Effects of cannabinoid receptor-2 activation on accelerated gastrointestinal transit in lipopolysaccharide-treated rats.

The biological effects of cannabinoids (CB) are mediated by CB(1) and CB(2) receptors. The role of CB(2) receptors in the gastrointestinal tract is uncertain. In this study, we examined whether CB(2) receptor activation is involved in the regulation of gastrointestinal transit in rats. Basal and lipopolysaccharide (LPS)-stimulated gastrointestinal transit was measured after instillation of an Evans blue-gum Arabic suspension into the stomach, in the presence of specific CB(1) and CB(2) agonists and antagonists, or after treatment with inhibitors of mediators implicated in the transit process. In control rats a CB(1) (ACEA; 1 mg kg(-1)), but not a CB(2) (JWH-133; 1 mg kg(-1)), receptor agonist inhibited basal gastrointestinal transit. The effects of the CB(1) agonist were reversed by the CB(1) antagonist AM-251, which alone increased basal transit. LPS treatment increased gastrointestinal transit. This increased transit was reduced to control values by the CB(2), but not the CB(1), agonist. This inhibition by the CB(2) agonist was dose dependent and prevented by a selective CB(2) antagonist (AM-630; 1 mg kg(-1)). By evaluating the inhibition of LPS-enhanced gastrointestinal transit by different antagonists, the effects of the CB(2) agonist (JWH-133; 1 mg kg(-1)) were found to act via cyclooxygenase, and to act independently of inducible nitric oxide synthase (NOS) and platelet-activating factor. Interleukin-1 beta and constitutive NOS isoforms may be involved in the accelerated LPS transit. The activation of CB(2) receptors in response to LPS is a mechanism for the re-establishment of normal gastrointestinal transit after an inflammatory stimulus.