Tag Archives: endocannabinoid system

Cannabinoid HU210 Protects Isolated Rat Stomach against Impairment Caused by Serum of Rats with Experimental Acute Pancreatitis

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“Acute pancreatitis (AP), especially severe AP, is a potentially lethal inflammatory disease of pancreas which often leads to extra-pancreatic complications, even multiple systemic organ dysfunctions. It has been reported that 52% of patients with acute pancreatitis develop acute gastrointestinal mucosal lesion (AGML) or stress ulcer.

For centuries, Cannabis plant and its extracts have been used to alleviate symptoms of gastrointestinal inflammatory diseases.

It has been established that D9-tetrahydrocannabinol, the major psychoactive component of Cannabis, exerts its primary cellular actions though two G protein-coupled receptors, cannabinoid 1 (CB1) and cannabinoid 2 (CB2) receptors.

Since then, these two receptors have been recognized as the major regulators of physiological and pathological processes. Cannabinoids can reduce gastrointestinal secretion, and the activation of CB1 receptor exhibits protective role against stress-induced AGML, but the mechanisms of their action remain elusive.

The results from this study prove that the inflammatory responses and the imbalance of the gastric secretion during the development of AP are responsible for the pathogenesis of AGML, and suggest the therapeutic potential of HU210 for AGML associated with acute pancreatitis.

Therefore, our experimental results suggest a novel mechanism in the onset of AGML and new therapeutic values of cannabinoids as supplement of anti-inflammatory therapy in acute pancreatitis.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3532296/

Activation of cannabinoid receptor 2 reduces inflammation in acute experimental pancreatitis via intra-acinar activation of p38 and MK2-dependent mechanisms.

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“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

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“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/

Anti-inflammatory role of cannabidiol and O-1602 in cerulein-induced acute pancreatitis in mice.

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“The anti-inflammatory effects of O-1602 and cannabidiol (CBD), the ligands of G protein-coupled receptor 55 (GPR55), on experimental acute pancreatitis (AP) were investigated.

Cannabidiol or O-1602 treatment significantly improved the pathological changes of mice with AP and decreased the enzyme activities, IL-6 and tumor necrosis factor α; levels, and the myeloperoxidase activities in plasma and in the organ tissues.

G protein-coupled receptor 55 mRNA and protein expressed in the pancreatic tissue, and the expressions were decreased in the mice with AP, and either CBD or O-1602 attenuated these changes to a certain extent.

CONCLUSION:

Cannabidiol and O-1602 showed anti-inflammatory effects in mice with AP and improved the expression of GPR55 in the pancreatic tissue as well.”

https://www.ncbi.nlm.nih.gov/pubmed/22850623

Cannabinoids Ameliorate Pain and Reduce Disease Pathology in Cerulein-Induced Acute Pancreatitis

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“The endocannabinoid system has been identified as a major regulator of physiological and pathological processes, such as pain, inflammation, cell growth, cell death, and as a regulator of diverse gastrointestinal functions, such as intestinal motility and secretion.

Although cannabinoid-induced analgesia was initially primarily attributed to the activation of cannabinoid receptor 1 (CB1) in the nervous system, later studies demonstrated a contribution of cannabinoid receptor 2 (CB2), localized peripherally on immune cells as well as in the nervous system.

A complex interplay between endogenously released cannabinoids, such as anandamide or 2-arachidonoylglycerol, and their receptors both on inflammatory cells and neurons is involved in modulation of inflammatory pain.

In this article, we demonstrate the in vivo significance and therapeutic potential of cannabinoids in inflammation and pain associated with pancreatitis using human specimens and mouse models as test systems.

Our results are more in line with a recent study reporting a protective role for the endogenous cannabinoid system against colonic inflammation in a mouse model of experimental colitis.

Consistent with the above, we now show that acute pancreatitis, a visceral inflammatory disease in humans, is associated with an activation of the endocannabinoid system.

