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Dual inhibition of endocannabinoid catabolic enzymes produces enhanced antiwithdrawal effects in morphine-dependent mice

Academic Article
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Overview

authors

  • Ramesh, D.
  • Gamage, T. F.
  • Vanuytsel, T.
  • Owens, R. A.
  • Abdullah, R. A.
  • Niphakis, M. J.
  • Shea-Donohue, T.
  • Cravatt, Benjamin
  • Lichtman, A. H.

publication date

  • May 2013

journal

  • Neuropsychopharmacology  Journal

abstract

  • Inhibition of the endocannabinoid catabolic enzymes, monoacylglycerol lipase (MAGL) or fatty acid amide hydrolase (FAAH) attenuates naloxone-precipitated opioid withdrawal signs in mice via activation of CB1 receptors. Complete FAAH inhibition blocks only a subset of withdrawal signs, whereas complete MAGL inhibition elicits enhanced antiwithdrawal efficacy, but is accompanied with some cannabimimetic side effects. Thus, the primary objective of the present study was to determine whether combined, full FAAH inhibition and partial MAGL represents an optimal strategy to reduce opioid withdrawal. To test this hypothesis, we examined whether combined administration of high-dose of the FAAH inhibitor PF-3845 and low-dose of the MAGL inhibitor JZL184, as well as the novel dual FAAH-MAGL inhibitor SA-57, which is 100-fold more potent in inhibiting FAAH than MAGL, would prevent spontaneous withdrawal in morphine-dependent mice, a model with greater face validity than precipitating withdrawal with μ-opioid receptor antagonists. Strikingly, a combination of low-dose JZL184 and high-dose PF-3845 as well as the dual inhibitor SA-57 reduced all abrupt withdrawal signs (ie, platform jumping, paw flutters, head shakes, diarrhea, and total body weight loss), but did not elicit any cannabimimetic side effects. In addition, JZL184 or PF-3845 blocked naloxone-precipitated hypersecretion in morphine-dependent small intestinal tissue. Collectively, these results are the first to show that endocannabinoid catabolic enzyme inhibitors reduce abrupt withdrawal in morpine-dependent mice and are effective in a novel in vitro model of opioid withdrawal. More generally, these findings support the idea that joint MAGL and FAAH inhibition represents a promising approach for the treatment of opioid dependence.

subject areas

  • Amidohydrolases
  • Animals
  • Benzodioxoles
  • Endocannabinoids
  • Enzyme Inhibitors
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred ICR
  • Monoacylglycerol Lipases
  • Morphine
  • Morphine Dependence
  • Piperidines
  • Substance Withdrawal Syndrome
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Research

keywords

  • 2-AG
  • anandamide
  • endocannabinoid
  • fatty acid amide hydrolase (FAAH)
  • monoacylglycerol lipase (MAGL)
  • morphine withdrawal
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Identity

PubMed Central ID

  • PMC3629394

International Standard Serial Number (ISSN)

  • 0893-133X

Digital Object Identifier (DOI)

  • 10.1038/npp.2012.269

PubMed ID

  • 23303065
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Additional Document Info

start page

  • 1039

end page

  • 1049

volume

  • 38

issue

  • 6

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