Suppression of acute and anticipatory nausea by peripherally restricted fatty acid amide hydrolase inhibitor in animal models: role of PPARα and CB₁ receptors

Abstract

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 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 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 RESULTSURB937 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 IMPLICATIONSThe 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. Abbreviations

Nausea-Induced 5-HT Release in the Interoceptive Insular Cortex and Regulation by Monoacylglycerol Lipase (MAGL) Inhibition and Cannabidiol

“…On the other hand, FAAH inhibition has been found to reduce LiCl-induced nausea when administered systemically ( Rock et al, 2015 ; Parker et al, 2016 ). This effect may be mediated by a peripheral mechanism, since Rock et al (2017) found that the peripherally restricted FAAH inhibitor, URB937, reduced LiCl-induced conditioned gaping, potentially by its action on the area postrema, an area of weakened blood brain barrier. Future research needs to address potential central sites of action of FAAH inhibition in the reduction of nausea.…”

Biologically active metabolite(s) from haemolymph of red-headed centipede Scolopendra subspinipes possess broad spectrum antibacterial activity

“…Exact structure: endogenous peroxisome proliferator-activated receptor alpha (PPAR-α) agonist (Gaetani et al 2003), antitussive activity (Wortley et al 2017), anti-inflammatory activity (Toguri et al 2018), used to treat post-traumatic stress disorder by fatty acid amide hydrolase (FAAH) inhibition (Danandeh et al 2018), useful in the treatment of neurological disorders (Pandey et al 2018), anti-nausea effect (Rock et al 2017), analgesic activity (Zubrzycki et al 2017), anticancer activity against colon cancer cells (Pagano et al 2017)…”

Inhibition of fatty acid amide hydrolase in the CNS prevents and reverses morphine tolerance in male and female mice

“…While many of the effects exerted by these agents—including reduced anxiety‐, depression‐, and pain‐related behaviours in animal models (Bortolato et al, 2007; Gobbi et al, 2005; Russo et al, 2007)—may primarily depend on increased anandamide activity at cannabinoid receptors, other responses appear to involve the amplification of different FAAH‐regulated lipid signals. For example, endogenous PPAR‐α agonists (most likely PEA and/or OEA) have been implicated in the effects of FAAH inhibition on acute nausea (Rock et al, 2017), cognition (Mazzola et al, 2009; Panlilio et al, 2016), and inflammatory pain (Sagar, Kendall, & Chapman, 2008). Synergistic interactions between CB 1 receptors and PPAR‐α have also been documented (Calignano, La Rana, Giuffrida, & Piomelli, 1998; Russo et al, 2007).…”