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

Abstract

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.

The endocannabinoid system in inflammatory bowel diseases: from pathophysiology to therapeutic opportunity

“…This study suggests that central cannabinoid receptor activation might be required to achieve the anti-inflammatory effect of cannabinoid agonists on colitis; however, the doses used were low compared with other cannabinoid agonists used in the same models or to the doses of WIN55,212-2 used in the same study. Higher doses of SAB378 were suggested (but not tested) to be potentially efficient in reducing colitis, with the concern that they might exert inhibitory actions on gastrointestinal transit [12]. However, inhibition of gastrointestinal transit could prove beneficial in acute colitis where bowel dysmotility and diarrhea are often observed.…”

“…SAB378, a CB 1 /CB 2 peripherally restricted agonist has been studied for treatment of DSSinduced colitis (0.1 mg/kg or 1 mg/kg, b.i.d.) and TNBSinduced colitis (0.1 mg/kg or 1 mg/kg, 1 h pre-TNBS and then 8 h and 24 h later), and its effect was compared to that of the brain-penetrating CB 1 /CB 2 agonist WIN55,212-2 [12]. SAB378 treatment reduced inflammation in TNBSinduced colitis by an amount that was not statistically significant, and was ineffective in DSS-colitis [12].…”

“…and TNBSinduced colitis (0.1 mg/kg or 1 mg/kg, 1 h pre-TNBS and then 8 h and 24 h later), and its effect was compared to that of the brain-penetrating CB 1 /CB 2 agonist WIN55,212-2 [12]. SAB378 treatment reduced inflammation in TNBSinduced colitis by an amount that was not statistically significant, and was ineffective in DSS-colitis [12]. This study suggests that central cannabinoid receptor activation might be required to achieve the anti-inflammatory effect of cannabinoid agonists on colitis; however, the doses used were low compared with other cannabinoid agonists used in the same models or to the doses of WIN55,212-2 used in the same study.…”

“…Cannabinoids and endocannabinoid degradation inhibitors decrease intestinal motility, peristalsis, and colonic propulsion in rodents, primarily in a CB 1 -dependent manner [7][8][9][10][11][12]. Accordingly, [8,9,13,14].…”

“…[50], WIN55,212-2 (2 mg/kg, b.i.d.) [12], or anandamide (5 mg/kg, q.d.) [63] were beneficial in murine models of colitis and reduced colon inflammation.…”