Advertisement

Fatty Acid Amide Hydrolase and Monoacylglycerol Lipase Inhibitors Produce Anti-Allodynic Effects in Mice Through Distinct Cannabinoid Receptor Mechanisms

      Abstract

      The endocannabinoids anandamide and 2-arachidonoylglycerol are predominantly regulated by the respective catabolic enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). Inhibition of these enzymes elevates endocannabinoid levels and attenuates neuropathic pain. In the present study, CB1 and CB2 receptor-deficient mice were subjected to chronic constriction injury (CCI) of the sciatic nerve to examine the relative contribution of each receptor for the anti-allodynic effects of the FAAH inhibitor, PF-3845, and the MAGL inhibitor, JZL184. CCI caused marked hypersensitivity to mechanical and cold stimuli, which was not altered by deletion of either the CB1 or CB2 receptor, but was attenuated by gabapentin, as well as by each enzyme inhibitor. Whereas PF-3845 lacked anti-allodynic efficacy in both knockout lines, JZL184 did not produce anti-allodynic effects in CB1 (-/-) mice, but retained its anti-allodynic effects in CB2 (-/-) mice. These data indicate that FAAH and MAGL inhibitors reduce nerve injury-related hyperalgesic states through distinct cannabinoid receptor mechanisms of action. In conclusion, although endogenous cannabinoids do not appear to play a tonic role in long-term expression of neuropathic pain states, both FAAH and MAGL represent potential therapeutic targets for the development of pharmacological agents to treat chronic pain resulting from nerve injury.

      Perspective

      This article presents data addressing the cannabinoid receptor mechanisms underlying the anti-allodynic actions of endocannabinoid catabolic enzyme inhibitors in the mouse sciatic nerve ligation model. Fatty acid amide hydrolase and monoacylglycerol lipase inhibitors reduced allodynia through distinct cannabinoid receptor mechanisms. These enzymes offer potential targets to treat neuropathic pain.

      Key words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to The Journal of Pain
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Agarwal N.
        • Pacher P.
        • Tegeder I.
        • Amaya F.
        • Constantin C.E.
        • Brenner G.J.
        • Rubino T.
        • Michalski C.W.
        • Marsicano G.
        • Monory K.
        • Mackie K.
        • Marian C.
        • Batkai S.
        • Parolaro D.
        • Fischer M.J.
        • Reeh P.
        • Kunos G.
        • Kress M.
        • Lutz B.
        • Woolf C.J.
        • Kuner R.
        Cannabinoids mediate analgesia largely via peripheral type 1 cannabinoid receptors in nociceptors.
        Nat Neurosci. 2007; 10: 870-879
        • Ahn K.
        • Johnson D.S.
        • Mileni M.
        • Beidler D.
        • Long J.Z.
        • McKinney M.K.
        • Weerapana E.
        • Sadagopan N.
        • Liimatta M.
        • Smith S.E.
        • Lazerwith S.
        • Stiff C.
        • Kamtekar S.
        • Bhattacharya K.
        • Zhang Y.
        • Swaney S.
        • Van Becelaere K.
        • Stevens R.C.
        • Cravatt B.F.
        Discovery and characterization of a highly selective FAAH inhibitor that reduces inflammatory pain.
        Chem Biol. 2009; 16: 411-420
        • Blankman J.L.
        • Simon G.M.
        • Cravatt B.F.
        A comprehensive profile of brain enzymes that hydrolyze the endocannabinoid 2-arachidonoylglycerol.
        Chem Biol. 2007; 14: 1347-1356
        • Chang L.
        • Luo L.
        • Palmer J.A.
        • Sutton S.
        • Wilson S.J.
        • Barbier A.J.
        • Breitenbucher J.G.
        • Chaplan S.R.
        • Webb M.
        Inhibition of fatty acid amide hydrolase produces analgesia by multiple mechanisms.
