Palmitoylethanolamide, a naturally occurring lipid, is an orally effective intestinal anti‐inflammatory agent

Borrelli, Francesca; Romano, Barbara; Petrosino, Stefania; Pagano, Ester; Capasso, Raffaele; Coppola, Diana; Battista, Giovanni; Orlando, Pierangelo; Marzo, Vincenzo Di; Izzo, Angelo A.

doi:10.1111/bph.12907

Cited by 150 publications

(171 citation statements)

References 82 publications

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“…Levels of PEA are increased in intestinal tissues of patients with ulcerative colitis 105 . PEA is a powerful anti-inflammatory agent that reduces features of colitis in mice and secretion of inflammatory cytokines 106 . PEA binds to peroxisome proliferator-activated receptor-α and inhibits the expression of S100B and toll-like receptor 4 on enteric glia, to reduce inflammation induced by nuclear factor-κB 107 .…”

Section: Regulation Of Intestinal Inflammation By Cannabinoids and Famentioning

confidence: 99%

The Role of the Endocannabinoid System in the Brain–Gut Axis

2016

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The actions of cannabis are mediated by receptors that are part of an endogenous cannabinoid system. The endocannabinoid system (ECS) consists of the naturally occurring ligands N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol (2-AG), their biosynthetic and degradative enzymes, and the cannabinoid receptors CB1 and CB2. The ECS is a widely distributed transmitter system that controls gut functions peripherally and centrally. It is an important physiologic regulator of gastrointestinal motility. Polymorphisms in the gene encoding CB1 (CNR1) have been associated with some forms of irritable bowel syndrome. The ECS is involved in the control of nausea and vomiting and visceral sensation. The homeostatic role of the ECS also extends to the control of intestinal inflammation. We review the mechanisms by which the ECS links stress and visceral pain. CB1 in sensory ganglia controls visceral sensation, and transcription of CNR1 is modified through epigenetic processes under conditions of chronic stress. These processes might link stress with abdominal pain. The ECS is also involved centrally in the manifestation of stress, and endocannabinoid signaling reduces the activity of hypothalamic–pituitary–adrenal pathways via actions in specific brain regions—notably the prefrontal cortex, amygdala, and hypothalamus. Agents that modulate the ECS are in early stages of development for treatment of gastrointestinal diseases. Increasing our understanding of the ECS will greatly advance our knowledge of interactions between the brain and gut and could lead to new treatments for gastrointestinal disorders.

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Section: Regulation Of Intestinal Inflammation By Cannabinoids and Famentioning

confidence: 99%

The Role of the Endocannabinoid System in the Brain–Gut Axis

2016

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“…In several chemically induced colitis models in mice, PEA has been shown to reduce inflammation [49,50] and to protect intestinal permeability via PPARα, CB 2 , and GPR55 [49]. In line with these results, inhibition of the PEA-degrading enzyme N-acylethanolamine hydrolyzing acid amidase increased PEA levels and also protected against colitis [51].…”

Section: Insights From Animal Modelsmentioning

confidence: 57%

“…The EC-like compound PEA is endogenously produced upon an inflammatory insult and has been described to act through CB 1 , CB 2 , GPR55, PPARα, and TRPV1 [49]. In several chemically induced colitis models in mice, PEA has been shown to reduce inflammation [49,50] and to protect intestinal permeability via PPARα, CB 2 , and GPR55 [49].…”

Section: Insights From Animal Modelsmentioning

confidence: 99%

Medical Cannabis and Cannabinoids: An Option for the Treatment of Inflammatory Bowel Disease and Cancer of the Colon?

