The FAAH inhibitor URB-597 interferes with cisplatin- and nicotine-induced vomiting in the Suncus murinus (house musk shrew)

Abstract

Considerable evidence implicates the endocannabinoid system as a neuromodulator of nausea and vomiting. The action of anandamide (AEA) can be prolonged by inhibiting its degradation, through the use of URB597 (URB), a Fatty Acid Amide Hydrolase (FAAH) enzyme inhibitor. Here we present evidence that the FAAH inhibitor, URB, interferes with cisplatin- and nicotine -induced vomiting in the Suncus murinus. In Experiment 1, shrews were injected with URB (0.9 mg/kg) or vehicle 120 min prior to the behavioral testing. They received a second injection of AEA (5 mg/kg) or vehicle 15 min prior to being injected with cisplatin (20 mg/kg) or saline and the number of vomiting episodes were counted for 60 min. In Experiment 2, shrews were injected with vehicle or URB (0.9 mg/kg) 120 min prior to receiving an injection of nicotine (5 mg/kg) or saline and the number of vomiting episodes were counted for 15 min. Experiment 3 evaluated the potential of the CB1 antagonist, SR141716, to reverse the effect of URB on nicotine-induced vomiting. URB attenuated vomiting produced by cisplatin and nicotine and the combination of URB+AEA suppressed vomiting produced by cisplatin. The effect of URB on nicotine-induced vomiting was reversed by SR141716. These data suggest that the EC system plays a tonic role in the regulation of toxin-induced vomiting.

Effects of parabolic flight and spaceflight on the endocannabinoid system in humans

“…Recent animal experiments have confirmed the antinausea and antiemetic effects of cannabinoids and their receptors (Van Sickle et al, 2003;Parker et al, 2009). Cannabinoids are also used to treat chemotherapy-induced emesis in cancer patients (Machado Rocha et al, 2008).…”

Chemical Probes of Endocannabinoid Metabolism

“…URB597 (0.9 mg/kg) treatment reduced cisplatin and nicotine-induced emetic episodes, and the effects on nicotine vomiting were CB1-dependent and reversed by rimonabant (Parker et al, 2009). JZL184 (16 and 40 mg/kg i.p.)…”

Comparisons of 9-Tetrahydrocannabinol and Anandamide on a Battery of Cognition-Related Behavior in Nonhuman Primates

“…From a clinical perspective, the present findings may become especially meaningful if FAAH inhibitors and/or metabolically stable forms of anandamide can provide medicinal (e.g., antinauseant, antiemetic, or appetite stimulant) effects in humans that have been reported in other species (e.g., Williams and Kirkham, 1999;Cross-Mellor et al, 2007;Rock et al, 2008;Parker et al, 2009;Limebeer et al, 2014;Sharkey et al, 2014). In that case, the present data support the view that the activation of CB 1 receptors by endocannabinoidsand in particular anandamide-may provide a therapeutic avenue with fewer deleterious effects on cognitive performance than produced by D 9 -THC.…”

“…One recent approach that has yielded encouraging preclinical results does not target the development of novel CB 1 agonists but instead involves enhancing endogenous cannabinergic activity by pharmacologically inhibiting the rapid metabolism of anandamide by fatty acid amide hydrolase (FAAH) (e.g., Kathuria et al, 2003;Seierstad and Breitenbucher, 2008;Gaetani et al, 2009;Pertwee, 2014). An emerging literature in which this approach is explored provides some preclinical evidence of efficacy in animal models of nausea, vomiting, and appetite (e.g., Williams and Kirkham, 1999;Cross-Mellor et al, 2007;Rock et al, 2008;Parker et al, 2009;Limebeer et al, 2014). However, the effects of anandamide on cognitive function in nonhuman primates have not yet been fully delineated, and consequently it is unclear whether anandamide (or other endocannabinoids) offer a therapeutic advantage over CB 1 agonists such as D 9 -THC.…”