Melanocortin 4 receptor stimulation decreases pancreatitis severity in rats by activation of the cholinergic anti-inflammatory pathway.
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.


METHODS
Randomized experiment.


METHODS
Research laboratory at a university hospital.


METHODS
Experimental pancreatitis in rats.


METHODS
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.


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.
Department of Experimental and Clinical Medicine and Pharmacology, Section of Pharmacology, University of Messina, Messina, Italy. lminutoli@unime.it
Letteria
L
Minutoli
Francesco
F
Squadrito
Piero Antonio
PA
Nicotina
Daniela
D
Giuliani
Alessandra
A
Ottani
Francesca
F
Polito
Alessandra
A
Bitto
Natasha
N
Irrera
Giuseppe
G
Guzzo
Luca
L
Spaccapelo
Carmine
C
Fazzari
Antonio
A
Macrì
Herbert
H
Marini
Salvatore
S
Guarini
Domenica
D
Altavilla
D000208:Acute Disease; D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D002108:Ceruletide / Q000494:pharmacology; D018678:Cholinergic Agents / Q000378:metabolism*; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D018836:Inflammation Mediators / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D010195:Pancreatitis / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology*; D010455:Peptides / Q000494:pharmacology*; D009195:Peroxidase / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D044105:Receptor, Melanocortin, Type 4 / Q000819:agonists* / Q000627:therapeutic use; D011978:Receptors, Nicotinic / Q000378:metabolism; D012680:Sensitivity and Specificity; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014630:Vagus Nerve / Q000187:drug effects
D018678:Cholinergic Agents; D018836:Inflammation Mediators; D015850:Interleukin-6; D010455:Peptides; D044105:Receptor, Melanocortin, Type 4; D011978:Receptors, Nicotinic; D014409:Tumor Necrosis Factor-alpha; C560214:butir-His-Phe-Arg-Trp-Sar-NH2; D002108:Ceruletide; D009195:Peroxidase