The endogenous cannabinoid system protects against colonic inflammation

Abstract

Excessive inflammatory responses can emerge as a potential danger for organisms' health. Physiological balance between pro- and anti-inflammatory processes constitutes an important feature of responses against harmful events. Here, we show that cannabinoid receptors type 1 (CB1) mediate intrinsic protective signals that counteract proinflammatory responses. Both intrarectal infusion of 2,4-dinitrobenzene sulfonic acid (DNBS) and oral administration of dextrane sulfate sodium induced stronger inflammation in CB1-deficient mice (CB1 -/- ) than in wild-type littermates (CB1 +/+ ). Treatment of wild-type mice with the specific CB1 antagonist N-(piperidino-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-pyrazole-3- carboxamide (SR141716A) mimicked the phenotype of CB1 -/- mice, showing an acute requirement of CB1 receptors for protection from inflammation. Consistently, treatment with the cannabinoid receptor ago- nist R(-)-7-hydroxy-delta6 -tetra-hydrocannabinol-dimethylheptyl (HU210) or genetic ablation of the endo- cannabinoid-degrading enzyme fatty acid amide hydrolase (FAAH) resulted in protection against DNBS-induced colitis. Electrophysiological recordings from circular smooth muscle cells, performed 8 hours after DNBS treatment, revealed spontaneous oscillatory action potentials in CB1 -/- but not in CB1 +/+ colons, indi- cating an early CB1-mediated control of inflammation-induced irritation of smooth muscle cells. DNBS treatment increased the percentage of myenteric neurons expressing CB1 receptors, suggesting an enhancement of cannabinoid signaling during colitis. Our results indicate that the endogenous cannabinoid system represents a promising therapeutic target for the treatment of intestinal disease conditions characterized by excessive inflammatory responses

The Gastrointestinal Pharmacology of Cannabinoids: Focus on Motility

“…A beneficial effect has been shown for THC, CB1 and CB2 agonists and inhibitors of anandamide or 2-AG degradation/reuptake [11,16,67]. Activation of not only CB1 [68], but also CB2 receptors [14] reduced electrically evoked contractions of muscle preparations from inflamed gut. Inhibitors of anandamide reuptake or enzymatic hydrolysis, which increase intestinal anandamide levels, reduced dinitrobenzene sulphonic acid-induced colonic inflammation in wild-type, but not CB1 or CB2 receptor-deficient mice [69].…”

“…Mutated mice lacking CB2 receptors were more sensitive to the inflammatory effects of trinitrobenzene sulphonic acid [69,70]. FAAH-deficient mice, which are expected to have higher levels of anandamide, showed significant protection against intestinal inflammation due to dinitrobenzene sulphonic acid [68] or endotoxin [71] administration. …”

Role of the Endocannabinoid System in Alcoholic Liver Disease

“…The endocannabinoid system is involved in the regulation of a variety of physiological processes including nociception, food intake, intestinal motility, lipogenesis and inflammation [5]. Although CB1 and CB2 receptors display the highest expression in the brain and the immune system, respectively, they are also expressed in peripheral tissues including the liver and have been implicated in the pathophysiology of inflammatory and metabolic diseases such as atherosclerosis [8,9], chronic inflammatory bowel syndrome [10,11,12,13] or hepatic steatosis [14,15,16]. The important role of endocannabinoids in disease processes of peripheral tissues and the finding that components of the endocannabinoid system are expressed in the injured liver has led to detailed studies on the role of the endocannabinoid system in hepatic injury and wound-healing responses [17].…”

Relationships between the Autonomic Nervous System, Humoral Factors and Immune Functions in the Intestine

“…These developments include the identification, cloning, and expression of cannabinoid receptors [50,51,52], isolation of endogenous cannabinoid ligands [53,54,55], and synthesis of nonselective and selective cannabinoid receptor agonists and antagonists [56]. A century ago, extracts of cannabis were used in the United States to treat gastrointestinal pain of different origins, gastroenteritis, and diarrhea [57]. There are also anecdotal reports suggesting that marijuana (Cannabis sativa) may be effective in alleviating systems of Crohn’s disease [58].…”

“…Endocannabinoids, their endogenous ligands, and the proteins participating in the inactivation of these latter compounds, such as the AEA membrane transporter and AEA amidohydrolase, are components of the so-called ‘endogenous cannabinoid system’ [72]. The endogenous cannabinoid system plays a role in the control of various functions, including gastroprotection, intestinal motility, and secretion [73]. The endogenous cannabinoid system is physiologically involved in the protection against excessive inflammation in the colon, both by dampening smooth muscular irritation caused by inflammation and by controlling cellular pathways leading to inflammatory responses.…”