Effects of N-oleoylethanolamine-evoked satiety results from peripheral actions independent of entourage effects on endocannabinoid levels

Patel,A.; Sarmad,S.; Barrett,D.A.; Kendall,D.A.; Alexander,S.P.H. University of Nottingham, Nottingham, UK.

N-Oleoylethanolamine (OEA) is a naturally occurring endocannabinoid-like compound (ECL), whose levels increase in the small intestine in response to feeding, and which decreases food intake upon exogenous administration (Fu et al, 2003). Although OEA appears to lack direct effects at CB1 and CB2 receptors, it has previously been hypothesised (along with other ECLs) to have indirect effects on cannabinoid receptors by diverting the hydrolytic activity of FAAH, thereby leading to accumulation of canonical ECLs (“entourage effect”, Alexander & Kendall, 2007). The aims of this investigation were, first to determine the distribution of OEA following acute intraperitoneal (i.p) administration, to help determine a locus of action and, second, whether administration of OEA was able to influence levels of other ECLs in the mouse.

Using the Comprehensive Lab Animal Monitoring System (CLAMS), OEA (10 mg kg-1, i.p in C57bl male mice, 12 weeks at the start of the experiment) was observed to elicit a transient decrease in food intake in the first 2 hours post-injection (vehicle 0.19 ± 0.02, OEA 0.075 ± 0.02 g; P<0.05). In a parallel experiment, four groups of four adult male C57bl mice (16 weeks) received a single i.p injection of either vehicle (5% Tween 80, 5% polyethylene glycol, 90% sterile saline) or OEA (10 mg kg-1). 30 or 60 min after injection, ECL levels in brain, gut and liver tissues were quantified by LC-MS.

Basal levels of OEA in the hippocampus and hypothalamus were 844 ± 102 and 755 ± 63 pmol g-1, respectively, and were unaltered following OEA administration (1-way ANOVA with Bonferroni post-test). In the liver, OEA levels were considerably lower: 85 ± 16 pmol g-1 and tended to increase following OEA administration at both 30 min and 60 min (422 ± 219; 473 ± 160 pmol g-1, respectively) albeit non-significantly. OEA levels were significantly elevated in ileum at 30 min (vehicle 0.5 ± 0.04; OEA, 14.3 ± 5.2 nmol g-1 of tissue; P<0.01) and at 60 min (vehicle 1.92 ± 1.10; OEA, 8.7 ± 4.9 nmol g-1; P<0.05) and in duodenum at 30 min (vehicle 0.2 ± 0.03; OEA, 3.1 ± 1.1 nmol g-1 of tissue; P<0.05) and at 60 min (vehicle, 0.01 ± 0.3; OEA, 2.9 ± 1.03 nmol g-1 of tissue; P<0.05). In the hippocampus and hypothalamus, anandamide (AEA) levels were 120 ± 4 and 66 ± 5 pmol g-1, respectively. In the liver, duodenum and ileum, AEA levels were lower (6 ± 1; 15 ± 2; 14 ± 0.9 pmol g-1), but AEA levels in all tissues were unaltered following OEA administration. N-Palmitoylethanolamine (PEA) levels followed a similar pattern of distribution with higher levels in the hippocampus and hypothalamus (902 ± 53 pmol g-1), compared to the peripheral tissues (133-295 pmol g-1). PEA levels in the brain, liver and duodenum were unchanged following OEA administration.

In summary, exogenous OEA administration, which reduces food intake, alters OEA levels in peripheral, but not central tissues, implicating peripheral tissues as the target for OEA-evoked satiety signalling. These effects appear to be independent of changes in other ECLs in the liver, brain and small intestine, indicating that the actions of OEA are not a result of an entourage effect in vivo.

Alexander SPH & Kendall DA. (2007). Br J Pharmacol, 152: 602-623.
Fu J et al. (2003). Nature 425: 90-93