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Selective monoacylglycerol lipase inhibitors: antinociceptive versus cannabimimetic effects in mice.
- Source :
-
The Journal of pharmacology and experimental therapeutics [J Pharmacol Exp Ther] 2015 May; Vol. 353 (2), pp. 424-32. Date of Electronic Publication: 2015 Mar 11. - Publication Year :
- 2015
-
Abstract
- The endogenous cannabinoid 2-arachidonoylglycerol (2-AG) plays an important role in a variety of physiologic processes, but its rapid breakdown by monoacylglycerol lipase (MAGL) results in short-lived actions. Initial MAGL inhibitors were limited by poor selectivity and low potency. In this study, we tested JZL184 [4-nitrophenyl 4-[bis(2H-1,3-benzodioxol-5-yl)(hydroxy)methyl]piperidine-1-carboxylate] and MJN110 [2,5-dioxopyrrolidin-1-yl 4-(bis(4-chlorophenyl)methyl)piperazine-1-carboxylate], MAGL inhibitors that possess increased selectivity and potency, in mouse behavioral assays of neuropathic pain [chronic constriction injury (CCI) of the sciatic nerve], interoceptive cannabimimetic effects (drug-discrimination paradigm), and locomotor activity in an open field test. MJN110 (1.25 and 2.5 mg/kg) and JZL184 (16 and 40 mg/kg) significantly elevated 2-AG and decreased arachidonic acid but did not affect anandamide in whole brains. Both MAGL inhibitors significantly reduced CCI-induced mechanical allodynia with the following potencies [ED50 (95% confidence limit [CL]) values in mg/kg: MJN110 (0.43 [0.30-0.63]) > JZL184 (17.8 [11.6-27.4])] and also substituted for the potent cannabinoid receptor agonist CP55,940 [2-[(1R,2R,5R)-5-hydroxy-2-(3-hydroxypropyl)cyclohexyl]-5-(2-methyloctan-2-yl)phenol] in the drug-discrimination paradigm [ED50 (95% CL) values in mg/kg: MJN110 (0.84 [0.69-1.02]) > JZL184 (24.9 [14.6-42.5])]; however, these compounds elicited differential effects on locomotor behavior. Similar to cannabinoid 1 (CB1) receptor agonists, JZL184 produced hypomotility, whereas MJN110 increased locomotor behavior and did not produce catalepsy or hypothermia. Although both drugs substituted for CP55,940 in the drug discrimination assay, MJN110 was more potent in reversing allodynia in the CCI model than in producing CP55,940-like effects. Overall, these results suggest that MAGL inhibition may alleviate neuropathic pain, while displaying limited cannabimimetic effects compared with direct CB1 receptor agonists.<br /> (Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.)
- Subjects :
- Analgesics therapeutic use
Animals
Benzodioxoles pharmacology
Benzodioxoles therapeutic use
Biomimetic Materials therapeutic use
Brain drug effects
Brain metabolism
Carbamates pharmacology
Carbamates therapeutic use
Constriction
Endocannabinoids metabolism
Enzyme Inhibitors therapeutic use
Hyperalgesia drug therapy
Hyperalgesia etiology
Male
Mice
Mice, Inbred C57BL
Motor Activity drug effects
Neuralgia drug therapy
Neuralgia etiology
Piperidines pharmacology
Piperidines therapeutic use
Succinimides pharmacology
Succinimides therapeutic use
Analgesics pharmacology
Biomimetic Materials pharmacology
Cannabinoids metabolism
Enzyme Inhibitors pharmacology
Monoacylglycerol Lipases antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1521-0103
- Volume :
- 353
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- The Journal of pharmacology and experimental therapeutics
- Publication Type :
- Academic Journal
- Accession number :
- 25762694
- Full Text :
- https://doi.org/10.1124/jpet.114.222315