        Br J Pharmacol. 2006; 148: 102-113
        • Chaplan S.R.
        • Bach F.W.
        • Pogrel J.W.
        • Chung J.M.
        • Yaksh T.L.
        Quantitative assessment of tactile allodynia in the rat paw.
        J Neurosci Methods. 1994; 53: 55-63
        • Choi Y.
        • Yoon Y.W.
        • Na H.S.
        • Kim S.H.
        • Chung J.M.
        Behavioral signs of ongoing pain and cold allodynia in a rat model of neuropathic pain.
        Pain. 1994; 59: 369-376
        • Cravatt B.F.
        • Giang D.K.
        • Mayfield S.P.
        • Boger D.L.
        • Lerner R.A.
        • Gilula N.B.
        Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides.
        Nature. 1996; 384: 83-87
        • Cravatt B.F.
        • Demarest K.
        • Patricelli M.P.
        • Bracey M.H.
        • Giang D.K.
        • Martin B.R.
        • Lichtman A.H.
        Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase.
        Proc Natl Acad Sci U S A. 2001; 98: 9371-9376
        • Decosterd I.
        • Woolf C.J.
        Spared nerve injury: An animal model of persistent peripheral neuropathic pain.
        Pain. 2000; 87: 149-158
        • Devane W.A.
        • Hanus L.
        • Breuer A.
        • Pertwee R.G.
        • Stevenson L.A.
        • Griffin G.
        • Gibson D.
        • Mandelbaum A.
        • Etinger A.
        • Mechoulam R.
        Isolation and structure of a brain constituent that binds to the cannabinoid receptor.
        Sci. 1992; 258: 1946-1949
        • Dinh T.P.
        • Carpenter D.
        • Leslie F.M.
        • Freund T.F.
        • Katona I.
        • Sensi S.L.
        • Kathuria S.
        • Piomelli D.
        Brain monoglyceride lipase participating in endocannabinoid inactivation.
        Proc Natl Acad Sci U S A. 2002; 99: 10819-10824
        • Gaoni Y.
        • Mechoulam R.
        Isolation, structure, and partial synthesis of an active constituent of hashish.
        J Amer Chem Soc. 1964; 86: 1646-1647
        • Guasti L.
        • Richardson D.
        • Jhaveri M.
        • Eldeeb K.
        • Barrett D.
        • Elphick M.R.
        • Alexander S.P.
        • Kendall D.
        • Michael G.J.
        • Chapman V.
        Minocycline treatment inhibits microglial activation and alters spinal levels of endocannabinoids in a rat model of neuropathic pain.
        Mol Pain. 2009; 5: 35
        • Kinsey S.G.
        • Long J.Z.
        • O'Neal S.T.
        • Abdullah R.A.
        • Poklis J.L.
        • Boger D.L.
        • Cravatt B.F.
        • Lichtman A.H.
        Blockade of endocannabinoid-degrading enzymes attenuates neuropathic pain.
        J Pharmacol Exp Ther. 2009; 330: 902-910
        • Kogan N.M.
        • Mechoulam R.
        Cannabinoids in health and disease.
        Dialogues Clin Neurosci. 2007; 9: 413-430
        • La Rana G.
        • Russo R.
        • D'Agostino G.
        • Sasso O.
        • Raso G.M.
        • Iacono A.
        • Meli R.
        • Piomelli D.
        • Calignano A.
        AM404, an anandamide transport inhibitor, reduces plasma extravasation in a model of neuropathic pain in rat: Role for cannabinoid receptors.
        Neuropharmacology. 2008; 54: 521-529
        • Landsman R.S.
        • Burkey T.H.
        • Consroe P.
        • Roeske W.R.
        • Yamamura H.I.
        SR141716A is an inverse agonist at the human cannabinoid CB1 receptor.
        Eur J Pharmacol. 1997; 334: R1-R2
        • 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. 2004; 109: 319-327
        • Long J.Z.
