title: Endocannabinoid metabolism and uptake: novel targets for neuropathic and inflammatory pain.
abstract: Cannabinoid CB1 and CB2 receptors are located at key sites involved in the relaying and processing of noxious inputs. Both CB1 and CB2 receptor agonists have analgesic effects in a range of models of inflammatory and neuropathic pain. Importantly, clinical trials of cannabis-based medicines indicate that the pre-clinical effects of cannabinoid agonists may translate into therapeutic potential in humans. One of the areas of concern with this pharmacological approach is that CB1 receptors have a widespread distribution in the brain and that global activation of CB1 receptors is associated with adverse side effects. Studies of the endogenous cannabinoids (endocannabinoids) have demonstrated that they are present in most tissues and that in some pain states, such as neuropathic pain, levels of endocannabinoids are elevated at key sites involved in pain processing. An alternative approach that can be used to harness the potential therapeutic effects of cannabinoids is to maximise the effects of the endocannabinoids, the actions of which are terminated by re-uptake and metabolism by various enzymes, including fatty acid amide hydrolase (FAAH), monoacylglycerol lipase (MAGL) and cyclooxygenase type 2 (COX2). Preventing the metabolism, or uptake, of endocannabinoids elevates levels of these lipid compounds in tissue and produces behavioural analgesia in models of acute pain. Herein we review recent studies of the effects of inhibition of metabolism of endocannabinoids versus uptake of endocannabinoids on nociceptive processing in models of inflammatory and neuropathic pain.
authors: School of Biomedical Sciences, Institute of Neuroscience, Queens Medical Centre, Nottingham, UK. maulik.jhaveri@nottingham.ac.uk
authors: M D
authors: MD
authors: Jhaveri
authors: D
authors: D
authors: Richardson
authors: V
authors: V
authors: Chapman
mesh_terms: D000818:Animals; D063387:Cannabinoid Receptor Antagonists; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism* / Q000493:pharmacokinetics; D063388:Endocannabinoids; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000503:physiopathology* / Q000517:prevention & control; D008954:Models, Biological; D010146:Pain / Q000378:metabolism / Q000503:physiopathology* / Q000517:prevention & control; D043882:Receptors, Cannabinoid / Q000502:physiology
chemical_list: D063387:Cannabinoid Receptor Antagonists; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D043882:Receptors, Cannabinoid
references: Nature. 1996 Nov 7;384(6604):83-7
references: 8900284
references: Biochem Biophys Res Commun. 1995 Oct 4;215(1):89-97
references: 7575630
references: J Biol Chem. 2005 Sep 9;280(36):31405-12
references: 15987694
references: J Pharmacol Exp Ther. 2006 Jun;317(3):1365-71
references: 16510698
references: Proc Natl Acad Sci U S A. 2004 Jul 20;101(29):10821-6
references: 15247426
references: Eur J Neurosci. 2004 Nov;20(9):2311-20
references: 15525273
references: Br J Pharmacol. 2006 Feb;147(3):281-8
references: 16331291
references: Biochem Pharmacol. 2003 May 1;65(9):1473-81
references: 12732359
references: Proc Natl Acad Sci U S A. 2001 Jul 31;98(16):9371-6
references: 11470906
references: J Pharmacol Exp Ther. 2005 Mar;312(3):1161-9
references: 15572651
references: J Pharmacol Exp Ther. 2005 Apr;313(1):352-8
references: 15579492
references: J Med Chem. 2001 Dec 20;44(26):4505-8
references: 11741470
references: Br J Pharmacol. 2002 Oct;137(4):413-20
references: 12359622
references: Pain. 2004 May;109(1-2):124-31
references: 15082134
