Painkiller resistance in pancreatic diseases deciphered

Severe and persistent pancreatic pain is difficult to treat because many painkillers do not work in this organ. In a recent study, a team has discovered the reason: A certain endogenous nerve messenger substance is present in the pancreas’ nerves in very high concentrations.

nNOS greatly elevated in pancreatic tissue

One of the worst symptoms of pancreatic cancer or inflammation is severe and persistent pain. This is difficult to treat because many painkillers do not work in this organ. In a recent study, a team from the Technical University of Munich (TUM) has discovered the reason for this: A certain endogenous nerve messenger substance is present in the pancreas’ nerves in very high concentrations.

In pancreatic diseases, only strong painkillers such as opiates can often alleviate the suffering of those affected. However, these drugs have serious side effects such as addiction, fatigue, and constipation. For this reason, scientists have long been looking for better pain therapies for these patients.

Dr. Ihsan Ekin Demir from the Department of Surgery at the University Hospital Rechts der Isar, Technical University of Munich, and his team wanted to find out why pain treatment for pancreatic diseases is so difficult and often ineffective.

Profiling the pancreas' pain messaging

The team examined tissue samples from the "head area" of the pancreas of 42 patients suffering from chronic pancreatitis or pancreatic carcinoma. Tissue donations from healthy individuals served as controls in the new study. The scientists determined the amount of the most important neurotransmitters that are released by nerve cells for communication and signal transmission.

"We have created a pain messaging profile for this area of the pancreas, which plays a decisive role in the development and perception of pain. This makes it easy to identify pathological changes," explains Dr. Demir, head of the study.

Inhibitor successfully tested in the animal model

The team discovered that a certain enzyme in the nerves of the pancreatic tissue of the patients examined was strongly elevated: neuronal nitric oxide synthase (nNOS). It is responsible for the production of the neurotransmitter NO, which plays a role in pain formation, among other things. In particular, NO leads to the overactivation of nerve cells by binding to its receptors on the neuron surface. When the team subsequently added extracts from the patient samples to nerve cell cultures, the amount of the enzyme nNOS increased in the nerve cells.

In an established mouse model for pancreatic diseases, they then used a specific inhibitor that blocks the enzyme nNOS. This substance has already been approved for experimental use, but cannot yet be used in humans. Dr. Demir and his team found that mice receiving the substance were much less sensitive to contact with the affected abdomen than control animals. This serves as an indicator of pain perception.

Dr. Demir and his team now hope to further test the new substance in initial preclinical and later clinical studies in order to be able to use it as an alternative pain therapy for patients suffering from pancreatic diseases.

Ihsan Ekin Demir, Tobias Heinrich, Dominique Carty, Ö. Cemil Saricaoglu, Sarah Klauss, Steffen Teller, Timo Kehl, Carmen M Reyes, Elke Tieftrunk, Maria Lazarou, Dorukhan H Bahceci, Betül Gökcek, Bahar E Ucurum, Matthias Maak, Kalliope N Diakopoulos, Marina Lesina, Michael Schemann, Mert Erkan, Achim Krüger, Hana Algül, Helmut Friess, Güralp O Ceyhan, Targeting nNOS ameliorates the severe neuropathic pain due to chronic pancreatitis, EBioMedicine, 2019, DOI: 10.1016/j.ebiom.2019.07.055

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