Targeting nNOS ameliorates the severe neuropathic pain due to chronic pancreatitis

dc.contributor.authorDemir, Ihsan Ekin
dc.contributor.authorHeinrich, Tobias
dc.contributor.authorCarty, Dominique G.
dc.contributor.authorSaricaoglu, Omer Cemil
dc.contributor.authorKlauss, Sarah
dc.contributor.authorTeller, Steffen
dc.contributor.authorKehl, Timo
dc.contributor.authorReyes, Carmen Mota
dc.contributor.authorTieftrunk, Elke
dc.contributor.authorLazarou, Maria
dc.contributor.authorBahceci, Dorukhan H.
dc.contributor.authorGokcek, Betul
dc.contributor.authorUcurum, Bahar E.
dc.contributor.authorMaak, Matthias
dc.contributor.authorDiakopoulos, Kalliope N.
dc.contributor.authorLesina, Marina
dc.contributor.authorSchemann, Michael
dc.contributor.authorErkane, Mert
dc.contributor.authorKrueger, Achim
dc.contributor.authorAlgul, Hana
dc.contributor.authorFriess, Helmut
dc.contributor.authorCeyhan, Guralp O.
dc.date.accessioned2023-02-21T12:38:00Z
dc.date.available2023-02-21T12:38:00Z
dc.date.issued2019-01-01
dc.description.abstractBackground: Pain due to pancreatic cancer/PCa or chronic pancreatitis/CP, is notoriously resistant to the strongest pain medications. Here, we aimed at deciphering the specific molecular mediators of pain at surgical-stage pancreatic disease and to discover novel translational targets. Methods: We performed a systematic, quantitative analysis of the neurotransmitter/neuroenzmye profile within intrapancreatic nerves of CP and PCa patients. Ex vivo neuronal cultures treated with human pancreatic extracts, conditional genetically engineered knockout mouse models of PCa and CP, and the cerulein-induced CP model were employed to explore the therapeutic potential of the identified targets. Findings: We identified a unique enrichment of neuronal nitric-oxide-synthase (nNOS) in the pancreatic nerves of CP patients with increasing pain severity. Employment of ex vivo neuronal cultures treated with pancreatic tissue extracts of CP patients, and brain-derived-neurotrophic-factor-deficient (BDNF+/-) mice revealed neuronal enrichment of nNOS to be a consequence of BDNI loss in the progressively destroyed pancreatic tissue. Mechanistically, nNOS upregulation in sensory neurons was induced by tryptase secreted from perineural mast cells. In a head-to-head comparison of several genetically induced, painless mouse models of PCa (KPC, KC mice) or CP (Ptf1a-Cre
dc.description.abstractArg5(f1/f1)) against the hypersecretion/cerulein-induced, painful CP mouse model, we show that a similar nNOS enrichment is present in the painful cerulein-CP model, but absent in painless genetic models. Consequently, mice afflicted with painful cerulein-induced CP could be significantly relieved upon treatment with the specific nNOS inhibitor NPLA. Interpretation: We propose nNOS inhibition as a novel strategy to treat the unbearable pain in CP. (C) 2019 The Authors. Published by Elsevier B.V.
dc.description.issueAUG
dc.description.pages431-443
dc.description.volume46
dc.identifier.doi10.1016/j.ebiom.2019.07.055
dc.identifier.urihttps://hdl.handle.net/11443/2323
dc.identifier.urihttp://dx.doi.org/10.1016/j.ebiom.2019.07.055
dc.identifier.wosWOS:000486592000052
dc.publisherELSEVIER
dc.relation.ispartofEBIOMEDICINE
dc.subjectPain
dc.subjectNeurology of the digestive tract
dc.subjectnNOS
dc.subjectNitrergic
dc.subjectChronic pancreatitis
dc.subjectPancreatic cancer
dc.subjectGenetically engineered mice
dc.subjectAtg5
dc.titleTargeting nNOS ameliorates the severe neuropathic pain due to chronic pancreatitis
dc.typeArticle

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