SR141716A and SR144528 were generously denoted by GlaxoSmithKline. Data presented within this article has been presented at NGM meetings: abstract FRI109 Switzerland 2008, abstracts 196 and 197 Chicago 2009.
Endocannabinoid modulation of jejunal afferent responses to LPS
Article first published online: 27 JUN 2012
© 2012 Blackwell Publishing Ltd
Neurogastroenterology & Motility
Volume 24, Issue 10, pages 956–e465, October 2012
How to Cite
Donovan, J. and Grundy, D. (2012), Endocannabinoid modulation of jejunal afferent responses to LPS. Neurogastroenterology & Motility, 24: 956–e465. doi: 10.1111/j.1365-2982.2012.01961.x
- Issue published online: 12 SEP 2012
- Article first published online: 27 JUN 2012
- Received: 29 March 2012 Accepted for publication: 18 May 2012
Background Endocannabinoids influence immune function and nociceptive signaling. This study examines cannabinoid modulation of sensory signaling from the GI tract following an acute inflammatory response triggered by systemic administration of bacterial lipopolysaccharide (LPS).
Methods A segment of proximal jejunum was intubated, to measure intraluminal pressure, in anesthetized rats. Afferent impulse traffic was recorded from a single isolated paravascular nerve bundle supplying the jejunal loop. Drugs and LPS were administered intravenously and changes in afferent firing were determined.
Key Results The non-selective cannabinoid agonist, WIN55,212-2 (1 mg kg−1 i.v.) and the anandamide transport inhibitor, VDM11 (1 mg kg−1 i.v.) but not the fatty acid amide hydrolase (FAAH) inhibitor, URB597 (0.3 mg kg−1) caused a significant increase in afferent activity. The WIN55,212-2-induced afferent response was mediated by activation of CB1 receptors whereas the VDM11 response was mediated by both CB1 and CB2 receptor mechanisms. LPS (10 mg kg−1) evoked an increase in afferent activity which was significantly reduced in the presence of WIN55,212-2 and VDM11 but not URB597. The inhibitory effect of WIN55,212-2 was prevented by CB1 but not CB2 receptor antagonism. In contrast, the inhibitory effect of VDM11 remained unaltered after CB1 or CB2 receptor blockade.
Conclusions & Inferences Endocannabinoids play a role in modulating afferent signaling and may represent a target for the treatment of visceral hypersensitivity. In contrast to the effects of blocking endocannabinoid uptake (VDM11), inhibiting breakdown of endocannabinoids (URB597) had no effect on baseline or LPS induced afferent firing. Therefore, uptake of cannabinoids rather than breakdown via FAAH terminates their action in the GI tract.