(2):269–77.PubMedPubMedCentralCrossRefGoogle Scholar
  216. Vaso A, Adahan HM, Gjika A, Zahaj S, Zhurda T, Vyshka G, Devor M. Peripheral nervous system origin of phantom limb pain. Pain. 2014;155:1384–91.PubMedCrossRefGoogle Scholar
  217. Vera-Portocarrero LP, Xie JY, Yie JX, Kowal J, Ossipov MH, King T, Porreca F. Descending facilitation from the rostral ventromedial medulla maintains visceral pain in rats with experimental pancreatitis. Gastroenterology. 2006;130:2155–64.PubMedCrossRefGoogle Scholar
  218. Vestergaard H, Kruse A, Rokkjaer M, Frobert O, Thommesen P, Funch-Jensen P. Endoscopic manometry of the sphincter of Oddi and the pancreatic and biliary ducts in patients with chronic pancreatitis. Scand J Gastroenterol. 1994;29:188–92.PubMedCrossRefGoogle Scholar
  219. Vijungco JD, Prinz RA. Management of biliary and duodenal complications of chronic pancreatitis. World J Surg. 2003;27:1258–70.PubMedCrossRefGoogle Scholar
  220. Wang RN, Kloppel G, Bouwens L. Duct- to islet-cell differentiation and islet growth in the pancreas of duct-ligated adult rats. Diabetologia. 1995;38(12):1405–11.PubMedCrossRefGoogle Scholar
  221. Wang Y, Wrennall JA, Cai Z, Li H, Sheppard DN. Understanding how cystic fibrosis mutations disrupt CFTR function: from single molecules to animal models. Int J Biochem Cell Biol. 2014;52:47–57. doi: 10.1016/j.biocel.2014.04.001.PubMedCrossRefGoogle Scholar
  222. Warshaw AL, Banks PA, Fernández-Del Castillo C. AGA technical review: treatment of pain in chronic pancreatitis. Gastroenterology. 1998;115:765–76.PubMedCrossRefGoogle Scholar
  223. Watanabe S, Abe K, Anbo Y, Katoh H. Changes in the mouse exocrine pancreas after pancreatic duct ligation: a qualitative and quantitative histological study. Arch Histol Cytol. 1995;58(3):365–74.PubMedCrossRefGoogle Scholar
  224. Watkins-Chow DE, Pavan WJ. Genomic copy number and expression variation within the C57BL/6J inbred mouse strain. Genome Res. 2008;18(1):60–6. doi: 10.1101/gr.6927808.PubMedPubMedCentralCrossRefGoogle Scholar
  225. Weiss FU, Simon P, Bogdanova N, et al. Complete cystic fibrosis transmembrane conductance regulator gene sequencing in patients with idiopathic chronic pancreatitis and controls. Gut. 2005;54(10):1456–60. doi: 10.1136/gut.2005.064808.PubMedPubMedCentralCrossRefGoogle Scholar
  226. Weiss FU, Schurmann C, Guenther A, et al. Fucosyltransferase 2 (FUT2) non-secretor status and blood group B are associated with elevated serum lipase activity in asymptomatic subjects, and an increased risk for chronic pancreatitis: a genetic association study. Gut. 2015;64(4):646–56. doi: 10.1136/gutjnl-2014-306930.PubMedCrossRefGoogle Scholar
  227. Whitcomb DC. Genetics of alcoholic and nonalcoholic pancreatitis. Curr Opin Gastroenterol. 2012;28(5):501–6. doi: 10.1097/MOG.0b013e328356e7f3.PubMedCrossRefGoogle Scholar
  228. Whitcomb DC, Gorry MC, Preston RA, et al. Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene. Nat Genet. 1996;14(2):141–5. doi: 10.1038/ng1096-141.PubMedCrossRefGoogle Scholar
  229. Whitcomb DC, LaRusch J, Krasinskas AM, et al. Common genetic variants in the CLDN2 and PRSS1-PRSS2 loci alter risk for alcohol-related and sporadic pancreatitis. Nat Genet. 2012;44(12):1349–54. doi: 10.1038/ng.2466.PubMedPubMedCentralCrossRefGoogle Scholar
  230. White TT, Bourde J. A new observation on human intraductal pancreatic pressure. Surg Gynecol Obstet. 1970;130:275–8.PubMedGoogle Scholar
  231. Wilcox CM, Yadav D, Ye T, et al. Chronic pancreatitis pain pattern and severity are independent of abdominal imaging findings. Clin Gastroenterol Hepatol. 2015;13:552–60,quiz e28–9.PubMedCrossRefGoogle Scholar
  232. Willert RP, Woolf CJ, Hobson AR, Delaney C, Thompson DG, Aziz Q. The development and maintenance of human visceral pain hypersensitivity is dependent on the N-methyl-d-aspartate receptor. Gastroenterology. 2004;126:683–92.PubMedCrossRefGoogle Scholar