In humans, acute pancreatitis is associated with up-regulation of ligands as well as receptors of the endocannabinoid system in the pancreas. Furthermore, our results suggest a therapeutic potential for cannabinoids in abolishing pain associated with acute pancreatitis and in partially reducing inflammation and disease pathology in the absence of adverse side effects.

Because management of visceral inflammatory diseases should ideally include antinociceptive as well as anti-inflammatory components, our results lay a basis for testing the therapeutic value of cannabinoids as supplements to conventional analgesic therapy.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2268094/

Cannabinoids Reduce Markers of Inflammation and Fibrosis in Pancreatic Stellate Cells

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“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.

Because drugs for the treatment of chronic pancreatitis should ideally exert anti-fibrotic and anti-inflammatory properties, their bimodal effects rather contradict a therapeutic use of CB-receptor antagonists and promote the hypothesis that (re-)activation of the (endo-)cannabinoid system in chronic pancreatitis may be beneficial for suppressing disease progress.

In conclusion, we show that the endocannabinoid system is downregulated in chronic pancreatitis and that its augmentation via exogenously administered cannabinoids specifically reduces activation of pancreatic stellate cells.

These experiments lay a basis for testing the value of synthetic cannabinoids in the treatment of chronic pancreatitis.”

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0001701

Effects of Intermittent Alcohol Exposure on Emotion and Cognition: A Potential Role for the Endogenous Cannabinoid System and Neuroinflammation.

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“Intermittent alcohol exposure is a common pattern of adolescent alcohol use that can lead to binge drinking episodes.

Alcohol use is known to modulate the endocannabinoid system (ECS), which is involved in neuronal communication, neuroplasticity, neuroinflammation and behavior.

In conclusion, rats exposed to adolescent intermittent alcohol displayed anxiety-like behavior and cognitive deficits in adulthood and these alterations were accompanied by brain region-dependent changes in the gene expression of the ECS and other signals associated with neuroinflammation and behavior.

An intermittent adolescent alcohol exposure has behavioral and molecular consequences in the adult brain, which might be linked to higher vulnerability to addictive behaviors and psychopathologies.”

https://www.ncbi.nlm.nih.gov/pubmed/28223925

Pregnenolone blocks cannabinoid-induced acute psychotic-like states in mice.

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“Cannabis-induced acute psychotic-like states (CIAPS) represent a growing health issue, but their underlying neurobiological mechanisms are poorly understood.

The use of antipsychotics and benzodiazepines against CIAPS is limited by side effects and/or by their ability to tackle only certain aspects of psychosis. Thus, safer wide-spectrum treatments are currently needed.

Although the blockade of cannabinoid type-1 receptor (CB1) had been suggested as a therapeutical means against CIAPS, the use of orthosteric CB1 receptor full antagonists is strongly limited by undesired side effects and low efficacy.

The neurosteroid pregnenolone has been recently shown to act as a potent endogenous allosteric signal-specific inhibitor of CB1 receptors. Thus, we tested in mice the potential therapeutic use of pregnenolone against acute psychotic-like effects of Δ9-tetrahydrocannabinol (THC), the main psychoactive component of cannabis.

We found that pregnenolone blocks a wide spectrum of THC-induced endophenotypes typically associated with psychotic-like states, including impairments in cognitive functions, somatosensory gating and social interaction. Overall, this work reveals that signal-specific inhibitors mimicking pregnenolone effects can be considered as promising new therapeutic tools to treat CIAPS.”  https://www.ncbi.nlm.nih.gov/pubmed/28220044

“Pregnenolone can protect the brain from cannabis intoxication. The administration of the main active principle of Cannabis sativa (marijuana), Δ(9)-tetrahydrocannabinol (THC), substantially increases the synthesis of pregnenolone in the brain via activation of the type-1 cannabinoid (CB1) receptor. Pregnenolone then, acting as a signaling-specific inhibitor of the CB1 receptor, reduces several effects of THC. This negative feedback mediated by pregnenolone reveals a previously unknown paracrine/autocrine loop protecting the brain from CB1 receptor overactivation that could open an unforeseen approach for the treatment of cannabis intoxication and addiction.”  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4057431/

Extinction of avoidance behavior by safety learning depends on endocannabinoid signaling in the hippocampus.

