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.severe acute pancreatitis; septic shock; anandamide; endocannabinoids; AM251

The Endocannabinoid System as an Emerging Target of Pharmacotherapy

“…This result was attributed to modulation of ␤-adrenergic vasodilation, rather than suppression of a direct vasodilator effect by endocannabinoids (Gardiner et al, 2005). Interestingly, in a recent study, Matsuda et al (2005) demonstrated that AM251 improved mean arterial pressure and survival rate in models of severe acute necrotizing pancreatitis without affecting inflammatory changes, which suggests the involvement of cardiac or vascular CB 1 receptors in the hypotension associated with this condition.…”

“…Circulatory Shock. The profound hypotension that can be elicited through pharmacological activation of CB 1 receptors (Lake et al, 1997a) triggered numerous studies to investigate the role of the endocannabinoid system in the hypotension associated with various forms of shock, including hemorrhagic (Wagner et al, 1997;Cainazzo et al, 2002), endotoxic (Varga et al, 1998;Wang et al, 2001;Liu et al, 2003a;Bá tkai et al, 2004a;Gardiner et al, 2005;Kadoi et al, 2005), and cardiogenic shock (Wagner et al, 2001a, and the shock associated with necrotizing pancreatitis (Matsuda et al, 2005). Initial studies demonstrated that the putative CB 1 receptor antagonist SR141716 prevented or reversed the hypotension associated with hemorrhagic, endotoxic, and cardiogenic shock (Wagner et al, 1997(Wagner et al, , 2001aVarga et al, 1998).…”

“…Surprisingly, the use of cannabinoid receptor antagonists, including SR141716, AM281, AM251, and SR144528, also leads to survival benefits in endotoxic and septic shock or necrotizing pancreatitis (Varga et al, 1998;Smith et al, 2000Smith et al, , 2001Cainazzo et al, 2002;Kadoi et al, 2005a,b;Matsuda et al, 2005). In contrast, CB 1 receptor blockade increased mortality in hemorrhagic (Wagner et al, 1997) and cardiogenic shock (Wagner et al, 2001a, despite the increase in blood pressure.…”

Severity and outcomes of acute alcoholic pancreatitis in cannabis users

“…CB1 receptor activation has shown to induce fibrosis while activation of CB2 receptor is linked with antifibrogenic effects in the pancreas (1,20). Matsuda et al (24) showed that down regulation of endocannabinoid system by AM251 (a CB1 receptor inhibitor) improved survival in rats with severe AP. This finding was later confirmed by another study (25).…”

Effects of Cannabinoid and Trpv1 in Formalin-induced Orofacial Pain

“…And it has been reported that they are anatomically distributed in the spinal dorsal horn that is involved in the conduction and control of pain. A lot of findings from research using laboratory animals revealed that cannabinoid receptors typically show analgesic action 3 . A cannabinoid receptor agonist injected in the meningeal space alleviated hyperalgesia and allodynia in neuropathic and inflammatory pain models, and D9-tetrahydrocannabinol (THC) and anandamide (AEA), which were injected into the abdominal cavity, reduced pain from excitotoxic pressure on the plantar surface in animal models of arthritis.…”