“Acute pancreatitis is an inflammatory disease, which has several causes and symptoms and requires immediate medical attention. The cannabinoid receptor type 2 (CB2R) is a G protein-coupled receptor that, in humans, is encoded by the CNR2 gene. CB2Rs are predominantly expressed in the periphery, especially in immune cells, suggesting that CB2R mediates the effects of cannabinoids mainly in the immune system. Emerging evidence demonstrates that the blockade of intracellular Ca2+ signals may protect pancreatic acinar cells against Ca2+ overload, intracellular protease activation, and necrosis. The activation of cannabinoid receptor subtype 2 (CB2R) prevents acinar cell pathogenesis in animal models of acute pancreatitis. Collectively, we provide novel evidence that activation of CB2Rs eliminates ACh-induced Ca2+ oscillations and L-arginine-induced enhancement of Ca2+ signaling in mouse pancreatic acinar cells, which suggests a potential cellular mechanism of CB2R-mediated protection in acute pancreatitis. These results suggest that a CB2R agonist may serve as a novel therapeutic strategy to prevent and/or treat acute pancreatitis. This conclusion is consistent with previous report that a CB2R agonist exhibits a protective effect on pathogenesis in an acute pancreatitis animal model. Our data showing a reduction of intracellular Ca2+ signaling by GW also provide a new target to interpret the role of CB2R agonists in treating acute pancreatitis in addition to CB2R-mediated anti-inflammation.” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4949433/]]>
Tag Archives: agonists
Activation of cannabinoid receptor 2 reduces inflammation in acute experimental pancreatitis via intra-acinar activation of p38 and MK2-dependent mechanisms.
“The endocannabinoid system has been shown to mediate beneficial effects on gastrointestinal inflammation via cannabinoid receptors 1 (CB(1)) and 2 (CB(2)).
These receptors have also been reported to activate the MAP kinases p38 and c-Jun NH(2)-terminal kinase (JNK), which are involved in early acinar events leading to acute pancreatitis and induction of proinflammatory cytokines.
Our aim was to examine the role of cannabinoid receptor activation in an experimental model of acute pancreatitis and the potential involvement of MAP kinases.
The unselective CB(1)/CB(2) agonist HU210 ameliorated pancreatitis in wild-type and CB(1)-/- mice, indicating that this effect is mediated by CB(2).
Furthermore, blockade of CB(2), not CB(1), with selective antagonists engraved pathology.
Stimulation with a selective CB(2) agonist attenuated acute pancreatitis and an increased activation of p38 was observed in the acini.
With use of MK2-/- mice, it could be demonstrated that this attenuation is dependent on MK2. Hence, using the MK2-/- mouse model we reveal a novel CB(2)-activated and MAP kinase-dependent pathway that modulates cytokine expression and reduces pancreatic injury and affiliated complications.”
https://www.ncbi.nlm.nih.gov/pubmed/23139224
Cannabinoid receptor 2 agonist attenuates pain related behavior in rats with chronic alcohol/high fat diet induced pancreatitis
“Chronic Pancreatitis (CP) is a complex and multifactorial syndrome. Many contributing factors result in development of dysfunctional pain in a significant number of patients. Drugs developed to treat a variety of pain states fall short of providing effective analgesia for patients with chronic pancreatitis, often providing minimal to partial pain relief over time with significant side effects. Recently, availability of selective pharmacological tools has enabled great advances in our knowledge of the role of the cannabinoid receptors in pathophysiology. In particular, cannabinoid receptor 2 (CB2) has emerged as an attractive target for management of chronic pain, as demonstrated in several studies with inflammatory and neuropathic preclinical pain models. In this study, the analgesic efficacy of a novel, highly selective CB2 receptor agonist, LY3038404 HCl, is investigated in a chronic pancreatitis pain model, induced with an alcohol/high fat (AHF) diet. LY3038404 HCl, a potent CB2 receptor agonist, possesses tissue protective and analgesic properties without effects on higher brain function. Thus, activation of CB2 receptors is suggested as a potential therapeutic target for visceral inflammation and pain management. The major finding of the present study is that LY3038404 HCl, a potent CB2 receptor agonist, possesses tissue protective and analgesic properties. No effects on higher brain functions were observed including the diminished fear responses induced by the alcohol diet. Thus, activation of CB2 receptors is suggested as a potential therapeutic target for pancreas protection and pain management.” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4242547/]]>
Cannabinoids Reduce Markers of Inflammation and Fibrosis in Pancreatic Stellate Cells
“While cannabinoids have been shown to ameliorate liver fibrosis, their effects in chronic pancreatitis and on pancreatic stellate cells (PSC) are unknown.
The activity of the endocannabinoid system was evaluated in human chronic pancreatitis (CP) tissues.
Augmentation of the endocannabinoid system via exogenously administered cannabinoid receptor agonists specifically induces a functionally and metabolically quiescent pancreatic stellate cell phenotype and may thus constitute an option to treat inflammation and fibrosis in chronic pancreatitis.
“1. Preparations from 
“The hallmark of vaccines is their ability to prevent the spread of infectious pathogens and thereby serve as invaluable public health tool. Despite their medical relevance, there is a gap in our understanding of the physiological factors that mediate innate and adaptive immune response to vaccines.
The endocannabinoid (eCB) system is a critical modulator of homeostasis in vertebrates. Our results indicate that macrophages and dendritic cells produce the endocannabinoid, 2-arachidonoyl-sn-glycerol (2-AG) upon antigen activation.
We have also established that 2-AG levels are upregulated in the serum and in the lymph node of mice during vaccination.
We hypothesized that the intrinsic release of eCBs from immune cells during activation by pathogenic antigens mitigate inflammation, but also suppress overall innate and adaptive immune response.
Here we demonstrate, for the first time, that transient administration of the