Gastric antisecretory effects of synthetic cannabinoids after central or peripheral administration in the rat

Adami, Maristella; Zamfirova, R; Sotirov, E.; Tashev, Roman; Dobrinova, Y.; Todorov, S; Coruzzi, Gabriella

doi:10.1016/j.brainresbull.2004.09.004

Cited by 22 publications

(14 citation statements)

References 36 publications

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“…Vagotomy blunted the acid-reducing effect of HU-210, indicating the involvement of peripheral cholinergic pathways and vagal afferents (Adami et al, 2002). These data are supported by a study in which intravenous, but not intracerebroventricular, administration of either HU-210 or WIN55,212-2 significantly reduced pentagastrin-induced acid production (Adami et al, 2004). Future studies will determine whether MAGL inhibition reduces basal or pentagastrin-induced gastric acid secretion as well as reduces NSAID-induced ulcers through this type of mechanism.…”

Section: Endocannabinoids Block Gastric Hemorrhages 799supporting

confidence: 52%

Inhibition of Monoacylglycerol Lipase Attenuates Nonsteroidal Anti-Inflammatory Drug-Induced Gastric Hemorrhages in Mice

Kinsey

Nomura²,

O’Neal³

et al. 2011

J Pharmacol Exp Ther

106

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Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used analgesics, but can cause gastric and esophageal hemorrhages, erosion, and ulceration. The endogenous cannabinoid (endocannabinoid; eCB) system possesses several potential targets to reduce gastric inflammatory states, including cannabinoid receptor type 1 (CB 1 ), cannabinoid receptor type 2 (CB 2 ), and enzymes that regulate the eCB ligands 2-arachidonoylglycerol (2-AG) and N-arachidonoyl ethanolamine (anandamide; AEA). In the presented study, we tested whether 4-nitrophenyl, a selective inhibitor of the primary catabolic enzyme of 2-AG, monoacylglycerol lipase (MAGL), would protect against NSAID-induced gastric damage. Food-deprived mice administered the nonselective cyclooxygenase inhibitor diclofenac sodium displayed gastric hemorrhages and increases in proinflammatory cytokines. JZL184, the proton pump inhibitor omeprazole (positive control), or the primary constituent of marijuana, ⌬ 9 -tetrahydrocannabinol (THC), significantly prevented diclofenac-induced gastric hemorrhages. JZL184 also increased stomach levels of 2-AG, but had no effect on AEA, arachidonic acid, or the prostaglandins E 2 and D 2 . MAGL inhibition fully blocked diclofenac-induced increases in gastric levels of proinflammatory cytokines interleukin (IL)-1␤, IL-6, tumor necrosis factor ␣, and granulocyte colony-stimulating factor, as well as IL-10. Pharmacological inhibition or genetic deletion of CB 1 or CB 2 revealed that the gastroprotective effects of JZL184 and THC were mediated via CB 1 . The antihemorrhagic effects of JZL184 persisted with repeated administration, indicating a lack of tolerance. These data indicate that increasing 2-AG protects against gastric damage induced by NSAIDs, and its primary catabolic enzyme MAGL offers a promising target for the development of analgesic therapeutics possessing gastroprotective properties.

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Section: Endocannabinoids Block Gastric Hemorrhages 799supporting

confidence: 52%

Inhibition of Monoacylglycerol Lipase Attenuates Nonsteroidal Anti-Inflammatory Drug-Induced Gastric Hemorrhages in Mice

Kinsey

Nomura²,

O’Neal³

et al. 2011

J Pharmacol Exp Ther

106

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“…CB 1 receptor agonists decreased the gastric acid secretion induced by pentagastrin given intravenously (Adami et al, 2002), but i.c.v. injection of the synthetic non-selective agonist WIN 55,212-2 was ineffective in preventing the pentagastrin stimulated gastric acid secretion (Adami et al, 2004). Cannabinoids have been shown to decrease the formation of experimental gastric ulcers as well.…”

Section: Discussionmentioning

confidence: 99%

Angiotensin II-induced activation of central AT1 receptors exerts endocannabinoid-mediated gastroprotective effect in rats

