title: CB2 Cannabinoid receptors as a therapeutic target-what does the future hold?
abstract: The past decades have seen an exponential rise in our understanding of the endocannabinoid system, comprising CB1 and CB2 cannabinoid receptors, endogenous cannabinoids (endocannabinoids), and the enzymes that synthesize and degrade endocannabinoids. The primary focus of this review is the CB2 receptor. CB2 receptors have been the subject of considerable attention, primarily due to their promising therapeutic potential for treating various pathologies while avoiding the adverse psychotropic effects that can accompany CB1 receptor-based therapies. With the appreciation that CB2-selective ligands show marked functional selectivity, there is a renewed opportunity to explore this promising area of research from both a mechanistic as well as a therapeutic perspective. In this review, we summarize our present knowledge of CB2 receptor signaling, localization, and regulation. We discuss the availability of genetic tools (and their limitations) to study CB2 receptors and also provide an update on preclinical data on CB2 agonists in pain models. Finally, we suggest possible reasons for the failure of CB2 ligands in clinical pain trials and offer possible ways to move the field forward in a way that can help reconcile the inconsistencies between preclinical and clinical data.
authors.affiliation: Department of Psychological and Brain Sciences and Gill Center, Indiana University, Bloomington, Indiana.
authors.forename: Amey
authors.initials: A
authors.lastname: Dhopeshwarkar
authors.affiliation: Department of Psychological and Brain Sciences and Gill Center, Indiana University, Bloomington, Indiana kmackie@indiana.edu.
authors.forename: Ken
authors.initials: K
authors.lastname: Mackie
mesh_terms: D000818:Animals; D063386:Cannabinoid Receptor Agonists / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D010146:Pain / Q000188:drug therapy*; D021381:Protein Transport; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D063386:Cannabinoid Receptor Agonists; D043885:Receptor, Cannabinoid, CB2
references.citation: Curr Top Behav Neurosci. 2009;1:37-63
references.pmid: 21104379
references.citation: Sci Transl Med. 2013 Feb 6;5(171):171cm1
references.pmid: 23390245
references.citation: J Pharmacol Exp Ther. 1999 Nov;291(2):618-26
references.pmid: 10525080
references.citation: Br J Pharmacol. 2008 Jan;153(2):252-62
references.pmid: 18026124
references.citation: Adv Exp Med Biol. 1993;335:115-20
references.pmid: 8237584
references.citation: Mol Neurobiol. 2007 Aug;36(1):45-59
references.pmid: 17952649
references.citation: Can J Physiol Pharmacol. 1996 Oct;74(10):1095-110
references.pmid: 9022829
references.citation: Eur J Med Chem. 2013 Nov;69:881-907
references.pmid: 24125850
references.citation: Br J Pharmacol. 2006 Sep;149(2):145-54
references.pmid: 16894349
references.citation: Mol Pharmacol. 2012 Feb;81(2):250-63
references.pmid: 22064678
references.citation: Pharmacol Res. 2012 Nov;66(5):437-42
references.pmid: 22921769
references.citation: Recept Channels. 1999;6(5):363-74
references.pmid: 10551268
references.citation: J Neuroimmunol. 2003 Dec;145(1-2):46-54
references.pmid: 14644030
references.citation: Pharmaceuticals (Basel). 2010 Aug 10;3(8):2517-2553
references.pmid: 27713365
references.citation: J Med Chem. 2013 Nov 14;56(21):8224-56
references.pmid: 23865723
references.citation: Pharmacotherapy. 2013 Feb;33(2):195-209
references.pmid: 23386598
references.citation: Mol Pharmacol. 2013 Jul;84(1):158-69
references.pmid: 23632086
references.citation: Proc Natl Acad Sci U S A. 2005 Feb 22;102(8):3093-8
references.pmid: 15705714
references.citation: J Biomol Screen. 2009 Jan;14(1):49-58
references.pmid: 19171920
references.citation: Br J Pharmacol. 2008 Jan;153(2):290-8
references.pmid: 17965744
references.citation: Biol Psychiatry. 2015 Mar 1;77(5):475-87
references.pmid: 24853387
references.citation: Proc Natl Acad Sci U S A. 2003 Sep 2;100(18):10529-33
references.pmid: 12917492
references.citation: Pharmacol Rev. 2001 Mar;53(1):1-24
references.pmid: 11171937
references.citation: Neuropharmacology. 2003 May;44(6):773-86
references.pmid: 12681376
references.citation: FASEB J. 2007 Aug;21(10):2455-65
