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Suppression of acute and anticipatory nausea by peripherally restricted fatty acid amide hydrolase inhibitor in animal models: role of PPARα and CB 1 receptors
Author(s) -
Rock Erin M,
MorenoSanz Guillermo,
Limebeer Cheryl L,
Petrie Gavin N,
Angelini Roberto,
Piomelli Daniele,
Parker Linda A
Publication year - 2017
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.13980
Subject(s) - nausea , fatty acid amide hydrolase , palmitoylethanolamide , endocannabinoid system , pharmacology , agonist , cannabinoid receptor , receptor , medicine
Background and Purpose Effective treatments of nausea are limited. In this study we evaluated the ability of the peripherally restricted fatty acid amide hydrolase (FAAH) inhibitor, URB937, to suppress acute and anticipatory nausea in rats and examined the pharmacological mechanism of this effect. Experimental Approach We investigated the potential of URB937 (administered i.p.) to reduce the establishment of lithium chloride‐induced conditioned gaping (model of acute nausea) and to reduce the expression of contextually‐elicited conditioned gaping (model of anticipatory nausea) in rats. The role of CB 1 receptors, CB 2 receptors and PPARα 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 (OEO) and N‐palmitoylethanolamide (PEA) – in the AP was also evaluated. Key Results URB937 reduced acute nausea by a PPARα‐dependent mechanism and reduced anticipatory nausea by a CB 1 receptor‐dependent mechanism. The PPARα 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 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 PPARα to suppress acute nausea and CB 1 receptors to suppress anticipatory nausea.