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Effect of selective inhibition of monoacylglycerol lipase (MAGL) on acute nausea, anticipatory nausea, and vomiting in rats and Suncus murinus

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Abstract

Rationale

To determine the role of the endocannabinoid, 2-arachodonyl glycerol (2-AG), in the regulation of nausea and vomiting.

Objective

We evaluated the effectiveness of the potent selective monoacylglycerol lipase (MAGL) inhibitor, MJN110, which selectively elevates the endocannabinoid 2-AG, to suppress acute nausea and vomiting, as well as anticipatory nausea in rat and shrew models.

Methods

The rat gaping models were used to evaluate the potential of MJN110 (5, 10, and 20 mg/kg, intraperitoneally [IP]) to suppress acute nausea produced by LiCl and of MJN110 (10 and 20 mg/kg, IP) to suppress anticipatory nausea elicited by a LiCl-paired context. The potential as well of MJN110 (10 and 20 mg/kg, IP) to suppress vomiting and contextually elicited gaping in the Suncus murinus was evaluated.

Results

MJN110 suppressed acute nausea in rats, LiCl-induced vomiting in shrews and contextually-elicited anticipatory nausea in both rats (accompanied by elevation of 2-AG in the visceral insular cortex) and shrews. These effects were reversed by the CB1 antagonist/inverse agonist, SR141716. The MAGL inhibitor did not modify locomotion at any dose. An activity-based protein profiling analysis of samples of tissue collected from the visceral insular cortex in rats and whole brain tissues in shrews revealed that MJN110 selectively inhibited MAGL and the alternative 2-AG hydrolase, ABHD6.

Conclusions

MAGL inhibition by MJN110 which selectively elevates endogenous 2-AG has therapeutic potential in the treatment of acute nausea and vomiting as well as anticipatory nausea, a distressful symptom that is resistant to currently available treatments.

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Acknowledgment

The research reported here was supported research grants from the Natural sciences and Engineering Council of Canada (92957), from the Canadian Institute of Health Research (334086) to LAP and from the National Institutes of Health (P30DA033934, R01DA032933, P01DA009789) to AHL and (DA032933 and DA033760) to BFC.

Conflict of interest

There are no conflicts of interest.

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Authors and Affiliations

  1. Department of Psychology and Collaborative Neuroscience Program, University of Guelph, Guelph, ON, N1G2W1, Canada

    Linda A. Parker, Rachel Downey, Cheryl L. Limebeer, Erin M. Rock, Martin A. Sticht & Heather Morris

  2. The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA, 92037, USA

    Micah J. Niphakis & Benjamin F. Cravatt

  3. Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA, USA

    Rehab A. Abdullah & Aron H. Lichtman

Authors
  1. Linda A. Parker
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  2. Micah J. Niphakis
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  3. Rachel Downey
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  4. Cheryl L. Limebeer
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  5. Erin M. Rock
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  6. Martin A. Sticht
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  7. Heather Morris
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  8. Rehab A. Abdullah
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  9. Aron H. Lichtman
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  10. Benjamin F. Cravatt
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Correspondence to Linda A. Parker.

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Parker, L.A., Niphakis, M.J., Downey, R. et al. Effect of selective inhibition of monoacylglycerol lipase (MAGL) on acute nausea, anticipatory nausea, and vomiting in rats and Suncus murinus . Psychopharmacology 232, 583–593 (2015). https://doi.org/10.1007/s00213-014-3696-x

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