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Chronic monoacylglycerol lipase blockade causes functional antagonism of the endocannabinoid system

Abstract

Prolonged exposure to drugs of abuse, such as cannabinoids and opioids, leads to pharmacological tolerance and receptor desensitization in the nervous system. We found that a similar form of functional antagonism was produced by sustained inactivation of monoacylglycerol lipase (MAGL), the principal degradative enzyme for the endocannabinoid 2-arachidonoylglycerol. After repeated administration, the MAGL inhibitor JZL184 lost its analgesic activity and produced cross-tolerance to cannabinoid receptor (CB1) agonists in mice, effects that were phenocopied by genetic disruption of Mgll (encoding MAGL). Chronic MAGL blockade also caused physical dependence, impaired endocannabinoid-dependent synaptic plasticity and desensitized brain CB1 receptors. These data contrast with blockade of fatty acid amide hydrolase, an enzyme that degrades the other major endocannabinoid anandamide, which produced sustained analgesia without impairing CB1 receptors. Thus, individual endocannabinoids generate distinct analgesic profiles that are either sustained or transitory and associated with agonism and functional antagonism of the brain cannabinoid system, respectively.

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Figure 1: Characterization of endocannabinoid metabolism in mice with chronic disruptions of MAGL or FAAH.
Figure 2: Prolonged blockade of MAGL and FAAH causes differential analgesic tolerance.
Figure 3: Chronic disruption of MAGL produces behavioral cross-tolerance to a subset of the pharmacological effects of the cannabinoid receptor agonist WIN55,212-2.
Figure 4: Chronic disruption of MAGL produces CB1 receptor downregulation and desensitization in the mouse brain.
Figure 5: Regional changes in cannabinoid agonist–stimulated [35S]GTPγS binding following chronic disruption of MAGL.
Figure 6: Chronic disruption of MAGL impairs CB1-dependent forms of synaptic plasticity.

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References

  1. Pacher, P., Bátkai, S. & Kunos, G. The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol. Rev. 58, 389–462 (2006).

    Article  CAS  Google Scholar 

  2. Devane, W.A. et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 258, 1946–1949 (1992).

    Article  CAS  Google Scholar 

  3. Mechoulam, R. et al. Identification of an endogenous 2-monoglyceride, present in canine gut, that binds cannabinoid receptors. Biochem. Pharmacol. 50, 83–90 (1995).

    Article  CAS  Google Scholar 

  4. Sugiura, T. et al. 2-Arachidonylglycerol: a possible endogenous cannabinoid receptor ligand in brain. Biochem. Biophys. Res. Commun. 215, 89–97 (1995).

    Article  CAS  Google Scholar 

  5. Mackie, K. Cannabinoid receptors as therapeutic targets. Annu. Rev. Pharmacol. Toxicol. 46, 101–122 (2006).

    Article  CAS  Google Scholar 

  6. Marsicano, G. et al. CB1 cannabinoid receptors and on-demand defense against excitotoxicity. Science 302, 84–88 (2003).

    Article  CAS  Google Scholar 

  7. Fowler, C.J. The cannabinoid system and its pharmacological manipulation–a review, with emphasis upon the uptake and hydrolysis of anandamide. Fundam. Clin. Pharmacol. 20, 549–562 (2006).

    Article  CAS  Google Scholar 

  8. Ahn, K., McKinney, M.K. & Cravatt, B.F. Enzymatic pathways that regulate endocannabinoid signaling in the nervous system. Chem. Rev. 108, 1687–1707 (2008).

    Article  CAS  Google Scholar 

  9. Deutsch, D.G. & Chin, S.A. Enzymatic synthesis and degradation of anandamide, a cannabinoid receptor agonist. Biochem. Pharmacol. 46, 791–796 (1993).

    Article  CAS  Google Scholar 

  10. Cravatt, B.F. et al. Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase. Proc. Natl. Acad. Sci. USA 98, 9371–9376 (2001).

    Article  CAS  Google Scholar 

  11. Lichtman, A.H., Shelton, C.C., Advani, T. & Cravatt, B.F. Mice lacking fatty acid amide hydrolase exhibit a cannabinoid receptor–mediated phenotypic hypoalgesia. Pain 109, 319–327 (2004).

