The Mechanism of HDAC2 Inhibitors on Chronic Pancreatitis Pain.

Abstract

Background: Chronic pancreatitis (CP) is marked by persistent inflammation and fibrosis of the pancreas, often causing severe abdominal pain. The pain mechanism involves complex interactions between pancreatic inflammation and spinal nerve activity. Histone deacetylase 2 (HDAC2) is implicated in neural processes and pain modulation, making it a potential target for CP pain management.

Aim: This study investigates HDAC2's role in CP pain and evaluates the effects of its inhibition in a CP rat model.

Methods: CP was induced in male Sprague-Dawley rats using dibutyltin dichloride (DBTC). HDAC2 expression in spinal and pancreatic tissues was assessed through western blotting, quantitative Real-Time PCR, and enzyme-linked immunosorbent assay (ELISA). Pain sensitivity was evaluated using paw withdrawal tests. Co-cultures of AR42J pancreatic acinar cells and F11 spinal neurons were used to explore pancreatic-neural interactions. Chromatin immunoprecipitation (ChIP) and promoter assays examined HDAC2 transcriptional regulation.

Results: HDAC2 expression was significantly elevated in CP rats, which also displayed increased pain sensitivity and higher inflammatory markers (interleukin [IL]-1β [IL-1β], tumor necrosis factor-α [TNF-α], IL-6, and chemokine ligand 2 [CCL-2]). HDAC2 inhibition reduced pain sensitivity and pancreatitis. Co-culture experiments revealed that pancreatic inflammatory mediators upregulate HDAC2 in neurons. ChIP identified Sp1 as a regulatory factor for HDAC2, with the extracellular signal-regulated kinase-Specific protein 1 (ERK-Sp1) pathway critical for its expression.

Conclusion: HDAC2 is crucial in CP pain sensitization and inflammation. Its inhibition reduces pain and inflammation, offering potential for targeted pain management in CP.