Interference with acute nausea and anticipatory nausea in rats by fatty acid amide hydrolase (FAAH) inhibition through a PPARα and CB1 receptor mechanism, respectively: a double dissociation.

Abstract

RATIONALE:

Fatty acid amide hydrolase (FAAH) inhibition elevates anandamide (AEA), which acts on cannabinoid (CB1 and CB2) receptors, as well as N-palmitoylethanolamide (PEA) and N-oleoylethanolamine (OEA), which act on peroxisome proliferator-activated receptor alpha (PPARα). Here, we determine the mechanism of action of FAAH inhibition on acute and anticipatory nausea (AN).

OBJECTIVE:

We compared the effectiveness and mechanism of action of two FAAH inhibitors, URB597 and PF-3845, to reduce acute nausea and AN in rodent models of conditioned gaping.

MATERIALS AND METHODS:

For assessment of acute nausea, rats were pretreated with vehicle (VEH), URB597 (0.3 and 10 mg/kg, experiment 1a) or PF-3845 (10 mg/kg, experiment 1b) 120 min prior to a saccharin-lithium chloride (LiCl) pairing. To assess the CB1 receptor or PPARα mediation of the effect of PF-3845 on acute nausea, rats were also pretreated with rimonabant or MK886, respectively. For assessment of AN, following four pairings of a novel context with LiCl, rats received a pretreatment of VEH, URB597 (0.3 mg/kg, experiment 2a), or PF-3845 (10, 20 mg/kg, experiment 2b) 120 min prior to placement in the AN context. To assess the CB1 receptor or PPARα mediation of the effect, rats were also pretreated with rimonabant or MK886, respectively.

RESULTS:

PF-3845 (10 mg/kg, but not URB597 0.3 or 10 mg/kg) suppressed acute nausea via PPARα, but not CB1 receptors. URB597 (0.3 and 10 mg/kg) or PF-3845 (10 and 20 mg/kg) reduced AN via CB1 receptors, but not PPARα.

CONCLUSIONS:

FAAH inhibition reduces acute nausea and AN through PPARα and CB1 receptor mediated effects, respectively.

• Authors: Erin M Rock, Cheryl L Limebeer, Jordan M Ward, Arianne Cohen, Katherine Grove, Micah J Niphakis, Benjamin F Cravatt, Linda A Parker
• Journal: Psychopharmacology (Psychopharmacology (Berl)) Vol. 232 Issue 20 Pg. 3841-8 (Oct 2015) ISSN: 1432-2072 [Electronic] Germany
• PMID: 26297326 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Benzamides
• Carbamates
• PF 3845
• PPAR alpha
• Piperidines
• Pyridines
• Receptor, Cannabinoid, CB1
• cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester
• Amidohydrolases
• fatty-acid amide hydrolase

Topics

• Acute Disease
• Amidohydrolases (antagonists & inhibitors, metabolism)
• Animals
• Anticipation, Psychological (drug effects, physiology)
• Benzamides (pharmacology, therapeutic use)
• Carbamates (pharmacology, therapeutic use)
• Male
• Nausea (metabolism, prevention & control)
• PPAR alpha (physiology)
• Piperidines (pharmacology, therapeutic use)
• Pyridines (pharmacology, therapeutic use)
• Rats
• Rats, Sprague-Dawley
• Receptor, Cannabinoid, CB1 (physiology)