  233. Wolf MJ, Seleznik GM, Zeller N, Heikenwalder M. The unexpected role of lymphotoxin beta receptor signaling in carcinogenesis: from lymphoid tissue formation to liver and prostate cancer development. Oncogene. 2010;29(36):5006–18. doi: 10.1038/onc.2010.260.PubMedCrossRefGoogle Scholar
  234. Wong GY, Gavva NR. Therapeutic potential of vanilloid receptor TRPV1 agonists and antagonists as analgesics: recent advances and setbacks. Brain Res Rev. 2009;60:267–77.PubMedCrossRefGoogle Scholar
  235. Woodruff TM, Nandakumar KS, Tedesco F. Inhibiting the C5-C5a receptor axis. Mol Immunol. 2011;48(14):1631–42. doi: 10.1016/j.molimm.2011.04.014.PubMedCrossRefGoogle Scholar
  236. Woolf CJ. Central sensitization: implications for the diagnosis and treatment of pain. Pain. 2011;152:S2–15.PubMedCrossRefGoogle Scholar
  237. Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain. Science. 2000;288:1765–9.PubMedCrossRefGoogle Scholar
  238. Woolf CJ, Safieh-Garabedian B, Ma QP, Crilly P, Winter J. Nerve growth factor contributes to the generation of inflammatory sensory hypersensitivity. Neuroscience. 1994;62:327–31.PubMedCrossRefGoogle Scholar
  239. Xu G-Y, Winston JH, Shenoy M, Yin H, Pendyala S, Pasricha PJ. Transient receptor potential vanilloid 1 mediates hyperalgesia and is up-regulated in rats with chronic pancreatitis. Gastroenterology. 2007;133:1282–92.PubMedCrossRefGoogle Scholar
  240. Yadav D, Lowenfels AB. The epidemiology of pancreatitis and pancreatic cancer. Gastroenterology. 2013;144(6):1252–61. doi: 10.1053/j.gastro.2013.01.068.PubMedPubMedCentralCrossRefGoogle Scholar
  241. Yadav D, Timmons L, Benson JT, Dierkhising RA, Chari ST. Incidence, prevalence, and survival of chronic pancreatitis: a population-based study. Am J Gastroenterol. 2011;106(12):2192–9. doi: 10.1038/ajg.2011.328.PubMedCrossRefGoogle Scholar
  242. Yadav D, O’Connell M, Papachristou GI. Natural history following the first attack of acute pancreatitis. Am J Gastroenterol. 2012;107(7):1096–103. doi: 10.1038/ajg.2012.126.PubMedCrossRefGoogle Scholar
  243. Yamamoto M, Otani M, Otsuki M. A new model of chronic pancreatitis in rats. Am J Physiol Gastrointest Liver Physiol. 2006;291(4):G700–8. doi: 10.1152/ajpgi.00502.2005.PubMedCrossRefGoogle Scholar
  244. Yarnitsky D, Granot M, Nahman-Averbuch H, Khamaisi M, Granovsky Y. Conditioned pain modulation predicts duloxetine efficacy in painful diabetic neuropathy. Pain. 2012;153:1193–8.PubMedCrossRefGoogle Scholar
  245. Zambreanu L, Wise RG, Brooks JCW, Iannetti GD, Tracey I. A role for the brainstem in central sensitisation in humans. Evidence from functional magnetic resonance imaging. Pain. 2005;114:397–407.PubMedCrossRefGoogle Scholar
  246. Zhao HF, Ito T, Gibo J, et al. Anti-monocyte chemoattractant protein 1 gene therapy attenuates experimental chronic pancreatitis induced by dibutyltin dichloride in rats. Gut. 2005;54(12):1759–67. doi: 10.1136/gut.2004.049403.PubMedPubMedCentralCrossRefGoogle Scholar
  247. Zhu Y, Colak T, Shenoy M, Liu L, Pai R, Li C, Mehta K, Pasricha PJ. Nerve growth factor modulates TRPV1 expression and function and mediates pain in chronic pancreatitis. Gastroenterology. 2011;141:370–7.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. and Shanghai Scientific and Technical Publishers 2017

Authors and Affiliations

  • Jakob Lykke Poulsen
    • 1
  • Søren Schou Olesen
    • 1
  • Asbjørn Mohr Drewes
    • 1
    Email author
  • Bo Ye
    • 2
  • Wei-Qin Li
    • 2
    Email author
  • Ali A. Aghdassi
    • 3
  • Matthias Sendler
    • 3
  • Julia Mayerle
    • 3
  • Markus M. Lerch
    • 3
    Email author
  1. 1.Mech-Sense, Department of Gastroenterology and HepatologyClinical Institute, Centre for Pancreatic Diseases, Aalborg University HospitalAalborgDenmark
  2. 2.Department of General SurgeryJinling Hospital, Medical School of Nanjing UniversityNanjingChina
  3. 3.Department of Medicine AUniversity Medicine GreifswaldGreifswaldGermany

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