references: Life Sci. 2005 Aug 19;77(14):1584-604
references: 15979096
references: J Neurosci. 2006 Dec 20;26(51):13318-27
references: 17182782
references: Prostaglandins Other Lipid Mediat. 2002 Aug;68-69:521-34
references: 12432941
references: Proc Natl Acad Sci U S A. 2003 Sep 2;100(18):10529-33
references: 12917492
references: J Med Chem. 1999 Mar 11;42(5):896-902
references: 10072686
references: J Med Invest. 1998 Aug;45(1-4):27-36
references: 9864962
references: Nature. 2005 Jun 23;435(7045):1108-12
references: 15973410
references: J Biol Chem. 1997 Aug 22;272(34):21181-6
references: 9261124
references: J Neurosci. 2007 Mar 14;27(11):2883-9
references: 17360910
references: Eur J Neurosci. 2005 Jul;22(2):371-9
references: 16045490
references: Biochem Pharmacol. 1999 Feb 15;57(4):417-23
references: 9933030
references: J Biol Chem. 2005 May 6;280(18):18488-97
references: 15749716
references: J Biol Chem. 2000 Oct 27;275(43):33744-9
references: 10931854
references: Microvasc Res. 2005 Jan;69(1-2):28-35
references: 15797258
references: J Biol Chem. 2002 Jun 28;277(26):23278-86
references: 11956198
references: J Neurosci. 2004 Mar 17;24(11):2727-32
references: 15028765
references: Pharmacol Biochem Behav. 2006 Apr;83(4):508-16
references: 16647109
references: Biochemistry. 2003 Aug 5;42(30):9041-9
references: 12885237
references: Brain Res Rev. 2006 Sep;52(2):201-43
references: 16647138
references: J Neurosci. 2001 Aug 15;21(16):5847-53
references: 11487607
references: Eur J Pharmacol. 2000 May 19;396(2-3):85-92
references: 10822060
references: Reg Anesth Pain Med. 2005 Jul-Aug;30(4):351-5
references: 16032587
references: Pain. 2002 Apr;96(3):253-260
references: 11972997
references: Neuropharmacology. 2005 Apr;48(5):658-72
references: 15814101
references: Eur J Pharmacol. 2006 Nov 21;550(1-3):68-77
references: 17027744
references: J Neurochem. 2000 Jun;74(6):2597-606
references: 10820223
references: Biochem Pharmacol. 2001 Sep 1;62(5):517-26
references: 11585048
references: Biochem J. 2000 Nov 1;351 Pt 3:817-24
references: 11042139
references: Pharmacol Res. 2006 Dec;54(6):481-5
references: 16997568
references: Biochem J. 2004 May 15;380(Pt 1):265-72
references: 14969584
references: Pharmacol Rev. 2006 Sep;58(3):389-462
references: 16968947
references: Neuroscience. 2003;119(3):747-57
references: 12809695
references: Neuropharmacology. 2005 Jun;48(8):1072-8
references: 15910883
references: J Med Chem. 2003 Apr 10;46(8):1512-22
references: 12672252
references: Br J Pharmacol. 2006 Aug;148(7):1022-32
references: 16770320
references: FEBS Lett. 1998 Jan 23;422(1):69-73
references: 9475172
references: Biochemistry. 2001 Jan 30;40(4):861-6
references: 11170406
references: Biochemistry. 2004 Jun 29;43(25):8184-90
references: 15209515
references: J Immunol. 2003 May 15;170(10):4953-62
references: 12734338
references: Proc Natl Acad Sci U S A. 2002 Jun 11;99(12):8400-5
references: 12060783
references: Cardiovasc Drug Rev. 2004 Summer;22(2):103-20
references: 15179448
references: FEBS Lett. 2000 Feb 25;468(2-3):176-80
references: 10692582
references: Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):4269-74
references: 12655057
references: Eur J Pharmacol. 2005 Dec 28;528(1-3):65-72
references: 16316650
references: J Biol Chem. 2002 Nov 22;277(47):44877-85
references: 12244105
references: Br J Pharmacol. 2007 Mar;150(6):693-701
references: 17179944
references: AAPS J. 2006;8(2):E409-12
references: 16808043
references: J Pharmacol Exp Ther. 2007 Jul;322(1):236-42
references: 17412883
references: J Dermatol Sci. 2005 Jun;38(3):177-88
references: 15927811
