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

Abstract

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 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 results: URB937 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 implications: The 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.

Figure 1

Effect of URB937 (0.3, 1, 3 mg·kg⁻¹, i.p.) or VEH administered 120 min prior to a saccharin‐LiCl pairing on conditioned gaping reactions in a subsequent drug‐free taste reactivity test (a rat model of acute nausea). Each bar represents the mean ± SEM (n = 8) number of gapes. The asterisks indicate a significant difference from the VEH‐treated control animals (*P < 0.05).

Figure 2

Effect of administration of rimonabant (1 mg·kg⁻¹, i.p.) (A), AM‐630 (1 mg·kg⁻¹, i.p.) (B) or MK‐886 (1 mg·kg⁻¹, i.p.) (C) on URB937 (3 mg·kg⁻¹, i.p.) or VEH administered 120 min prior to a saccharin‐LiCl pairing on conditioned gaping reactions in a subsequent drug‐free taste reactivity test (a rat model of acute nausea). Groups were as follows: VEH‐VEH (n = 8); 0.3 mg·kg⁻¹ URB937‐VEH (n = 8); 1 mg·kg⁻¹ URB937‐VEH (n = 8); 3.0 mg·kg⁻¹ URB937‐VEH (n = 8); VEH‐1 mg·kg⁻¹ rimonabant (n = 8); 3 mg·kg⁻¹ URB937–1 mg·kg⁻¹ rimonabant (n = 8); VEH–1 mg·kg⁻¹ AM‐630 (n = 7); 3 mg·kg⁻¹ URB937–1 mg·kg⁻¹ AM‐630 (n = 12); VEH–1 mg·kg⁻¹ MK‐886 (n = 8); 3 mg·kg⁻¹ URB937–1 mg·kg⁻¹ MK‐886 (n = 8). Each bar represents the mean ± SEM number of gapes. The asterisks indicate a significant difference from the VEH‐treated control animals (*P < 0.05).

Figure 3

Effect of the PPARα agonist GW7647 (3 mg·kg⁻¹, i.p.) or VEH administered 30 min prior to a saccharin infusion (paired with either LiCl or saline) on conditioned gaping reactions in a subsequent drug‐free taste reactivity test (a rat model of acute nausea). Each bar represents the mean ± SEM (n = 8) number of gapes. The asterisks indicate a significant difference from all other groups (*P < 0.05).

Figure 4

Effect of URB937 (3 mg·kg⁻¹, i.p.) or VEH (n = 8 per group) administered 120 min prior to the anticipatory nausea test. Additional groups (n = 8 per group) were also administered rimonabant (1 mg·kg⁻¹, i.p.), AM‐630 (1 mg·kg⁻¹, i.p.) or MK‐886 (1 mg·kg⁻¹, i.p.) 30 min prior to the test. The mean number of conditioned gaping responses was measured during the anticipatory nausea test trial. Each bar represents the mean ± SEM. The asterisks indicate a significant difference from the VEH‐VEH group (*P < 0.05).

Figure 5

The mean distance (cm) travelled was measured in a 15 min activity test that occurred after the anticipatory nausea test in Experiment 3. Each bar represents the mean ± SEM.

Figure 6

Effects of URB937 on FAAH activity and levels of FAEs in rats. (A) A single injection of URB937 (3 mg·kg⁻¹, i.p., n = 6) blocked FAAH activity in peripheral tissues [liver (LIV) and duodenum (DUO)] 2 h after administration. Cortical (PFC) FAAH activity remained unaltered, and a partial inhibition was observed in the AP compared to animals treated with VEH (n = 6). Analysis of local concentrations of FAEs, which are substrates for FAAH, revealed significantly increased levels of AEA (B), OEA (C) and PEA (D) but not 2‐AG (E) in the AP of rats treated with URB937 (3 mg·kg⁻¹, i.p., n = 6, solid bars) compared to VEH‐treated animals (n = 6, open bars). Each bar represents the mean ± SEM. The asterisks indicate a significant difference from the VEH control animals (*P < 0.05).