Dataset Information

Targeting nNOS ameliorates the severe neuropathic pain due to chronic pancreatitis.

ABSTRACT:

Background

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 BDNF 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;Atg5^fl/fl) 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. FUND: Deutsche Forschungsgemeinschaft/DFG (DE2428/3-1 and 3-2).

SUBMITTER: Demir IE

PROVIDER: S-EPMC6711864 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Publications

Targeting nNOS ameliorates the severe neuropathic pain due to chronic pancreatitis.

Demir Ihsan Ekin IE Heinrich Tobias T Carty Dominique G DG Saricaoglu Ömer Cemil ÖC Klauss Sarah S Teller Steffen S Kehl Timo T Mota Reyes Carmen C Tieftrunk Elke E Lazarou Maria M Bahceci Dorukhan H DH Gökcek Betül B Ucurum Bahar E BE Maak Matthias M Diakopoulos Kalliope N KN Lesina Marina M Schemann Michael M Erkan Mert M Krüger Achim A Algül Hana H Friess Helmut H Ceyhan Güralp O GO

EBioMedicine 20190808

<h4>Background</h4>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.<h4>Methods</h4>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 ...[more]

PMID: 31401195

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Dataset Information

Targeting nNOS ameliorates the severe neuropathic pain due to chronic pancreatitis.

Background

Methods

Findings

Interpretation

Publications

Targeting nNOS ameliorates the severe neuropathic pain due to chronic pancreatitis.

Similar Datasets

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