High activity of the endogenous opioid system and acute but not chronic stress influence experimental colitis development in mice.

Exposition to environmental factors is one of the major underlying causes in inflammatory bowel diseases (IBD), with several endogenous systems involved. Our aim was to characterize the impact of stress on the colitis development in relation to the endogenous opioid system (EOS) activity in mice. A unique mouse model of high and low activity of EOS (namely high (HA)/low (LA) stress-induced analgesia) was employed. Mice were bred using bidirectional selection and classified as HA or LA line based on the measurement of analgesia. Colitis was induced by instillation of trinitrobenzenesulfonic acid in 30% EtOH/0.9% NaCl. After 4 days, the macroscopic score was assessed and samples for molecular and histological studies were collected. To evaluate the influence of stress on colitis development, chronic mild stress (exposure to stress stimuli for 2 and 5 weeks) and acute stress (short restraint over 3 days) were applied before colitis induction. We observed a difference in the colitis development between non-stressed HA and LA mice, as indicated by macroscopic and ulcer scores. Acute stress improved colitis in HA mice but did not change the inflammation score in LA line as compared to respective non-stressed mice. Chronic mild stress had no influence on colitis in either of mouse lines. Our study supports the hypothesis that the activity of EOS may be crucial in IBD development. We also evidence that acute, but not chronic stress influenced IBD exacerbation, depending on EOS function.

Relamorelin and other ghrelin receptor agonists - future options for gastroparesis, functional dyspepsia and proton pump inhibitors-resistant non-erosive reflux disease.

There is an unmet need for effective pharmacological therapies for the treatment of gastroparesis and other upper gastrointestinal (GI) motility disorders, which reduce patients' quality of life and are a burden to the healthcare system. Ghrelin is an endogenous growth hormone secretagogue receptor ligand and has been shown to exert prokinetic effects on GI motility. Nevertheless, considering the short half-life of ghrelin its use in clinical practice is limited. Thus, ghrelin receptor agonists with enhanced pharmacokinetics were developed; they accelerate gastric emptying and improve symptoms of gastroparesis in animal models and humans. This review summarizes the current knowledge on relamorelin, a potent ghrelin mimetic, and other analogs which are in preclinical or clinical development stages for the management of upper GI disorders.

Highly selective CB2 receptor agonist A836339 has gastroprotective effect on experimentally induced gastric ulcers in mice.

Cannabinoid type 2 (CB2) receptors are distributed in central and peripheral tissues, including immunocytes and the gastrointestinal (GI) tract, suggesting that CB2 receptor agonists represent potential therapeutics in GI inflammatory states. In this study, we investigated the effect of highly selective CB2 agonist, A836339, on the development of gastric lesions. We used two models of gastric ulcer (GU) induced by ethanol (EtOH) and diclofenac. To confirm the involvement of CB2 receptors, a selective CB2 antagonist, AM630 was used. Clinical parameters for gastroprotection were assessed based on inhibition of the gastric lesion area. To investigate the anti-inflammatory effect of A836339, the expression of TNF-α and IL-1ß was assessed. To establish the mechanism of gastroprotective action, catalase (CAT), superoxide dismutase (SOD) activity and H2O2 and glutathione (GSH) levels were measured. Moreover, expression of CB2 and cyclooxygenase-2 (COX-2) was characterized using immunohistochemistry (IHC). A836339 reduced ulcer index in a dose-dependent manner in both EtOH- and diclofenac-induced GU models. This effect was reversed by the CB2 antagonist AM630. Administration of A836339 reduced TNF-α and IL-1ß levels in gastric tissue. Furthermore, A836339 exhibited potent anti-oxidant activity, as demonstrated by reduced H2O2 levels and increased CAT and SOD activities. IHC studies revealed a co-localization of CB2 receptors and COX-2 in the gastric tissue. Activation of CB2 receptors exhibited gastroprotective effect through enhancement of anti-oxidative pathways in the stomach. Activation of CB2 receptors may thus become a novel therapeutic approach in the treatment of GU.

Selective inhibition of FAAH produces antidiarrheal and antinociceptive effect mediated by endocannabinoids and cannabinoid-like fatty acid amides.

BACKGROUND: The endogenous cannabinoid system (ECS) plays a crucial role in multiple physiological processes in the central nervous system and in the periphery. The discovery that selective cannabinoid (CB) receptor agonists exert a potent inhibitory action on gastrointestinal (GI) motility and pain has placed the ECS in the center of attention as a possible target for the treatment of functional GI diseases. However, side effects of CB agonists prompted the search for novel therapeutic targets. Here, the effect of PF-3845, a potent and selective fatty acid amide hydrolase (FAAH) inhibitor in the GI tract was investigated. METHODS: The effect of PF-3845 on GI motility was characterized in vitro and in vivo, using mouse models that mimic physiological and pathophysiological conditions. The antinociceptive action of PF-3845 was evaluated on the basis of behavioral pain models. Endocannabinoid degradation product levels after inhibition of FAAH were quantified using HPLC-MS/MS. KEY RESULTS: PF-3845 significantly inhibited mouse colonic motility in vitro and in vivo. Selective inhibition of FAAH reversed hypermotility and reduced pain in mouse models mimicking functional GI disorders. The effects of PF-3845 were mediated by endogenous CBs and non-CB lipophilic compounds via classical (CB1) and atypical CB receptors. CONCLUSIONS & INFERENCES: These data expand our understanding of the ECS function and provide a novel framework for the development of future potential treatments of functional GI disorders.

Experimental colitis in mice is attenuated by changes in the levels of endocannabinoid metabolites induced by selective inhibition of fatty acid amide hydrolase (FAAH).

BACKGROUND AND AIMS: Pharmacological treatment and/or maintenance of remission in inflammatory bowel diseases (IBD) is currently one of the biggest challenge in the field of gastroenterology. Available therapies are mostly limited to overcoming the symptoms, but not the cause of the disease. Recently, the endocannabinoid system has been proposed as a novel target in the treatment of IBD. Here we aimed to assess the anti-inflammatory action of the novel fatty acid amide hydrolase (FAAH) inhibitor PF-3845 and its effect on the endocannabinoid and related lipid metabolism during the course of experimental colitis. METHODS: We used two models of experimental colitis in mice (TNBS- and DSS-induced) and additionally, we employed LC/MS/MS spectrometry to determine the changes in biolipid levels in the mouse colon during inflammation. RESULTS: We showed that the FAAH inhibitor PF-3845 reduced experimental TNBS-induced colitis in mice and its anti-inflammatory action is associated with altering the levels of selected biolipids (arachidonic and oleic acid derivatives, prostaglandins and biolipids containing glycine in the mouse colon). CONCLUSIONS: We show that FAAH is a promising pharmacological target and the FAAH-dependent biolipids play a major role in colitis. Our results highlight and promote therapeutic strategy based on targeting FAAH-dependent metabolic pathways in order to alleviate intestinal inflammation.