    Article  CAS  Google Scholar 

  12. Kathuria, S. et al. Modulation of anxiety through blockade of anandamide hydrolysis. Nat. Med. 9, 76–81 (2003).

    Article  CAS  Google Scholar 

  13. Lichtman, A.H. et al. Reversible inhibitors of fatty acid amide hydrolase that promote analgesia: evidence for an unprecedented combination of potency and selectivity. J. Pharmacol. Exp. Ther. 311, 441–448 (2004).

    Article  CAS  Google Scholar 

  14. Jhaveri, M.D., Richardson, D., Kendall, D.A., Barrett, D.A. & Chapman, V. Analgesic effects of fatty acid amide hydrolase inhibition in a rat model of neuropathic pain. J. Neurosci. 26, 13318–13327 (2006).

    Article  CAS  Google Scholar 

  15. Ahn, K. et al. Discovery and characterization of a highly selective FAAH inhibitor that reduces inflammatory pain. Chem. Biol. 16, 411–420 (2009).

    Article  CAS  Google Scholar 

  16. Cravatt, B.F. et al. Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides. Nature 384, 83–87 (1996).

    Article  CAS  Google Scholar 

  17. Long, J.Z. et al. Selective blockade of 2-arachidonoylglycerol hydrolysis produces cannabinoid behavioral effects. Nat. Chem. Biol. 5, 37–44 (2009).

    Article  CAS  Google Scholar 

  18. Kinsey, S.G. et al. Blockade of endocannabinoid-degrading enzymes attenuates neuropathic pain. J. Pharmacol. Exp. Ther. 330, 902–910 (2009).

    Article  CAS  Google Scholar 

  19. Long, J.Z. et al. Dual blockade of FAAH and MAGL identifies behavioral processes regulated by endocannabinoid crosstalk in vivo. Proc. Natl. Acad. Sci. USA 106, 20270–20275 (2009).

    Article  CAS  Google Scholar 

  20. Pan, B. et al. Blockade of 2-arachidonoylglycerol hydrolysis by selective monoacylglycerol lipase inhibitor 4-nitrophenyl 4-(dibenzo[d][1,3]dioxol-5-yl(hydroxy)methyl)piperidine-1-carboxylate (JZL184) enhances retrograde endocannabinoid signaling. J. Pharmacol. Exp. Ther. 331, 591–597 (2009).

    Article  CAS  Google Scholar 

  21. Straiker, A. et al. Monoacylglycerol lipase limits the duration of endocannabinoid-mediated depolarization-induced suppression of excitation in autaptic hippocampal neurons. Mol. Pharmacol. 76, 1220–1227 (2009).

    Article  CAS  Google Scholar 

  22. Wilson, R.I. & Nicoll, R.A. Endocannabinoid signaling in the brain. Science 296, 678–682 (2002).

    Article  CAS  Google Scholar 

  23. Tanimura, A. et al. The endocannabinoid 2-arachidonoylglycerol produced by diacylglycerol lipase alpha mediates retrograde suppression of synaptic transmission. Neuron 65, 320–327 (2010).

    Article  CAS  Google Scholar 

  24. Gao, Y. et al. Loss of retrograde endocannabinoid signaling and reduced adult neurogenesis in diacylglycerol lipase knock-out mice. J. Neurosci. 30, 2017–2024 (2010).

    Article  CAS  Google Scholar 

  25. Haller, J. et al. Interactions between environmental aversiveness and the anxiolytic effects of enhanced cannabinoid signaling by FAAH inhibition in rats. Psychopharmacology (Berl.) 204, 607–616 (2009).

    Article  CAS  Google Scholar 

  26. Liu, Y., Patricelli, M.P. & Cravatt, B.F. Activity-based protein profiling: the serine hydrolases. Proc. Natl. Acad. Sci. USA 96, 14694–14699 (1999).

    Article  CAS  Google Scholar 

  27. Blankman, J.L., Simon, G.M. & Cravatt, B.F. A comprehensive profile of brain enzymes that hydrolyze the endocannabinoid 2-arachidonoylglycerol. Chem. Biol. 14, 1347–1356 (2007).

