Neuroenzyme inhibition a possible analgesic for chronic pancreatitis

Severe chronic pain in patients with inflammation of the pancreas could be relieved by inhibiting a specific neuroenzyme, according to a new study.

Researchers from the Department of Surgery in Rechts der Isar, university hospital of the Technical University of Munich (TUM), Germany, reported that high concentrations of neuronal nitric oxide synthase (nNOS) in the pancreatic nerves appeared to be the underlying cause behind refractory pain in cases of chronic pancreatitis. [EBioMedicine 2019;46:431–443]

Severe chronic pain is a distressing symptom associated with pancreatic cancer or pancreatitis. In many patients, most analgesics apart from opiates have little effect in treating it. However, given the potential adverse effects from opiate treatment and the risk of dependency, medical researchers have been searching for alternative therapeutic options.

The TUM study examined tissue samples from the pancreatic head regions of 42 patients with chronic pancreatitis (n=23) or pancreatic carcinoma (n=19). All patients had undergone resection due to either intractable pain that was not responding to medical or endoscopic therapy, or suspected malignancies. The pancreatic head is particularly dense with nerves and is often targeted for resection to treat pain.

The pancreatic tissue samples were compared to those from healthy patients. By examining the levels of neurotransmitters and neuroenzymes related to signal transmission in the tissue, the team found the presence of nNOS in high concentrations in pancreatic nerves in the patients with chronic pancreatitis, with higher concentrations corresponding to patients who reported more severe pain levels.

The nNOS enzyme is involved in synthesizing nitric oxide (NO), which plays a role in pain development, particularly through binding to receptors on neuron surfaces to induce neuronal hyperactivation.

The team found that adding tissue extracts from patient samples to nerve cell cultures also resulted in an observed increase in nNOS production in the cultured nerve cells.

Using mouse models for chronic pancreatitis, the team tested the use of N(ω)-propyl-L-arginine (NPLA), an nNOS inhibitor, on pain levels. NPLA reportedly reduced pain in the mice models versus those treated with saline solution (mechanosensitivity/Von Frey scores, 67.9 ± 2.3 versus 74.7 ± 4.7, p=0.001).

“Based on our findings, we believe that nNOS inhibitors should find access into early phase clinical trials on pain in chronic pancreatitis for alleviation of the huge burden that pain inflicts on these patients,” said the study authors. “By analyzing the nerves from resection specimens of chronic pancreatitis patients, we could for the first time identify nNOS as a neuronal enzyme that was enriched in pancreatic nerves of chronic pancreatitis patients in a pain-severity-dependent manner.”

In the same study, the researchers reported that elevated nNOS levels were not observed in samples taken from patients with pancreatic cancer.

“Despite structural similarities such as nerve hypertrophy or nerve sprouting [in the two diseases], there are obvious mechanistic differences in the pain caused by chronic pancreatitis versus pancreatic cancer,” said the researchers, who added that other areas of neuropathy besides nNOS would need to be examined to treat chronic pain in those patients.