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Inhibition of monoacylglycerol lipase attenuates vomiting in Suncus murinus and 2-arachidonoyl glycerol attenuates nausea in rats.
Br J Pharmacol. 2012 Apr; 165(8):2425-35.BJ

Abstract

BACKGROUND AND PURPOSE

To evaluate the role of 2-arachidonoyl glycerol (2AG) in the regulation of nausea and vomiting using animal models of vomiting and of nausea-like behaviour (conditioned gaping).

EXPERIMENTAL APPROACH

Vomiting was assessed in shrews (Suncus murinus), pretreated with JZL184, a selective monoacylglycerol lipase (MAGL) inhibitor which elevates endogenous 2AG levels, 1 h before administering the emetogenic compound, LiCl. Regulation of nausea-like behaviour in rats by exogenous 2AG or its metabolite arachidonic acid (AA) was assessed, using the conditioned gaping model. The role of cannabinoid CB(1) receptors, CB(2) receptors and cyclooxygenase (COX) inhibition in suppression of vomiting or nausea-like behaviour was assessed.

KEY RESULTS

JZL184 dose-dependently suppressed vomiting in shrews, an effect prevented by pretreatment with the CB(1) receptor inverse agonist/antagonist, AM251. In shrew brain tissue, JZL184 inhibited MAGL activity in vivo. In rats, 2AG suppressed LiCl-induced conditioned gaping but this effect was not prevented by AM251 or the CB(2) receptor antagonist, AM630. Instead, the COX inhibitor, indomethacin, prevented suppression of conditioned gaping by 2AG or AA. However, when rats were pretreated with a high dose of JZL184 (40 mg·kg(-1)), suppression of gaping by 2AG was partially reversed by AM251. Suppression of conditioned gaping was not due to interference with learning because the same dose of 2AG did not modify the strength of conditioned freezing to a shock-paired tone.

CONCLUSIONS AND IMPLICATIONS

Our results suggest that manipulations that elevate 2AG may have anti-emetic or anti-nausea potential.

LINKED ARTICLES

This article is part of a themed section on Cannabinoids in Biology and Medicine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-8. To view Part I of Cannabinoids in Biology and Medicine visit http://dx.doi.org/10.1111/bph.2011.163.issue-7.

Authors+Show Affiliations

Department of Psychology and Collaborative Neuroscience Program, University of Guelph, Guelph, ON, Canada.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21470205

Citation

Sticht, Martin A., et al. "Inhibition of Monoacylglycerol Lipase Attenuates Vomiting in Suncus Murinus and 2-arachidonoyl Glycerol Attenuates Nausea in Rats." British Journal of Pharmacology, vol. 165, no. 8, 2012, pp. 2425-35.
Sticht MA, Long JZ, Rock EM, et al. Inhibition of monoacylglycerol lipase attenuates vomiting in Suncus murinus and 2-arachidonoyl glycerol attenuates nausea in rats. Br J Pharmacol. 2012;165(8):2425-35.
Sticht, M. A., Long, J. Z., Rock, E. M., Limebeer, C. L., Mechoulam, R., Cravatt, B. F., & Parker, L. A. (2012). Inhibition of monoacylglycerol lipase attenuates vomiting in Suncus murinus and 2-arachidonoyl glycerol attenuates nausea in rats. British Journal of Pharmacology, 165(8), 2425-35. https://doi.org/10.1111/j.1476-5381.2011.01407.x
Sticht MA, et al. Inhibition of Monoacylglycerol Lipase Attenuates Vomiting in Suncus Murinus and 2-arachidonoyl Glycerol Attenuates Nausea in Rats. Br J Pharmacol. 2012;165(8):2425-35. PubMed PMID: 21470205.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibition of monoacylglycerol lipase attenuates vomiting in Suncus murinus and 2-arachidonoyl glycerol attenuates nausea in rats. AU - Sticht,Martin A, AU - Long,Jonathan Z, AU - Rock,Erin M, AU - Limebeer,Cheryl L, AU - Mechoulam,Raphael, AU - Cravatt,Benjamin F, AU - Parker,Linda A, PY - 2011/4/8/entrez PY - 2011/4/8/pubmed PY - 2012/7/28/medline SP - 2425 EP - 35 JF - British journal of pharmacology JO - Br J Pharmacol VL - 165 IS - 8 N2 - BACKGROUND AND PURPOSE: To evaluate the role of 2-arachidonoyl glycerol (2AG) in the regulation of nausea and vomiting using animal models of vomiting and of nausea-like behaviour (conditioned gaping). EXPERIMENTAL APPROACH: Vomiting was assessed in shrews (Suncus murinus), pretreated with JZL184, a selective monoacylglycerol lipase (MAGL) inhibitor which elevates endogenous 2AG levels, 1 h before administering the emetogenic compound, LiCl. Regulation of nausea-like behaviour in rats by exogenous 2AG or its metabolite arachidonic acid (AA) was assessed, using the conditioned gaping model. The role of cannabinoid CB(1) receptors, CB(2) receptors and cyclooxygenase (COX) inhibition in suppression of vomiting or nausea-like behaviour was assessed. KEY RESULTS: JZL184 dose-dependently suppressed vomiting in shrews, an effect prevented by pretreatment with the CB(1) receptor inverse agonist/antagonist, AM251. In shrew brain tissue, JZL184 inhibited MAGL activity in vivo. In rats, 2AG suppressed LiCl-induced conditioned gaping but this effect was not prevented by AM251 or the CB(2) receptor antagonist, AM630. Instead, the COX inhibitor, indomethacin, prevented suppression of conditioned gaping by 2AG or AA. However, when rats were pretreated with a high dose of JZL184 (40 mg·kg(-1)), suppression of gaping by 2AG was partially reversed by AM251. Suppression of conditioned gaping was not due to interference with learning because the same dose of 2AG did not modify the strength of conditioned freezing to a shock-paired tone. CONCLUSIONS AND IMPLICATIONS: Our results suggest that manipulations that elevate 2AG may have anti-emetic or anti-nausea potential. LINKED ARTICLES: This article is part of a themed section on Cannabinoids in Biology and Medicine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-8. To view Part I of Cannabinoids in Biology and Medicine visit http://dx.doi.org/10.1111/bph.2011.163.issue-7. SN - 1476-5381 UR - https://www.unboundmedicine.com/medline/citation/21470205/Inhibition_of_monoacylglycerol_lipase_attenuates_vomiting_in_Suncus_murinus_and_2_arachidonoyl_glycerol_attenuates_nausea_in_rats_ L2 - https://doi.org/10.1111/j.1476-5381.2011.01407.x DB - PRIME DP - Unbound Medicine ER -