    Article  CAS  Google Scholar 

  28. Nomura, D.K. et al. Activation of the endocannabinoid system by organophosphorus nerve agents. Nat. Chem. Biol. 4, 373–378 (2008).

    Article  CAS  Google Scholar 

  29. Long, J.Z., Nomura, D.K. & Cravatt, B.F. Characterization of monoacylglycerol lipase inhibition reveals differences in central and peripheral endocannabinoid metabolism. Chem. Biol. 16, 744–753 (2009).

    Article  CAS  Google Scholar 

  30. Aceto, M.D., Scates, S.M., Lowe, J.A. & Martin, B.R. Cannabinoid precipitated withdrawal by the selective cannabinoid receptor antagonist, SR 141716A. Eur. J. Pharmacol. 282, R1–R2 (1995).

    Article  CAS  Google Scholar 

  31. Falenski, K.W. et al. Faah−/− mice display differential tolerance, dependence and cannabinoid receptor adaptation following Δ9-tetrahydrocannabinol and anandamide administration. Neuropsychopharmacology 35, 1775–1787 (2010).

    Article  CAS  Google Scholar 

  32. Lichtman, A.H., Hawkins, E.G., Griffin, G. & Cravatt, B.F. Pharmacological activity of fatty acid amides is regulated, but not mediated, by fatty acid amide hydrolase in vivo. J. Pharmacol. Exp. Ther. 302, 73–79 (2002).

    Article  CAS  Google Scholar 

  33. Wilson, R.I., Kunos, G. & Nicoll, R.A. Presynaptic specificity of endocannabinoid signaling in the hippocampus. Neuron 31, 453–462 (2001).

    Article  CAS  Google Scholar 

  34. Kreitzer, A.C. & Regehr, W.G. Retrograde signaling by endocannabinoids. Curr. Opin. Neurobiol. 12, 324–330 (2002).

    Article  CAS  Google Scholar 

  35. Monory, K. et al. Genetic dissection of behavioural and autonomic effects of Δ9-tetrahydrocannabinol in mice. PLoS Biol. 5, e269 (2007).

    Article  Google Scholar 

  36. Lichtman, A.H. & Martin, B.R. Cannabinoid tolerance and dependence. Handb. Exp. Pharmacol. 168, 691–717 (2005).

    Article  CAS  Google Scholar 

  37. Sim, L.J., Hampson, R.E., Deadwyler, S.A. & Childers, S.R. Effects of chronic treatment with Δ9-tetrahydrocannabinol on cannabinoid-stimulated [35S]GTPγS autoradiography in rat brain. J. Neurosci. 16, 8057–8066 (1996).

    Article  CAS  Google Scholar 

  38. Romero, J. et al. Effects of chronic exposure to Δ9-tetrahydrocannabinol on cannabinoid receptor binding and mRNA levels in several rat brain regions. Brain Res. Mol. Brain Res. 46, 100–108 (1997).

    Article  CAS  Google Scholar 

  39. Sun, M., Lee, C.J. & Shin, H.S. Reduced nicotinic receptor function in sympathetic ganglia is responsible for the hypothermia in the acetylcholinesterase knockout mouse. J. Physiol. (Lond.) 578, 751–764 (2007).

    Article  CAS  Google Scholar 

  40. Lanoir, J., Hilaire, G. & Seif, I. Reduced density of functional 5-HT1A receptors in the brain, medulla and spinal cord of monoamine oxidase-A knockout mouse neonates. J. Comp. Neurol. 495, 607–623 (2006).

    Article  CAS  Google Scholar 

  41. Luk, T. et al. Identification of a potent and highly efficacious, yet slowly desensitizing CB1 cannabinoid receptor agonist. Br. J. Pharmacol. 142, 495–500 (2004).

    Article  CAS  Google Scholar 

  42. Hillard, C.J. Biochemistry and pharmacology of the endocannabinoids arachidonylethanolamide and 2-arachidonylglycerol. Prostaglandins Other Lipid Mediat. 61, 3–18 (2000).

