Endocannabinoid modulation of jejunal afferent responses to LPS.
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.


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 CB(1) receptors whereas the VDM11 response was mediated by both CB(1) and CB(2) 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 CB(1) but not CB(2) receptor antagonism. In contrast, the inhibitory effect of VDM11 remained unaltered after CB(1) or CB(2) receptor blockade.


CONCLUSIONS
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.
University of Sheffield, Department of Biomedical Sciences, Sheffield, UK. jemma.donovan@nottingham.ac.uk
J
J
Donovan
D
D
Grundy
D000818:Animals; D063385:Cannabinoid Receptor Modulators / Q000494:pharmacology; D063388:Endocannabinoids / Q000378:metabolism*; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism*; D007583:Jejunum / Q000187:drug effects / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D009475:Neurons, Afferent / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D008070:Lipopolysaccharides