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“The development of exaggerated avoidance behavior is largely responsible for the decreased quality of life in patients suffering from anxiety disorders. Studies using animal models have contributed to the understanding of the neural mechanisms underlying the acquisition of avoidance responses. However, much less is known about its extinction.

Here we provide evidence in mice that learning about the safety of an environment (i.e., safety learning) rather than repeated execution of the avoided response in absence of negative consequences (i.e., response extinction) allowed the animals to overcome their avoidance behavior in a step-down avoidance task.

This process was context-dependent and could be blocked by pharmacological (3 mg/kg, s.c.; SR141716) or genetic (lack of cannabinoid CB1 receptors in neurons expressing dopamine D1 receptors) inactivation of CB1 receptors. In turn, the endocannabinoid reuptake inhibitor AM404 (3 mg/kg, i.p.) facilitated safety learning in a CB1-dependent manner and attenuated the relapse of avoidance behavior 28 days after conditioning.

Safety learning crucially depended on endocannabinoid signaling at level of the hippocampus, since intrahippocampal SR141716 treatment impaired, whereas AM404 facilitated safety learning.

Other than AM404, treatment with diazepam (1 mg/kg, i.p.) impaired safety learning. Drug effects on behavior were directly mirrored by drug effects on evoked activity propagation through the hippocampal trisynaptic circuit in brain slices: As revealed by voltage-sensitive dye imaging, diazepam impaired whereas AM404 facilitated activity propagation to CA1 in a CB1-dependent manner. In line with this, systemic AM404 enhanced safety learning-induced expression of Egr1 at level of CA1.

Together, our data render it likely that AM404 promotes safety learning by enhancing information flow through the trisynaptic circuit to CA1.”

https://www.ncbi.nlm.nih.gov/pubmed/28222356

Gut-brain axis: Role of lipids in the regulation of inflammation, pain and CNS diseases.

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“The human gut is a composite anaerobic environment with a large, diverse and dynamic enteric microbiota, represented by more than 100 trillion microorganisms, including at least 1000 distinct species. The discovery that a different microbial composition can influence behavior and cognition, and in turn the nervous system can indirectly influence enteric microbiota composition, has significantly contributed to establish the well-accepted concept of gut-brain axis.

This hypothesis is supported by several evidence showing mutual mechanisms, which involve the vague nerve, the immune system, the hypothalamic-pituitary-adrenal (HPA) axis modulation and the bacteria-derived metabolites. Many studies have focused on delineating a role for this axis in health and disease, ranging from stress-related disorders such as depression, anxiety and irritable bowel syndrome (IBS) to neurodevelopmental disorders, such as autism, and to neurodegenerative diseases, such as Parkinson Disease, Alzheimer Disease etc.

Based on this background, and considering the relevance of alteration of the symbiotic state between host and microbiota, this review focuses on the role and the involvement of bioactive lipids, such as the N-acylethanolamine (NAE) family whose main members are N-arachidonoylethanolamine (AEA), palmitoylethanolamide (PEA) and oleoilethanolamide (OEA), and short chain fatty acids (SCFAs), such as butyrate, belonging to a large group of bioactive lipids able to modulate peripheral and central pathologic processes.

It is well established their effective role in inflammation, acute and chronic pain, obesity and central nervous system diseases. It has been shown a possible correlation between these lipids and gut microbiota through different mechanisms.

Indeed, systemic administration of specific bacteria can reduce abdominal pain through the involvement of cannabinoid receptor 1 in rat; on the other hand, PEA reduces inflammation markers in a murine model of inflammatory bowel disease (IBD), and butyrate, producted by gut microbiota, is effective in reducing inflammation and pain in irritable bowel syndrome and IBD animal models.

In this review, we underline the relationship among inflammation, pain, microbiota and the different lipids, focusing on a possible involvement of NAEs and SCFAs in the gut-brain axis and their role in central nervous system diseases.”

https://www.ncbi.nlm.nih.gov/pubmed/28215162