    Article  CAS  Google Scholar 

  43. Sim-Selley, L.J. & Martin, B.R. Effect of chronic administration of R-(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-b enzoxazinyl]-(1-naphthalenyl)methanone mesylate (WIN55,212–2) or Δ9-tetrahydrocannabinol on cannabinoid receptor adaptation in mice. J. Pharmacol. Exp. Ther. 303, 36–44 (2002).

    Article  CAS  Google Scholar 

  44. Caillé, S., Alvarez-Jaimes, L., Polis, I., Stouffer, D.G. & Parsons, L.H. Specific alterations of extracellular endocannabinoid levels in the nucleus accumbens by ethanol, heroin and cocaine self-administration. J. Neurosci. 27, 3695–3702 (2007).

    Article  Google Scholar 

  45. Ohno-Shosaku, T., Maejima, T. & Kano, M. Endogenous cannabinoids mediate retrograde signals from depolarized postsynaptic neurons to presynaptic terminals. Neuron 29, 729–738 (2001).

    Article  CAS  Google Scholar 

  46. Fan, F., Compton, D.R., Ward, S., Melvin, L. & Martin, B.R. Development of cross-tolerance between Δ9-tetrahydrocannabinol, CP 55,940 and WIN 55,212. J. Pharmacol. Exp. Ther. 271, 1383–1390 (1994).

    CAS  PubMed  Google Scholar 

  47. Pertwee, R.G. & Wickens, A.P. Enhancement by chlordiazepoxide of catalepsy induced in rats by intravenous or intrapallidal injections of enantiomeric cannabinoids. Neuropharmacology 30, 237–244 (1991).

    Article  CAS  Google Scholar 

  48. Lichtman, A.H., Cook, S.A. & Martin, B.R. Investigation of brain sites mediating cannabinoid-induced antinociception in rats: evidence supporting periaqueductal gray involvement. J. Pharmacol. Exp. Ther. 276, 585–593 (1996).

    CAS  PubMed  Google Scholar 

  49. Thomas, E.A. et al. Clozapine increases apolipoprotein D expression in rodent brain: towards a mechanism for neuroleptic pharmacotherapy. J. Neurochem. 76, 789–796 (2001).

    Article  CAS  Google Scholar 

  50. Schlosburg, J.E. et al. Inhibitors of endocannabinoid-metabolizing enzymes reduce precipitated withdrawal responses in THC-dependent mice. AAPS J. 11, 342–352 (2009).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank S. Niessen and H. Hoover for assistance with proteomics studies, I. Beletskaya and R. Abdullah for technical support and the Cravatt and Lichtman laboratories for critical reading of the manuscript. This work was supported by the US National Institutes of Health (grants DA017259, DA009789, DA025285, DA005274, DA015683, DA03672, DA005274, DA07027, DA014277, DA023758 and DA024741), Ruth L. Kirschstein US National Institutes of Health Predoctoral Fellowships (DA026261 to J.L.B., DA026279 to J.E.S., DA028333 to L.B. and DA023758 to P.T.N.), the American Cancer Society (D.K.N.) and the Skaggs Institute for Chemical Biology.

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J.E.S. performed behavioral and receptor adaptation experiments. J.L.B. performed the metabolic biochemistry, proteomic and in situ hybridization experiments and contributed to behavioral experiments. J.Z.L. contributed to metabolic biochemistry and behavioral experiments. D.K.N., S.G.K., D.R. and L.B. contributed to behavioral experiments. B.P. performed the electrophysiology experiments. P.T.N. and J.J.B. contributed to receptor adaptation experiments. E.A.T. contributed to the design and interpretation of in situ hybridization experiments. D.E.S and L.J.S.-S. contributed to the design and interpretation of receptor adaptation experiments. Q.-s.L. contributed to the design and interpretation of electrophysiology experiments. A.H.L. and B.F.C. supervised the design, execution and interpretation of the experiments and wrote the manuscript.

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Correspondence to Aron H Lichtman or Benjamin F Cravatt.

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The authors declare no competing financial interests.

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Schlosburg, J., Blankman, J., Long, J. et al. Chronic monoacylglycerol lipase blockade causes functional antagonism of the endocannabinoid system. Nat Neurosci 13, 1113–1119 (2010). https://doi.org/10.1038/nn.2616

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