Cited by 44Cannabis and Cannabinoid ResearchPain Mechanisms and TreatmentsNeuroscience and Neuropharmacology Research

Prolonged monoacylglycerol lipase blockade causes equivalent cannabinoid receptor type 1 receptor-mediated adaptations in fatty acid amide hydrolase wild-type and knockout mice

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Schlosburg, Joel E., Kinsey, Steven G., Ignatowska-Jankowska, Bogna, Ramesh, Divya, Abdullah, Rehab A., Tao, Qing, Booker, Lamont, Long, Jonathan Z. +3 more·2014·The Journal of Pharmacology and Experimental Therapeutics

Abstract

Complementary genetic and pharmacological approaches to inhibit monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH), the primary hydrolytic enzymes of the respective endogenous cannabinoids 2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine, enable the exploration of potential therapeutic applications and physiologic roles of these enzymes. Complete and simultaneous inhibition of both FAAH and MAGL produces greatly enhanced cannabimimetic responses, including increased antinociception, and other cannabimimetic effects, far beyond those seen with inhibition of either enzyme alone. While cannabinoid receptor type 1 (CB1) function is maintained following chronic FAAH inactivation, prolonged excessive elevation of brain 2-AG levels, via MAGL inhibition, elicits both behavioral and molecular signs of cannabinoid tolerance and dependence. Here, we evaluated the consequences of a high dose of the MAGL inhibitor JZL184 [4-nitrophenyl 4-(dibenzo[d][1,3]dioxol-5-yl(hydroxy)methyl)piperidine-1-carboxylate; 40 mg/kg] given acutely or for 6 days in FAAH(-/-) and (+/+) mice. While acute administration of JZL184 to FAAH(-/-) mice enhanced the magnitude of a subset of cannabimimetic responses, repeated JZL184 treatment led to tolerance to its antinociceptive effects, cross-tolerance to the pharmacological effects of Δ(9)-tetrahydrocannabinol, decreases in CB1 receptor agonist-stimulated guanosine 5'-O-(3-[(35)S]thio)triphosphate binding, and dependence as indicated by rimonabant-precipitated withdrawal behaviors, regardless of genotype. Together, these data suggest that simultaneous elevation of both endocannabinoids elicits enhanced cannabimimetic activity but MAGL inhibition drives CB1 receptor functional tolerance and cannabinoid dependence.

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  • Chronic high-dose MAGL inhibition desensitizes CB1R and produces a phenotype more akin to CB1R antagonism than agonism.

    “the ability of chronic, high-dose MAGL inhibition to desensitize the CB1R and produce a phenotype that is more akin to CB1R antagonism than agonism (Schlosburg et al., 2010; Schlosburg et al., 2014).”

    From The endocannabinoid system as a target for novel anxiolytic drugs (2017) · cites this paper as Schlosburg et al., 2014

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  1. Ignatowska-Jankowska BM, Ghosh S, Crowe MS, Kinsey SG, Niphakis MJ, Abdullah RA, Tao Q, O' Neal ST, Walentiny DM, and Wiley JL, et al. (2014) In vivo char- acterization of the highly selective monoacylglycerol lipase inhibitor KML29: antinociceptive activity without cannabimimetic side effects. Br J Pharmacol 171: 1392-1407.

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Authors
Schlosburg, J. E., Kinsey, S. G., Ignatowska-Jankowska, B., Ramesh, D., Abdullah, R. A., Tao, Q., Booker, L., Long, J. Z., Selley, D. E., Cravatt, B. F., & Lichtman, A. H.
Affiliations
West Virginia University (US)
Venue
The Journal of Pharmacology and Experimental Therapeutics
Publisher
Elsevier BV
Published
2014-06
Volume
350
Issue
2
Pages
196-204
ISSN
0022-3565 (ISSN-L)
OpenAlex
W1986509856
Cited by
44
References
55
Citations by year
2026: 1 · 2025: 4 · 2023: 6 · 2022: 5 · 2021: 5 · 2020: 2 · 2019: 1 · 2018: 6 · 2017: 7 · 2015: 4 · 2014: 3
FWCI
3.39
Type
journal article
Language
en
Open access
Locations
  • Journal of Pharmacology and Experimental Therapeutics (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Institute on Drug Abuse (F31DA026279, P01DA009789, R01DA015197, R01DA032933, P30DA033934, F31DA028333, P01DA017259, T32DA007027)
Topics
  • Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
  • Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
monoacylglycerol lipase, fatty acid amide hydrolase, cannabinoid receptor type 1, 2-arachidonoylglycerol, JZL184, endocannabinoid system, cannabinoid tolerance, antinociception, cross-tolerance, tetrahydrocannabinol
MeSH terms
Fatty Acid Amide Hydrolases, Adaptation, Physiological, Amidohydrolases, Animals, Male, Mice, Inbred C57BL, Monoacylglycerol Lipases, Piperidines, Dronabinol, Mice, Knockout, Receptor, Cannabinoid, CB1, Mice, Benzodioxoles, Endocannabinoids

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