Gyires

Rónai

Zádori

et al. 2014

Molecular and Cellular Endocrinology

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The aim of the present study was to analyze whether angiotensin II via the endocannabinoid system can induce gastric mucosal protection, since transactivation of cannabinoid CB1 receptors by angiotensin AT1 receptor in CHO cells was described. Experimental ulcer was induced by acidified ethanol given orally in male Wistar rats, CB1(+/+) wild type and CB1(-/-) knock out mice. The compounds were administered intracerebroventricularly. It was found, that 1./ Angiotensin II inhibited the ethanol-induced gastric lesions (11.9-191 pmol); the effect of angiotensin II (191 pmol) was inhibited by the CB1 receptor inverse agonist AM 251 (1.8 nmol) and the inhibitor of diacylglycerol lipase (DAGL), tetrahydrolipstatin (0.2 nmol). 2./ Angiotensin II exerted gastroprotection in wild type, but not in CB1(-/-) mice. 3./ The gastroprotective effect of angiotensin II (191 pmol) was reduced by atropine (1 mg/kg i.v.) and bilateral cervical vagotomy. In conclusion, stimulation of central angiotensin AT1 receptors via activation of cannabinoid CB1 receptors induces gastroprotection in a DAGL-dependent and vagus-mediated mechanism.

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“…In a study with humans, THC caused a significant delay in gastric emptying [167]. In addition, CB agonists inhibited pentagastrin-induced gastric acid secretion in the rat [168], mediated by suppression of vagal drive to the stomach through activation of peripheral CB 1 receptors [169,170].…”

Section: Appetite Eating and Digestionmentioning

confidence: 97%

Cannabinoids

Grotenhermen

2005

CDTCNSND

111

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Since the discovery of an endogenous cannabinoid system, research into the pharmacology and therapeutic potential of cannabinoids has steadily increased. Two subtypes of G-protein coupled cannabinoid receptors, CB(1) and CB(1), have been cloned and several putative endogenous ligands (endocannabinoids) have been detected during the past 15 years. The main endocannabinoids are arachidonoyl ethanolamide (anandamide) and 2-arachidonoyl glycerol (2-AG), derivatives of arachidonic acid, that are produced "on demand" by cleavage of membrane lipid precursors. Besides phytocannabinoids of the cannabis plant, modulators of the cannabinoid system comprise synthetic agonists and antagonists at the CB receptors and inhibitors of endocannabinoid degradation. Cannabinoid receptors are distributed in the central nervous system and many peripheral tissues, including immune system, reproductive and gastrointestinal tracts, sympathetic ganglia, endocrine glands, arteries, lung and heart. There is evidence for some non-receptor dependent mechanisms of cannabinoids and for endocannabinoid effects mediated by vanilloid receptors. Properties of CB receptor agonists that are of therapeutic interest include analgesia, muscle relaxation, immunosuppression, anti-inflammation, antiallergic effects, improvement of mood, stimulation of appetite, antiemesis, lowering of intraocular pressure, bronchodilation, neuroprotection and antineoplastic effects. The current main focus of clinical research is their efficacy in chronic pain and neurological disorders. CB receptor antagonists are under investigation for medical use in obesity and nicotine addiction. Additional potential was proposed for the treatment of alcohol and heroine dependency, schizophrenia, conditions with lowered blood pressure, Parkinson's disease and memory impairment in Alzheimer's disease.

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Gastric antisecretory effects of synthetic cannabinoids after central or peripheral administration in the rat

Cited by 22 publications

References 36 publications

Inhibition of Monoacylglycerol Lipase Attenuates Nonsteroidal Anti-Inflammatory Drug-Induced Gastric Hemorrhages in Mice

Inhibition of Monoacylglycerol Lipase Attenuates Nonsteroidal Anti-Inflammatory Drug-Induced Gastric Hemorrhages in Mice

Angiotensin II-induced activation of central AT1 receptors exerts endocannabinoid-mediated gastroprotective effect in rats

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