Duloxetine ameliorates acute pancreatitis-associated inflammation and modulates pain related neuroinflammatory pathways via modulation of SP-related neurokinin signaling and PAR2/TRPV1 pathways.

BACKGROUND: Acute pancreatitis (AP) is an inflammatory pancreatic disorder, often illustrated by neuropathic, inflammatory, and/or visceral pain. Pain is a medical indicator of pancreatic inflammation and growing evidence evokes that it exerts a significant role in AP progression via the widespread neuronal network surrounding the pancreas. OBJECTIVES: evaluate the possible defensive action of duloxetine (DUX), a serotonin/norepinephrine reuptake inhibitor (SNRI), in L-arginine (L-Arg)- provoked AP and multiple organ injury (MOI), and to explore the potential mechanism of action of DUX-mediated modulation of neuroinflammatory pain in AP. METHODS: AP was induced in rats by intraperitoneal injection of L-Arg (100 mg/100 g) and two different doses of DUX (10 and 30 mg/kg) was examined. RESULTS: DUX improved the histopathological architecture of the pancreas, liver, lung, and kidney. Additionally, it restored the normal levels of serum pancreatic enzymes, liver enzymes, and kidney biomarkers that were significantly elevated following L-Arg administration. In addition, DUX improved tissue antioxidant state. Moreover, DUX decreased the levels of transient receptor potential cation channel subfamily V member 1 (TRPV1), proteinase-activated receptor-2 (PAR2), substance P (SP), neurokinin, trypsin, leukotriene B4 (LTB4), signal transducer and activator of transcription 3 (STAT3) and significantly reduced TNF-α expression in the pancreatic tissues. CONCLUSION: DUX displayed analgesic, anti-inflammatory, and antioxidant effects. Therefore, DUX is a promising therapeutic candidate for the management of AP-related neuroinflammatory pain. The proposed analgesic and anti-inflammatory mechanisms of DUX may be linked to the modulation of SP related NK signaling and PAR2/TRPV1 pathways pointing to a possible role for these pathways in the observed beneficial action of DUX.