Cannabinoid CB₂ receptors in the enteric nervous system modulate gastrointestinal contractility in lipopolysaccharide-treated rats

Abstract

Enhanced intestinal transit due to lipopolysaccharide (LPS) is reversed by cannabinoid (CB)2 receptor agonists in vivo, but the site and mechanism of action are unknown. We have tested the hypothesis that CB2 receptors are expressed in the enteric nervous system and are activated in pathophysiological conditions. Tissues from either saline- or LPS-treated (2 h; 65 microg/kg ip) rats were processed for RT-PCR, Western blotting, and immunohistochemistry or were mounted in organ baths where electrical field stimulation was applied in the presence or absence of CB receptor agonists. Whereas the CB2 receptor agonist JWH133 did not affect the electrically evoked twitch response of the ileum under basal conditions, in the LPS-treated tissues JWH133 was able to reduce the enhanced contractile response in a concentration-dependent manner. Rat ileum expressed CB2 receptor mRNA and protein under physiological conditions, and this expression was not affected by LPS treatment. In the myenteric plexus, CB2 receptors were expressed on the majority of neurons, although not on those expressing nitric oxide synthase. LPS did not alter the distribution of CB2 receptor expression in the myenteric plexus. In vivo LPS treatment significantly increased Fos expression in both enteric glia and neurons. This enhanced expression was significantly attenuated by JWH133, whose action was reversed by the CB2 receptor antagonist AM630. Taking these facts together, we conclude that activation of CB2 receptors in the enteric nervous system of the gastrointestinal tract dampens endotoxin-induced enhanced intestinal contractility.

Lipopolysaccharides Facilitate Colonic Motor Alterations Associated to the Sensitization to a Luminal Antigen in Rats

“…Indeed, low doses of LPS have been reported to enhance intestinal motility through mechanisms implicating the enteric nervous system and the modulation of the production of several neuroimmune mediators (including IL-1, cyclooxygenase, and constitutive nitric oxide synthase) in mice and rats. [43][44][45] Although not directly addressed, similar mechanisms might be contributing to the changes observed in the present study, with direct effects of LPS on local neuroimmune responses leading to alterations in smooth muscle contractility.…”

Pharmacological characterization of cannabinoid receptor activity in the rat‐isolated ileum myenteric plexus‐longitudinal muscle preparation

“…Recent studies have described the presence of the CB2 receptor mRNA and the CB2 receptor protein in the rat ileal myenteric plexus (Storr et al, 2002;Duncan et al, 2008). However, the ability of cannabinoid receptor agonists to delay small intestinal transit of the rat in vivo through this receptor has been reported to occur only after inflammation of the small intestine with the bacterial endotoxin lipopolysaccharide (Mathison et al, 2004), and not other inflammatory agents (Izzo et al, 1999).…”

“…In the rat ileum, the mRNAs of both cannabinoid receptors and their expression have been both identified and mapped in the myenteric plexus Valenti et al, 2005;Duncan et al, 2008). Furthermore, a number of endogenous cannabinoid ligands, exemplified by arachidonylethanolamide (AEA) and 2-arachidonylglycerol (2-AG), (Gomez et al, 2002;Mascolo et al, 2002;Izzo et al, 2003;Fegley et al, 2005;Valenti et al, 2005), along with the mechanisms for their enzymatic inactivation (Katayama et al, 1997), have been shown to be present in the rat ileum.…”

The endocannabinoid system in inflammatory bowel diseases: from pathophysiology to therapeutic opportunity

“…Under normal conditions, CB 1 mediates the effects of cannabinoids on motility; however, in inflammatory states both CB 1 and CB 2 receptor activation may reduce inflammation-induced hypermotility. For instance, in lipopolysaccharide (LPS)-induced intestinal inflammation, hypermotility was normalized following CB 2 (but not CB 1 ) activation [19,20], whereas in croton oil-induced hypermotility CB 2 antagonism did not reverse the effect of the cannabinoid agonist CP55,940 [8]. In another study of LPS-induced inflammation, the FAAH inhibitor AM3506 normalized hypermotility in a CB 1 -and CB 2 -dependent manner, whereas colonic propulsion was CB 1 -dependent [21].…”