Oleoylethanolamide: a novel potential pharmacological alternative to cannabinoid antagonists for the control of appetite

Abstract

The initial pharmaceutical interest for the endocannabinoid system as a target for antiobesity therapies has been restricted by the severe adverse effects of the CB1 antagonist rimonabant. This study points at oleoylethanolamide (OEA), a monounsaturated analogue, and functional antagonist of anandamide, as a potential and safer antiobesity alternative to CB1 antagonism. Mice treated with equal doses (5 or 10 mg/kg, i.p.) of OEA or rimonabant were analyzed for the progressive expression of spontaneous behaviors (eating, grooming, rearing, locomotion, and resting) occurring during the development of satiety, according to the paradigm called behavioral satiety sequence (BSS). Both drugs reduced food (wet mash) intake to a similar extent. OEA treatment decreased eating activity within the first 30 min and caused a temporary increase of resting time that was not accompanied by any decline of horizontal, vertical and total motor activity. Besides decreasing eating activity, rimonabant caused a marked increase of the time spent grooming and decreased horizontal motor activity, alterations that might be indicative of aversive nonmotivational effects on feeding. These results support the idea that OEA suppresses appetite by stimulating satiety and that its profile of action might be predictive of safer effects in humans as a novel antiobesity treatment.

Figure 1

(a) and (b) show, respectively, mean cumulative wet mash intake (±S.E.M) and mean time spent in eating activity (±S.E.M) by mice treated with vehicle, OEA 5 mg/kg i.p. (OEA 5), rimonabant 5 mg/kg i.p. (R 5), OEA 10 mg/kg i.p. (OEA 10), and rimonabant 10 mg/kg, i.p. (R 10) over the 45 min BSS, (n = 6 vehicle group and n = 8 both doses of rimonabant and OEA-treated mice). *P < 0.05 versus vehicle; ^# P < 0.05 versus OEA 5 (Tukey HSD test).

Figure 2

Panels illustrate the temporal development (duration of each behavior in sec) of eating (a), grooming (b), resting (c), horizontal motor activity (d), rearing activity (e), and total motor activity (f) in mice treated with vehicle, OEA 5 mg/kg i.p. (OEA 5), rimonabant 5 mg/kg i.p. (R 5), OEA 10 mg/kg i.p. (OEA 10), and rimonabant 10 mg/kg, i.p. (R 10). Represented on the x-axes are 3 time intervals of 15 min each for a total of 45 min of BSS analysis. Experiments were carried out during light-off period (08:00 PM-09:00 PM). *P < 0.05 versus vehicle group for each time interval (Tukey HSD test).