Endocannabinoids as physiological regulators of colonic propulsion in mice.
OBJECTIVE
Activation of enteric cannabinoid CB1 receptors inhibits motility in the small intestine; however, it is not known whether endogenous cannabinoids (anandamide and 2-arachidonylglycerol) play a physiologic role in regulating intestinal motility. In the present study, we investigated the possible involvement of endocannabinoids in regulating intestinal propulsion in the mouse colon in vivo.


METHODS
Intestinal motility was studied measuring the expulsion of a glass bead inserted into the distal colon; endocannabinoid levels were measured by isotope-dilution gas chromatography-mass spectrometry; anandamide amidohydrolase activity was measured by specific enzyme assays. CB1 receptors were localized by immunohistochemistry.


RESULTS
Anandamide, WIN 55,212-2, cannabinol (nonselective cannabinoid agonists), and ACEA (a selective CB1 agonist) inhibited colonic propulsion; this effect was counteracted by SR141716A, a CB1 receptor antagonist. Administered alone, SR141716A increased motility, whereas the inhibitor of anandamide cellular reuptake, VDM11, decreased motility. High amounts of 2-arachidonylglycerol and particularly anandamide were found in the colon, together with a high activity of anandamide amidohydrolase. CB1 receptor immunoreactivity was colocalized to a subpopulation of choline acetyltransferase-immunoreactive neurons and fiber bundles in the myenteric plexus.


CONCLUSIONS
We conclude that endocannabinoids acting on myenteric CB1 receptors tonically inhibit colonic propulsion in mice.
Pinto
Luisa
L
Department of Experimental Pharmacology, University of Naples Federico II, Naples, Italy.
Izzo
Angelo A
AA
Cascio
Maria Grazia
MG
Bisogno
Tiziana
T
Hospodar-Scott
Karen
K
Brown
David R
DR
Mascolo
Nicola
N
Di Marzo
Vincenzo
V
Capasso
Francesco
F
D000577:Amides; D000581:Amidohydrolases / Q000378:metabolism; D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology; D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids / Q000378:metabolism*; D003106:Colon / Q000502:physiology*; D063388:Endocannabinoids; D004983:Ethanolamines; D005769:Gastrointestinal Motility / Q000187:drug effects / Q000502:physiology*; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010169:Palmitic Acids / Q000378:metabolism; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000819:agonists / Q000037:antagonists & inhibitors; D000099252:Fatty Acid Amide Hydrolases
D000577:Amides; D000581:Amidohydrolases; D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids; D063388:Endocannabinoids; D004983:Ethanolamines; D010169:Palmitic Acids; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D000099252:Fatty Acid Amide Hydrolases; C462953:N-(2-methyl-3-hydroxyphenyl)-5,8,11,14-eicosatetraenamide; C005958:palmidrol