        • Li W.
        • Booker L.
        • Burston J.J.
        • Kinsey S.G.
        • Schlosburg J.E.
        • Pavon F.J.
        • Serrano A.M.
        • Selley D.E.
        • Parsons L.H.
        • Lichtman A.H.
        • Cravatt B.F.
        Selective blockade of 2-arachidonoylglycerol hydrolysis produces cannabinoid behavioral effects.
        Nat Chem Biol. 2009; 5: 37-44
        • Long J.Z.
        • Nomura D.K.
        • Vann R.E.
        • Walentiny D.M.
        • Booker L.
        • Jin X.
        • Burston J.J.
        • Sim-Selley L.J.
        • Lichtman A.H.
        • Wiley J.L.
        • Cravatt B.F.
        Dual blockade of FAAH and MAGL identifies behavioral processes regulated by endocannabinoid crosstalk in vivo.
        Proc Natl Acad Sci U S A. 2009; 106: 20270-20275
        • Luongo L.
        • Palazzo E.
        • Tambaro S.
        • Giordano C.
        • Gatta L.
        • Scafuro M.A.
        • Rossi F.S.
        • Lazzari P.
        • Pani L.
        • de Novellis V.
        • Malcangio M.
        • Maione S.
        1-(2',4'-dichlorophenyl)-6-methyl-N-cyclohexylamine-1,4-dihydroindeno[1,2-c]pyrazole-3-carboxamide, a novel CB2 agonist, alleviates neuropathic pain through functional microglial changes in mice.
        Neurobiol Dis. 2010; 37: 177-185
        • Malmberg A.B.
        • Basbaum A.I.
        Partial sciatic nerve injury in the mouse as a model of neuropathic pain: Behavioral and neuroanatomical correlates.
        Pain. 1998; 76: 215-222
        • Matsuda L.A.
        • Lolait S.J.
        • Brownstein M.J.
        • Young A.C.
        • Bonner T.I.
        Structure of a cannabinoid receptor and functional expression of the cloned cDNA.
        Nature. 1990; 346: 561-564
        • Mechoulam R.
        • Ben-Shabat S.
        • Hanus L.
        • Ligumsky M.
        • Kaminski N.
        • Schatz A.
        • Gopher A.
        • Almog S.
        • Martin B.
        • Compton D.
        • Pertwee R.
        • Griffin G.
        • Bayewitch M.
        • Barg J.
        • Vogel Z.
        Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors.
        Biochem Pharmacol. 1995; 50: 83-90
        • Mitrirattanakul S.
        • Ramakul N.
        • Guerrero A.V.
        • Matsuka Y.
        • Ono T.
        • Iwase H.
        • Mackie K.
        • Faull K.F.
        • Spigelman I.
        Site-specific increases in peripheral cannabinoid receptors and their endogenous ligands in a model of neuropathic pain.
        Pain. 2006; 126: 102-114
        • Munro S.
        • Thomas K.L.
        • Abu-Shaar M.
        Molecular characterization of a peripheral receptor for cannabinoids.
        Nature. 1993; 365: 61-64
        • Palazzo E.
        • de Novellis V.
        • Petrosino S.
        • Marabese I.
        • Vita D.
        • Giordano C.
        • Di Marzo V.
        • Mangoni G.S.
        • Rossi F.
        • Maione S.
        Neuropathic pain and the endocannabinoid system in the dorsal raphe: Pharmacological treatment and interactions with the serotonergic system.
        Eur J Neurosci. 2006; 24: 2011-2020
        • Petrosino S.
        • Palazzo E.
        • de Novellis V.
        • Bisogno T.
        • Rossi F.
        • Maione S.
        • Di Marzo V.
        Changes in spinal and supraspinal endocannabinoid levels in neuropathic rats.
        Neuropharmacology. 2007; 52: 415-422
        • Racz I.
        • Nadal X.
        • Alferink J.