references: Pain. 2006 Dec 15;126(1-3):102-14
references: 16844297
references: Pharmacol Ther. 2002 Aug;95(2):127-35
references: 12182960
references: Biochem Pharmacol. 2005 Aug 1;70(3):446-52
references: 15963472
references: Biochem Pharmacol. 1995 Jun 29;50(1):83-90
references: 7605349
references: Neuroscience. 2003;117(3):659-70
references: 12617970
references: Prog Neurobiol. 2001 Apr;63(5):569-611
references: 11164622
references: Biochem Biophys Res Commun. 2000 Nov 30;278(3):576-83
references: 11095952
references: Pain. 2005 Dec 5;118(3):327-335
references: 16289798
references: Science. 1992 Dec 18;258(5090):1946-9
references: 1470919
references: J Pharmacol Exp Ther. 2006 Mar;316(3):969-82
references: 16284279
references: Pharmacol Ther. 2004 Nov;104(2):117-35
references: 15518883
references: Nat Neurosci. 2007 Jul;10(7):870-9
references: 17558404
references: AAPS J. 2006 Nov 17;8(4):E693-708
references: 17233533
references: Nat Med. 2003 Jan;9(1):76-81
references: 12461523
references: J Enzyme Inhib Med Chem. 2003 Feb;18(1):55-8
references: 12751821
references: J Physiol. 2006 May 1;572(Pt 3):735-45
references: 16484297
references: Proc Natl Acad Sci U S A. 2002 Aug 6;99(16):10819-24
references: 12136125
references: Neuropharmacology. 2007 Feb;52(2):415-22
references: 17011598
references: Eur J Pharmacol. 2005 Jan 31;508(1-3):139-46
references: 15680264
references: Br J Pharmacol. 2001 Jun;133(4):513-20
references: 11399668
references: Eur J Pharmacol. 2007 Jan 5;554(1):12-7
references: 17112505
references: Br J Pharmacol. 2006 May;148(1):102-13
references: 16501580
references: Br J Pharmacol. 2007 Jan;150(2):186-91
references: 17143303
references: Eur J Pharmacol. 2003 Mar 19;464(2-3):229-35
references: 12620517
references: Anesthesiology. 2003 Oct;99(4):955-60
references: 14508331
references: Annu Rev Pharmacol Toxicol. 2002;42:553-83
references: 11807183
references: Mol Pharmacol. 2001 Jun;59(6):1369-75
references: 11353795
references: Br J Pharmacol. 2002 Nov;137(6):837-44
references: 12411415
references: Curr Pharm Des. 2004;10(6):659-67
references: 14965328
references: Br J Pharmacol. 2007 Mar;150(6):766-81
references: 17279090
references: Biochem J. 1997 Mar 1;322 ( Pt 2):671-7
references: 9065792
references: Drug Alcohol Depend. 1996 Nov;42(3):201-7
references: 8912803
references: Eur J Pharmacol. 2002 Aug 2;449(1-2):99-103
references: 12163112
references: J Neurobiol. 2004 Oct;61(1):149-60
references: 15362158
references: Proc Natl Acad Sci U S A. 1995 Apr 11;92(8):3376-80
references: 7724569
references: Br J Pharmacol. 2005 Oct;146(3):467-76
references: 16100529
references: FASEB J. 2006 Mar;20(3):568-70
references: 16403786
references: Nature. 1998 Jul 16;394(6690):277-81
references: 9685157
references: J Med Chem. 1996 Oct 25;39(22):4515-9
references: 8893848
references: Proc Natl Acad Sci U S A. 1999 Oct 12;96(21):12198-203
references: 10518599
references: J Biol Chem. 2001 Aug 10;276(32):30072-7
references: 11402053
references: J Pharmacol Exp Ther. 2004 Nov;311(2):441-8
references: 15229230
references: Brain Res. 1998 Feb 16;784(1-2):329-36
references: 9518675
references: Prog Neuropsychopharmacol Biol Psychiatry. 2004 Aug;28(5):849-63
references: 15363608
references: Proc Natl Acad Sci U S A. 2004 Jun 8;101(23):8756-61
references: 15138300
references: J Pharmacol Exp Ther. 1997 Dec;283(3):1069-75
references: 9399978
references: Eur J Neurosci. 2006 Oct;24(7):2011-20
references: 17040473
references: J Lipid Res. 2004 Apr;45(4):757-63
references: 14729864
references: Pain. 2001 Sep;93(3):239-245
references: 11514083