Grill

Hasenoehrl

Storr

et al. 2018

Med Cannabis Cannabinoids

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In the past few years, we have witnessed a surge of new reports dealing with the role of cannabinoids, synthetic as well as herbal, in the mechanisms of inflammation and carcinogenesis. However, despite the wealth of in vitro data and anecdotal reports, evidence that cannabinoids could act as beneficial drugs in inflammatory bowel disease (IBD) or in neoplastic development of the human gastrointestinal tract is lacking. Some insight into the effects of medical Cannabis (usually meaning dried flowers) and cannabinoids in IBD has been gained through questionnaires and small pilot studies. As to colorectal cancer, only preclinical data are available. Currently, Δ⁹-tetrahydrocannabinol (THC) and its synthetic forms, dronabinol and nabilone, are used as an add-on treatment to alleviate chronic pain and spasticity in multiple sclerosis patients as well as chemotherapy-induced nausea. The use of medical Cannabis is authorized only in a limited number of countries. None of the mentioned substances are currently indicated for IBD. This review is an update of our knowledge on the role of cannabinoids in intestinal inflammation and carcinogenesis and a discussion on their potential therapeutic use.

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“…In the DNBS-induced colitis model, the beneficial effects of treatment with atypical cannabinoid PEA were abolished by CB 2 antagonist AM630 (as well as by GPR55 and PPAR antagonists), but the CB 1 antagonist rimonabant did not have any effect 16 . The CB 2 receptor pathway was also found to modulate the favorable effects of cannabigerol (CBG), a non-psychotropic cannabinoid capable of reducing nitric oxide production in macrophages and attenuating murine DNBS-induced colitis in both a preventive (pretreatment) model and therapeutic (established colitis) model 26 .…”

Section: Cannabinoid 2 Receptormentioning

confidence: 96%

“…In addition, mRNA expression of CB 1 receptor is upregulated in both DNBS-induced colitis and control mice when treated with the atypical cannabinoid PEA 16 . Based on this link of upregulated expression of the CB 1 receptor in inflammation, many studies have sought to demonstrate the key role of the CB 1 receptor in attenuation of murine colitis.…”

Section: Cannabinoid 1 Receptormentioning

confidence: 99%

Manipulation of the Endocannabinoid System in Colitis

Leinwand

Gerich²,

Hoffenberg

et al. 2017

Inflammatory Bowel Diseases

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Background Inflammatory bowel disease is a lifelong disease of the gastrointestinal tract whose annual incidence and prevalence is on the rise. Current immunosuppressive therapies available for treatment of inflammatory bowel disease offer limited benefits and lose effectiveness, exposing a significant need for the development of novel therapies. In the clinical setting, cannabis has been shown to provide patients with inflammatory bowel disease symptomatic relief, although the underlying mechanisms of their anti-inflammatory effects remains unclear. Methods This review reflects our current understanding of how targeting the endocannabinoid system, including cannabinoid receptors 1 and 2, endogenous cannabinoids anandamide and 2-arachidonoylglycerol, atypical cannabinoids, and degrading enzymes including fatty acid amide hydrolase and monoacylglycerol lipase, impacts murine colitis. In addition, the impact of cannabinoids on the human immune system is summarized. Results Cannabinoid receptors 1 and 2, endogenous cannabinoids, and atypical cannabinoids are upregulated in inflammation, and their presence and stimulation attenuates murine colitis, while cannabinoid receptor antagonism and cannabinoid receptor deficient models reverse these anti-inflammatory effects. In addition, inhibition of endocannabinoid degradation via monoacylglycerol lipase and fatty acid amide hydrolase blockade can also attenuate colitis development, and is closely linked to cannabinoid receptor expression. Conclusions While manipulation of the endocannabinoid system in murine colitis has proven to be largely beneficial in attenuating inflammation, there is a paucity of human study data. Further research is essential to clearly elucidate the specific mechanisms driving this anti-inflammatory effect for the development of therapeutics to target inflammatory disease such as inflammatory bowel disease.

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Palmitoylethanolamide, a naturally occurring lipid, is an orally effective intestinal anti‐inflammatory agent

Cited by 150 publications

References 82 publications

The Role of the Endocannabinoid System in the Brain–Gut Axis

The Role of the Endocannabinoid System in the Brain–Gut Axis

Medical Cannabis and Cannabinoids: An Option for the Treatment of Inflammatory Bowel Disease and Cancer of the Colon?

Manipulation of the Endocannabinoid System in Colitis

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