Melanocortin 4 receptor stimulation decreases pancreatitis severity in rats by activation of the cholinergic anti-inflammatory pathway
Related Experiment Video
Updated: Jun 5, 2026
Preparing a Mice Model of Severe Acute Pancreatitis via a Combination of Caerulein and Lipopolysaccharide Intraperitoneal Injection
Published on: May 10, 2024
Letteria Minutoli1, Francesco Squadrito, Piero Antonio Nicotina
1Department of Experimental and Clinical Medicine and Pharmacology, Section of Pharmacology, University of Messina, Messina, Italy. lminutoli@unime.it
Objective:
Acute pancreatitis is an inflammatory condition that may lead to multisystemic organ failure. Melanocortin peptides have been successfully used in experimental models of organ failure and shock, and their protective effect occurs through the activation of a vagus nerve-mediated cholinergic anti-inflammatory pathway by acting at brain melanocortin 4 receptors. In the light of these observations, we studied the effects of the selective melanocortin 4 receptor agonist RO27-3225 in an experimental model of cerulein-induced pancreatitis.
Design:
Randomized experiment.
Setting:
Research laboratory at a university hospital.
Subject:
Experimental pancreatitis in rats.
Interventions:
Acute pancreatitis was induced in male Sprague-Dawley rats by intraperitoneal injections of cerulein (80 μg/kg, four injections at hourly intervals). Before pancreatitis induction, groups of animals were subjected to bilateral cervical vagotomy, pretreated with the nicotinic acetylcholine receptor antagonist chlorisondamine or the selective melanocortin 4 receptor antagonist HS024, or not pretreated. Thirty minutes after the first cerulein injection, rats were intraperitoneally treated with a nanomolar dose of RO27-3225 or vehicle. Some experimental groups were prepared for neural efferent activity recording along the vagus nerve starting 30 mins after treatment with RO27-3225 or vehicle, and for a 30-min period.
Measurements And Main Results:
Serum lipase and amylase activity, tumor necrosis factor-α and interleukin-6 expression, pancreatic myeloperoxidase activity, and histologic damage were evaluated; neural efferent activity of vagal fibers was also assessed. RO27-3225 reduced cerulein-induced serum lipase and amylase activity, blunted the expression of tumor necrosis factor-α and interleukin-6, abated the increase in pancreatic myeloperoxidase activity, and protected against histologic damage. Furthermore, RO27-3225 markedly increased neural efferent activity along the vagus nerve. Vagotomy, chlorisondamine, and HS024 abated these protective effects of RO27-3225.
Conclusions:
Our data show that melanocortin 4 receptor agonists reduce pancreatitis severity through the activation of the cholinergic anti-inflammatory pathway. These findings could be of particular interest in the clinical setting.
Insights
Selective melanocortin 4 receptor agonist RO27-3225 effectively reduced pancreatitis severity in rats. This protective effect was mediated by the vagus nerve-dependent cholinergic anti-inflammatory pathway.
Area of Science:
- Inflammation and immunology
- Gastroenterology
- Neuroscience
Background:
- Acute pancreatitis is a severe inflammatory condition with potential for multisystemic organ failure.
- Melanocortin peptides show protective effects in experimental organ failure and shock models.
- These protective effects are linked to the vagus nerve-mediated cholinergic anti-inflammatory pathway via brain melanocortin 4 receptors.
Purpose of the Study:
- To investigate the therapeutic effects of the selective melanocortin 4 receptor agonist RO27-3225.
- To evaluate its efficacy in a rat model of cerulein-induced acute pancreatitis.
- To elucidate the role of the cholinergic anti-inflammatory pathway in mediating these effects.
Main Methods:
- A randomized experimental design was employed in a university hospital research laboratory setting.
- Acute pancreatitis was induced in male Sprague-Dawley rats using cerulein injections.
- Rats were pretreated with vagotomy, receptor antagonists, or vehicle before administration of RO27-3225 or vehicle, with subsequent assessment of neural activity.
Main Results:
- RO27-3225 significantly reduced serum lipase and amylase activity, inflammatory markers (TNF-α, IL-6), and pancreatic myeloperoxidase activity.
- Histologic damage was ameliorated by RO27-3225 treatment.
- The agonist markedly increased vagal nerve efferent activity, an effect abolished by vagotomy or receptor antagonists.
Conclusions:
- Melanocortin 4 receptor agonists, such as RO27-3225, mitigate pancreatitis severity.
- The mechanism involves the activation of the cholinergic anti-inflammatory pathway via the vagus nerve.
- These findings hold potential clinical significance for managing acute pancreatitis.
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