title: The cannabinoid 1 receptor antagonist, AM251, prolongs the survival of rats with severe acute pancreatitis.
abstract: It has recently been recognized that anandamide (arachidonylethanolamide), which is an endogeneous-cannabinoid (endocannabinoid), mediates septic shock. Cannabinoid means a mind-active material in cannabis (marijuana). Anandamide is mainly produced by macrophages. Cannabinoid 1 (CB1) receptor, which is one of the cannabiniod receptors, is also known to mediate hypotensive shock. The role of endocannabinoids in the progression of acute pancreatitis is unclear. The aims of this study are to clarify their relationship and to find a new therapeutic strategy by regulating the endocannabinoid signaling in acute pancreatitis. Male Wistar rats were injected with caerulein intravenously to induce mild edematous pancreatitis or injected with 5% sodium taurocholate to the bilio-pancreatic duct to induce severe necrotizing pancreatitis. The animals in the latter group were also injected with a CB1 receptor antagonist, AM251, or vehicle solution to see if the inhibition of endocannabinoids improves their survival. Plasma anandamide level was measured by the liquid chromatography/tandem mass spectrometry method. In both models of acute pancreatitis, the plasma anandamide levels were increased, and the levels were significantly higher in rats with severe necrotizing pancreatitis than those in rats with mild edematous pancreatitis. The mean arterial pressure and survival rate were significantly improved by the treatment with AM251, despite that the local inflammatory changes in the pancreas and various parameters (white blood cells, hematocrit, serum amylase, and serum interleukin-6) were similar. This is the first report to show that endocannabinoids are involved in the deterioration of acute pancreatitis and that the down-regulation of endocannabinoid signaling may be a new therapeutic strategy for severe acute pancreatitis.
authors.affiliation: Division of Gastroenterological Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryomachi, Aoba-ku, Sendai, Japan. k_matsuda@surg1.med.tohoku.ac.jp
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Matsuda
authors.forename: Yukio
authors.initials: Y
authors.lastname: Mikami
authors.forename: Kazunori
authors.initials: K
authors.lastname: Takeda
authors.forename: Shoji
authors.initials: S
authors.lastname: Fukuyama
authors.forename: Shinichi
authors.initials: S
authors.lastname: Egawa
authors.forename: Makoto
authors.initials: M
authors.lastname: Sunamura
authors.forename: Ikurou
authors.initials: I
authors.lastname: Maruyama
authors.forename: Seiki
authors.initials: S
authors.lastname: Matsuno
mesh_terms: D000208:Acute Disease; D000818:Animals; D001095:Arachidonic Acids / Q000097:blood; D001794:Blood Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D063388:Endocannabinoids; D019084:Fluorescent Antibody Technique, Indirect; D007150:Immunohistochemistry; D008297:Male; D019283:Pancreatitis, Acute Necrotizing / Q000139:chemically induced / Q000188:drug therapy* / Q000401:mortality* / Q000473:pathology / Q000503:physiopathology; D010880:Piperidines / Q000378:metabolism / Q000494:pharmacology*; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles / Q000378:metabolism / Q000494:pharmacology*; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors*; D015996:Survival Rate; D013656:Taurocholic Acid; D013997:Time Factors
chemical_list: D001095:Arachidonic Acids; D063388:Endocannabinoids; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; C103505:AM 251; D013656:Taurocholic Acid; C078814:anandamide