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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

Psychopharmacology volume 232, pages 3841–3848 (2015)Cite this article

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.

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Acknowledgments

This work was supported by grants from the Natural Sciences and Engineering Research Council of Canada (92056) and Canadian Institute of Health Research (137122) to LAP, and National Institutes of Health (DA033760, DA032933) to BFC.

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Authors and Affiliations

  1. Department of Psychology and Collaborative Neuroscience Program, University of Guelph, Guelph, ON, N1G 2W1, Canada

    Erin M. Rock, Cheryl L. Limebeer, Jordan M. Ward, Arianne Cohen, Katherine Grove & Linda A. Parker

  2. The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, LaJolla, CA, USA

    Micah J. Niphakis & Benjamin F. Cravatt

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  1. Erin M. Rock
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  2. Cheryl L. Limebeer
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  3. Jordan M. Ward
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  4. Arianne Cohen
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  5. Katherine Grove
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  6. Micah J. Niphakis
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  7. Benjamin F. Cravatt
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  8. Linda A. Parker
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Correspondence to Linda A. Parker.

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Rock, E.M., Limebeer, C.L., Ward, J.M. et al. 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. Psychopharmacology 232, 3841–3848 (2015). https://doi.org/10.1007/s00213-015-4050-7

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  • DOI: https://doi.org/10.1007/s00213-015-4050-7

Keywords

  • FAAH inhibition
  • Acute nausea
  • Anticipatory nausea
  • PF-3845
  • URB597
  • MK886
  • Rimonabant
  • PPARα
  • CB1