The pancreatic proteases as new analgesic targets in acute and chronic pancreatitis

Introduction Acute (AP) and chronic pancreatitis (CP) are characterized by early protease activation with subsequent inflammation, tissue damage and therapy-resistant pain. These mechanisms are triggered by a perineural inflammatory response via proteinase-activated receptors.

Aim The long-term goal is the development of a drug, based on selective protease inhibition, for the treatment of acute and chronic pancreatitis. This should meet the demands of modern therapy with a pain-relieving and tissue-protective effect at the same time.

Methods We performed a quantification of all major protease classes in the pancreas of male C57Bl6/J mice with cerulein-induced AP and CP. For analgesic therapy, we implanted osmotic pumps filled with specific inhibitors of these protease classes for continuous s.c. application. The abdominal pain reaction was examined via standardized mechanosensitivity, using “von Frey” test (scale from 0 to 20). Pancreatic tissue was pathomorphological analyzed. To detect neuronal activity, posterior horn cells of the pancreas-innervating spinal cord segments between Th9-12 were immunohistochemically stained for cFos.

Results The expression of the cysteine protease Cathepsin S was three times higher in AP and CP than in the normal pancreas. Furthermore, there was an increase in the intrapancreatic amounts of ADAM9, MMP2, MMP3 and MMP9. Selective inhibition of these proteases led to a significantly lower pain level. In CP, when compared to placebo mice (Von-Frey-Score 11,2±1,08), treatment with SB3CT (inhibitor of MMP-2 and MMP-9) decreased pain to 9,13±1,05, APC366 (mast cell tryptase-inhibitor) to 8,33±1,55, SB366791 (TRPV1 antagonist) to 8,67±1,37, and LY3000328 (Cathepsin S-inhibitor) to 3,25±0,43. To verify the mechanism, MMP9^-/- mice were included, which showed almost complete absence of pain. In our histopathological analyses, there was much less tissue damage in the animals treated with the selective inhibitors. The pancreata had a significantly lower degree of fibrosis. Additionally, in CP, there was a clear reduction of cFos activity in the posterior horn cells (Th9-12).

Conclusion Selective protease inhibition ameliorates the severity of pain, tissue damage and neuronal activity in acute and chronic pancreatitis

Publication History

Article published online:
28 August 2023