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Research ArticleBehavioral Pharmacology

Blockade of Endocannabinoid Hydrolytic Enzymes Attenuates Precipitated Opioid Withdrawal Symptoms in Mice

Divya Ramesh, Gracious R. Ross, Joel E. Schlosburg, Robert A. Owens, Rehab A. Abdullah, Steven G. Kinsey, Jonathan Z. Long, Daniel K. Nomura, Laura J. Sim-Selley, Benjamin F. Cravatt, Hamid I. Akbarali and Aron H. Lichtman
Journal of Pharmacology and Experimental Therapeutics October 2011, 339 (1) 173-185; DOI: https://doi.org/10.1124/jpet.111.181370
Divya Ramesh
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Gracious R. Ross
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Joel E. Schlosburg
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Robert A. Owens
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Rehab A. Abdullah
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Steven G. Kinsey
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Jonathan Z. Long
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Daniel K. Nomura
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Laura J. Sim-Selley
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Benjamin F. Cravatt
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Hamid I. Akbarali
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Aron H. Lichtman
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Abstract

Δ9-Tetrahydrocannbinol (THC), the primary active constituent of Cannabis sativa, has long been known to reduce opioid withdrawal symptoms. Although THC produces most of its pharmacological actions through the activation of CB1 and CB2 cannabinoid receptors, the role these receptors play in reducing the variety of opioid withdrawal symptoms remains unknown. The endogenous cannabinoids, N-arachidonoylethanolamine (anandamide; AEA) and 2-arachidonylglycerol (2-AG), activate both cannabinoid receptors but are rapidly metabolized by fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), respectively. The objective of this study was to test whether increasing AEA or 2-AG, via inhibition of their respective hydrolytic enzymes, reduces naloxone-precipitated morphine withdrawal symptoms in in vivo and in vitro models of opioid dependence. Morphine-dependent mice challenged with naloxone reliably displayed a profound withdrawal syndrome, consisting of jumping, paw tremors, diarrhea, and weight loss. THC and the MAGL inhibitor 4-nitrophenyl 4-(dibenzo[d][1,3]dioxol-5-yl(hydroxy)methyl)piperidine-1-carboxylate (JZL184) dose dependently reduced the intensity of most measures through the activation of CB1 receptors. JZL184 also attenuated spontaneous withdrawal signs in morphine-dependent mice. The FAAH inhibitor N-(pyridin-3-yl)-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)benzyl)-piperdine-1-carboxamide (PF-3845) reduced the intensity of naloxone-precipitated jumps and paw flutters through the activation of CB1 receptors but did not ameliorate incidence of diarrhea or weight loss. In the final series of experiments, we investigated whether JZL184 or PF-3845 would attenuate naloxone-precipitated contractions in morphine-dependent ilea. Both enzyme inhibitors attenuated the intensity of naloxone-induced contractions, although this model does not account mechanistically for the autonomic withdrawal responses (i.e., diarrhea) observed in vivo. These results indicate that endocannabinoid catabolic enzymes are promising targets to treat opioid dependence.

Footnotes

  • This research was supported by the National Institutes of Health National Institute on Drug Abuse [Grants K99-DA030908, 1F3–1DA026279, T32-DA007027, P01-DA009789, P01-DA017259, P50-DA005274, R01-DA024009, R01-DA014277, R01-DA005488].

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    doi:10.1124/jpet.111.181370.

  • ↵Embedded Image The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    THC
    [Δ]9-tetrahydrocannabinol
    AEA
    N-arachidonylethanolamine (anandamide)
    2-AG
    2-arachidonylglycerol
    FAAH
    fatty acid amide hydrolase
    MAGL
    monoacylglycerol lipase
    JZL184
    4-nitrophenyl 4-(dibenzo[d][1,3]dioxol-5-yl(hydroxy)methyl)piperidine-1-carboxylate
    PF-3845
    N-(pyridin-3-yl)-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)benzyl)-piperdine-1-carboxamide
    LC
    locus coeruleus
    PAF
    periaqueductal gray
    EFS
    electric field-stimulated
    SR144528
    N-[(1S)-endo-1,3,3,-trimethylbicyclo[2.2.1]heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide
    MS
    mass spectrometry
    PG
    prostaglandin
    JZL195
    4-nitrophenyl 4-(3-phenoxybenzyl)piperazine-1-carboxylate.

  • Received March 18, 2011.
  • Accepted June 28, 2011.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 339 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 339, Issue 1
1 Oct 2011
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Research ArticleBehavioral Pharmacology

Endocannabinoid Modulation of Opioid Withdrawal

Divya Ramesh, Gracious R. Ross, Joel E. Schlosburg, Robert A. Owens, Rehab A. Abdullah, Steven G. Kinsey, Jonathan Z. Long, Daniel K. Nomura, Laura J. Sim-Selley, Benjamin F. Cravatt, Hamid I. Akbarali and Aron H. Lichtman
Journal of Pharmacology and Experimental Therapeutics October 1, 2011, 339 (1) 173-185; DOI: https://doi.org/10.1124/jpet.111.181370

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Research ArticleBehavioral Pharmacology

Endocannabinoid Modulation of Opioid Withdrawal

Divya Ramesh, Gracious R. Ross, Joel E. Schlosburg, Robert A. Owens, Rehab A. Abdullah, Steven G. Kinsey, Jonathan Z. Long, Daniel K. Nomura, Laura J. Sim-Selley, Benjamin F. Cravatt, Hamid I. Akbarali and Aron H. Lichtman
Journal of Pharmacology and Experimental Therapeutics October 1, 2011, 339 (1) 173-185; DOI: https://doi.org/10.1124/jpet.111.181370
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