        • Banos J.E.
        • Rehnelt J.
        • Martin M.
        • Pintado B.
        • Gutierrez-Adan A.
        • Sanguino E.
        • Manzanares J.
        • Zimmer A.
        • Maldonado R.
        Crucial role of CB(2) cannabinoid receptor in the regulation of central immune responses during neuropathic pain.
        J Neurosci. 2008; 28: 12125-12135
        • Rahn E.J.
        • Hohmann A.G.
        Cannabinoids as pharmacotherapies for neuropathic pain: From the bench to the bedside.
        Neurotherapeutics. 2009; 6: 713-737
        • Russo R.
        • Loverme J.
        • La Rana G.
        • Compton T.R.
        • Parrott J.
        • Duranti A.
        • Tontini A.
        • Mor M.
        • Tarzia G.
        • Calignano A.
        • Piomelli D.
        The fatty acid amide hydrolase inhibitor URB597 (cyclohexylcarbamic acid 3'-carbamoylbiphenyl-3-yl ester) reduces neuropathic pain after oral administration in mice.
        J Pharmacol Exp Ther. 2007; 322: 236-242
        • Schlosburg J.E.
        • Kinsey S.G.
        • Lichtman A.H.
        Targeting Fatty Acid Amide Hydrolase (FAAH) to Treat Pain and Inflammation.
        AAPS J. 2009; 11: 39-44
        • Stewart W.F.
        • Ricci J.A.
        • Chee E.
        • Morganstein D.
        • Lipton R.
        Lost productive time and cost due to common pain conditions in the US workforce.
        J Am Med Assoc. 2003; 290: 2443-2454
        • Tognetto M.
        • Amadesi S.
        • Harrison S.
        • Creminon C.
        • Trevisani M.
        • Carreras M.
        • Matera M.
        • Geppetti P.
        • Bianchi A.
        Anandamide excites central terminals of dorsal root ganglion neurons via vanilloid receptor-1 activation.
        J Neurosci. 2001; 21: 1104-1109
        • Van Sickle M.D.
        • Duncan M.
        • Kingsley P.J.
        • Mouihate A.
        • Urbani P.
        • Mackie K.
        • Stella N.
        • Makriyannis A.
        • Piomelli D.
        • Davison J.S.
        • Marnett L.J.
        • Di Marzo V.
        • Pittman Q.J.
        • Patel K.D.
        • Sharkey K.A.
        Identification and functional characterization of brainstem cannabinoid CB2 receptors.
        Sci. 2005; 310: 329-332
        • Vardanyan A.
        • Wang R.
        • Vanderah T.W.
        • Ossipov M.H.
        • Lai J.
        • Porreca F.
        • King T.
        TRPV1 receptor in expression of opioid-induced hyperalgesia.
        J Pain. 2009; 10: 243-252
        • Walczak J.S.
        • Beaulieu P.
        Comparison of three models of neuropathic pain in mice using a new method to assess cold allodynia: The double plate technique.
        Neurosci Lett. 2006; 399: 240-244
        • Walker J.M.
        • Huang S.M.
        • Strangman N.M.
        • Tsou K.
        • Sanudo-Pena M.C.
        Pain modulation by release of the endogenous cannabinoid anandamide.
        Proc Natl Acad Sci U S A. 1999; 96: 12198-12203
        • Wise L.E.
        • Cannavacciulo R.
        • Cravatt B.F.
        • Martin B.F.
        • Lichtman A.H.
        Evaluation of fatty acid amides in the carrageenan-induced paw edema model.
        Neuropharmacology. 2008; 54: 181-188
        • Zhang J.
        • Hoffert C.
        • Vu H.K.
        • Groblewski T.
        • Ahmad S.
        • O'Donnell D.
        Induction of CB2 receptor expression in the rat spinal cord of neuropathic but not inflammatory chronic pain models.
        Eur J Neurosci. 2003; 17: 2750-2754