Abstract
Pain is the most important clinical feature of acute pancreatitis (AP); however, its specific mechanism is currently unclear. In this study, we showed that AP caused an increase in nitric oxide (NO) secretion, activated the NF-κB pathway in the dorsal root ganglia (DRGs), and caused pain. We established an AP model in vivo and tested the expression of NO, the kappa opioid receptor (KOR), and pain factors. We showed that NO in AP was significantly elevated and increased the expression of pain factors. Next, by treating DRGs in vitro, it was found that NO activated the NF-κB pathway; conversely, NF-κB had no effect on NO. Moreover, inhibition of NF-κB promoted the KOR, whereas NF-κB did not change after KOR activation. Finally, behavioral experiments showed that a NO donor increased the pain behavior of mice, while a NO scavenger, NF-κB inhibitor, or KOR agonist attenuated the pain response in mice. These results suggest that iNOS/NO/NF-κB/KOR may be a key mechanism of pain in AP, providing a theoretical basis for the use of peripheral-restricted KOR agonists for pain treatment in AP.
Highlights
Acute pancreatitis (AP) is an inflammatory disease that causes pancreatic tissue digestion, edema, hemorrhage, and even necrosis of pancreatic tissue after activation of pancreatic enzyme by multiple causes
Immunohistochemistry confirmed that the protein expression of iNOS was increased in AP (Figure 1(b))
We used the in vivo cerulein to establish an AP model and in vitro treatment of DRGs to explore the effects of the peripheral nervous system on pancreatitis pain
Summary
Acute pancreatitis (AP) is an inflammatory disease that causes pancreatic tissue digestion, edema, hemorrhage, and even necrosis of pancreatic tissue after activation of pancreatic enzyme by multiple causes. Many studies have shown that in inflammatory diseases, the cause of pain involves inflammatory mediators, the nervous system, and the immune system. The interaction between nerves and diseased areas through neurotransmitters and inflammatory mediators affects the progression of pain and disease. NOS is divided into three subtypes, eNOS, iNOS, and nNOS. INOS can be expressed in a variety of cells and produce a large amount of NO in a continuous and uncontrolled manner. A growing amount of evidence suggests that a very early event in the development of acute pancreatitis is the release of endogenous inflammatory mediators from the inflamed pancreas. NF-κB has been shown to play a key role in the development of acute pancreatitis, and activation of the transcription factor NF-κB can be detected early in experimental pancreatitis [5]. The activation of the NF-κB-associated pathways mediates IL-1β-induced upregulation of spinal COX-2 and pain hypersensitivity
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