Naphthalen-1-yl-(4-pentyloxynaphthalen-1-yl)methanone (SAB378), a peripherally restricted cannabinoid CB1/CB2 receptor agonist, inhibits gastrointestinal motility but has no effect on experimental colitis in mice.
The endocannabinoid system is involved in the regulation of gastrointestinal (GI) motility and inflammation. Using the peripherally restricted cannabinoid (CB)(1)/CB(2) receptor agonist naphthalen-1-yl-(4-pentyloxynaphthalen-1-yl)methanone (SAB378), we investigated the role of peripheral cannabinoid receptors in the regulation of GI motility and the development of colitis in mice. The actions of SAB378 on whole gut transit, upper GI transit, colonic propulsion, and locomotor activity were investigated in C57BL/6N, CB(1) receptor knockout, and CB(2) receptor knockout mice. The potential for SAB378 to modify inflammation was studied by using dextran sulfate sodium (DSS) and 2,4,6-trinitrobenzene sulfonic acid (TNBS) models of experimental colitis. SAB378 did not modify locomotor activity. SAB378 slowed all parameters of GI motility, and these effects were significantly reduced by the CB(1) receptor antagonist N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3 carboxamide (AM251), but not by the CB(2) receptor antagonist 6-iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H- indol-3-yl](4-methoxyphenyl)methanone (AM630). SAB378 did not inhibit GI transit or colonic propulsion in CB(1) receptor knockout mice, whereas its effects were observed in CB(2) receptor knockout mice. SAB378 did not reduce the degree of colitis induced by DSS or TNBS. The actions of SAB378 on GI motility are mediated by peripherally located CB(1) receptors. SAB378 was not effective against two models of experimental colitis, which may indicate that peripheral cannabinoid receptor stimulation alone may not be sufficient to mediate the anti-inflammatory effects of cannabinoids.
Cluny
Nina L
NL
Hotchkiss Brain Institute and Snyder Institute of Infection, Immunity, and Inflammation, Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada.
Keenan
Catherine M
CM
Duncan
Marnie
M
Fox
Alyson
A
Lutz
Beat
B
Sharkey
Keith A
KA
D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D003106:Colon / Q000187:drug effects; D016264:Dextran Sulfate; D005260:Female; D005769:Gastrointestinal Motility / Q000187:drug effects*; D005772:Gastrointestinal Transit / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D009281:Naphthalenes / Q000494:pharmacology*; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists*; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists*; D014302:Trinitrobenzenesulfonic Acid
D009281:Naphthalenes; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D014302:Trinitrobenzenesulfonic Acid; D016264:Dextran Sulfate; C524107:naphthalen-1-yl-(4-pentyloxynaphthalen-1-yl)methanone