|Br J Pharmacol. 2017 Aug 14. doi: 10.1111/bph.13980. [Epub ahead of print]|
Suppression of acute and anticipatory nausea by peripherally restricted FAAH inhibitor in animal models: Role of PPARa and CB1 receptors.
Rock EM1, Moreno-Sanz G, Limebeer CL1, Petrie GN1, Angelini R2, Piomelli D2, Parker LA1.
Department of Psychology and Collaborative Neuroscience Program, University of Guelph, Guelph, ON, N1G 2W1.
Department of Anatomy and Neurobiology, University of California, Irvine, 92697-4621.
To evaluate the ability of the peripherally restricted fatty acid amide hydrolase (FAAH) inhibitor, URB937 (cyclohexylcarbamic acid 3'-carbamoyl-6-hydroxybiphenyl-3-yl ester) to suppress acute and anticipatory nausea in rats, and to examine the pharmacological mechanism of such an effect.
We investigated the potential of URB937 to reduce the establishment of lithium chloride (LiCl)-induced conditioned gaping (a model of acute nausea) and to reduce the expression of contextually elicited conditioned gaping (a model of anticipatory nausea) in rats. As well, the role of CB1 receptors, CB2 receptors and the peroxisome proliferator-activated receptor-a (PPARa) in the anti-nausea effect of URB937 was examined. The potential of URB937 to suppress FAAH activity in tissue collected from the area postrema (AP), prefrontal cortex (PFC), liver and duodenum, and to elevate levels of FAAH substrates - anandamide (AEA), N-oleoylethanolamide (OEA) and N-palmitoylethanolamide (PEA) - in the AP was also evaluated.
URB937 (1 and 3 mg/kg, i.p.) reduced acute nausea by a PPARa mechanism and reduced anticipatory nausea (3 mg/kg, ip) by a CB1 mechanism. The PPARa agonist, GW7647, similarly attenuated acute nausea. URB937 reduced FAAH activity in the liver and the duodenum, but not in the PFC. In addition, URB937 reduced FAAH activity and elevated levels of fatty-acid ethanolamides (FAEs) in the AP, a brain region that is not protected by the blood-brain barrier.
CONCLUSIONS AND IMPLICATIONS:
The anti-nausea action of URB937 may occur in the AP, and may involve PPARa to suppress acute nausea and CB1 to suppress anticipatory nausea.