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Background and purposeEffective 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 approachWe 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 CB1 receptors, CB2 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 resultsURB937 reduced acute nausea by a PPARα-dependent mechanism and reduced anticipatory nausea by a CB1 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 implicationsThe anti-nausea action of URB937 may occur in the AP and may involve PPARα to suppress acute nausea and CB1 receptors to suppress anticipatory nausea.

RationaleAnticipatory nausea (AN) experienced by chemotherapy patients is resistant to current anti-nausea treatments. In this study, the effect of manipulation of the endocannabinoid (EC) system on a rat model of nausea (conditioned gaping) was determined.ObjectiveThe potential of cannabidiol (CBD) and the fatty acid amide hydrolase (FAAH) inhibitor, URB597 (URB) to reduce conditioned gaping in rats were evaluated.Materials and methodsIn each experiment, rats received four conditioning trials in which they were injected with lithium chloride immediately before placement in a distinctive odor-laced context. During testing, in experiment 1, rats were injected with vehicle (VEH), 1, 5 or 10 mg/kg CBD 30 min before placement in the context previously paired with nausea and in experiment 2, rats were injected with VEH, 0.1 or 0.3 mg/kg URB 2 h before placement in the context. Additional groups evaluated the ability of the CB(1) antagonist/inverse agonist, SR141716A, to reverse the suppressive effects of URB. Experiment 3 measured the potential of URB to interfere with the establishment of conditioned gaping.ResultsWhen administered before testing, CBD (1 and 5, but not 10 mg/kg) and URB (0.3, but not 0.1 mg/kg) suppressed conditioned gaping. The effect of URB was reversed by pre-treatment with the CB(1) antagonist/inverse agonist, SR141716A. When administered before conditioning, URB also interfered with the establishment of conditioned gaping.ConclusionsManipulations of the EC system may have therapeutic potential in the treatment of AN.

The terms conditioned taste avoidance and conditioned taste aversion are often used interchangeably in the literature; however, considerable evidence indicates that they may represent different processes. Conditioned taste avoidance is measured by the amount that a rat drinks in a consumption test that includes both appetitive phases and consummatory phases of responding. However, conditioned taste aversion is more directly assessed using the taste reactivity (TR) test that includes only the consummatory phase of responding. Rats display a conditioned taste aversion as conditioned disgust reactions (gapes, chin rubs, and paw treads) during an intraoral infusion of a nausea-paired flavored solution. Only treatments that produce nausea produce conditioned disgust reactions, but even rewarding drugs produce conditioned taste avoidance. Furthermore, treatments that alleviate nausea prevent the establishment and the expression of conditioned disgust reactions, but they do not necessarily modify conditioned taste avoidance. Considerable evidence exists indicating that these two measures can be independent of one another. The potential of a compound to produce conditioned disgust reactions is a reflection of its nausea-inducing properties. Taste avoidance may be motivated by conditioned fear rather than conditioned nausea, but conditioned disgust is motivated by conditioned nausea. Keywords: nausea, serotonin, cannabinoids, classical conditioning, disgust Les termes evitement gustatif conditionne et aversion gustative conditionnee sont souvent utilises de facon interchangeable dans la litterature; cependant, plusieurs donnees indiquent qu'ils pourraient representer des processus differents. L'evitement gustatif conditionne est mesure par la quantite consommee par un rat dans un test de consommation incluant des phases appetitives et des phases de reponse consommatoire. Toutefois, l'aversion gustative conditionnee est evaluee plus directement en utilisant le test de reactivite gustative (RG) qui n'inclut que la phase de reponse consommatoire. Les rats manifestent leur aversion sous forme de reactions de degout conditionne (baillements, frottements de menton, agitations des pattes) durant l'infusion intra orale d'une solution nauseeuse associee a une saveur. Seuls les traitements produisant des nausees engendrent des reactions de degout conditionne, mais meme des drogues agissant comme recompense peuvent engendrer l'evitement gustatif conditionne. De plus, les traitements reduisant les nausees empechent l'etablissement et l'expression de reactions de degout, mais ne modifient pas necessairement l'evitement gustatif conditionne. Plusieurs donnees existantes indiquent que les deux mesures peuvent etre independantes. Le fait qu'un melange puisse produire des reactions de degout conditionne est un reflet de ses proprietes nauseeuses. L'evitement gustatif pourrait etre motive par la peur conditionnee plutet que la nausee conditionnee, mais le degout conditionne est motive par la nausee conditionnee. Mots-cles : nausee, serotonine, cannabinoides, conditionnement classique, degout