references.pmid: 17384143
references.citation: ACS Chem Neurosci. 2012 Mar 21;3(3):193-203
references.pmid: 22860188
references.citation: J Cereb Blood Flow Metab. 2007 Jul;27(7):1387-96
references.pmid: 17245417
references.citation: Philos Trans R Soc Lond B Biol Sci. 2012 Dec 5;367(1607):3364-78
references.pmid: 23108553
references.citation: Dtsch Arztebl Int. 2012 Jul;109(29-30):495-501
references.pmid: 23008748
references.citation: Pharmacol Ther. 1997;74(2):129-80
references.pmid: 9336020
references.citation: Toxicology. 2013 Dec 15;314(2-3):254-61
references.pmid: 24184660
references.citation: Br J Pharmacol. 2008 Jan;153(2):271-6
references.pmid: 17922025
references.citation: Pharmacol Rev. 2013 Jan 15;65(1):223-54
references.pmid: 23321159
references.citation: Eur J Pharmacol. 2000 May 19;396(2-3):141-9
references.pmid: 10822068
references.citation: J Neurochem. 2007 Apr;101(1):87-98
references.pmid: 17241118
references.citation: Biochem Pharmacol. 1998 Apr 1;55(7):1013-23
references.pmid: 9605425
references.citation: J Neurosci. 2002 Nov 15;22(22):9742-53
references.pmid: 12427829
references.citation: Br J Pharmacol. 2010 Jun;160(3):467-79
references.pmid: 20590558
references.citation: Biochem Biophys Res Commun. 2002 Jan 11;290(1):91-6
references.pmid: 11779138
references.citation: Biochem Pharmacol. 1994 Nov 16;48(10):1899-908
references.pmid: 7986201
references.citation: Proc Natl Acad Sci U S A. 2006 Jan 17;103(3):696-701
references.pmid: 16407142
references.citation: Br J Pharmacol. 2011 Jan;162(2):428-40
references.pmid: 20880025
references.citation: Curr Med Chem. 1999 Aug;6(8):635-64
references.pmid: 10469884
references.citation: PLoS One. 2013 Oct 09;8(10):e76907
references.pmid: 24130809
references.citation: PLoS One. 2014 Apr 02;9(4):e93746
references.pmid: 24695667
references.citation: Mol Pharmacol. 1995 Aug;48(2):352-61
references.pmid: 7651369
references.citation: Biochem Pharmacol. 1998 Aug 1;56(3):269-77
references.pmid: 9744561
references.citation: Nat Rev Drug Discov. 2010 Mar;9(3):203-14
references.pmid: 20168317
references.citation: Toxicol Appl Pharmacol. 1997 Feb;142(2):278-87
references.pmid: 9070350
references.citation: Eur J Biochem. 1995 Aug 15;232(1):54-61
references.pmid: 7556170
references.citation: J Pharmacol Exp Ther. 2011 Feb;336(2):296-302
references.pmid: 21030484
references.citation: Pain. 2011 Sep;152(9):1976-1987
references.pmid: 21550725
references.citation: Eur J Pharmacol. 2005 Dec 28;528(1-3):65-72
references.pmid: 16316650
references.citation: PLoS One. 2012;7(1):e29239
references.pmid: 22235275
references.citation: ACS Chem Biol. 2014 Jul 18;9(7):1499-507
references.pmid: 24831513
references.citation: Pain. 2014 Sep;155(9):1683-1695
references.pmid: 24865794
references.citation: Pharmacol Rev. 2010 Jun;62(2):265-304
references.pmid: 20392808
references.citation: Genes Brain Behav. 2009 Jul;8(5):519-30
references.pmid: 19496827
references.citation: Handb Exp Pharmacol. 2005;(168):283-97
references.pmid: 16596778
references.citation: Mini Rev Med Chem. 2014 May;14(5):426-43
references.pmid: 24766386
references.citation: Eur J Pharmacol. 2001 Dec 21;433(2-3):141-50
references.pmid: 11755145
references.citation: Diabetes. 2011 Sep;60(9):2386-96
references.pmid: 21810593
references.citation: Mol Pharmacol. 1995 Sep;48(3):443-50
references.pmid: 7565624
references.citation: FASEB J. 2007 Jun;21(8):1788-800
references.pmid: 17327359
references.citation: Expert Opin Ther Targets. 2007 Mar;11(3):403-9
references.pmid: 17298297
references.citation: Curr Med Chem. 2012;19(21):3457-74
references.pmid: 22709008
references.citation: J Biol Chem. 2000 Jan 7;275(1):605-12
references.pmid: 10617657
references.citation: Br J Pharmacol. 2008 Jan;153(2):263-70
references.pmid: 17906675
references.citation: Neuropharmacology. 2012 Sep;63(4):514-23
references.pmid: 22579668
references.citation: Mini Rev Med Chem. 2009 Jan;9(1):11-25
references.pmid: 19149657
references.citation: Biochim Biophys Acta. 2002 Jul 19;1576(3):255-64
references.pmid: 12084572
references.citation: J Neuroinflammation. 2005 Dec 12;2:29
references.pmid: 16343349
references.citation: J Biol Chem. 2012 Jun 15;287(25):20851-65
references.pmid: 22532560
references.citation: Nat Biotechnol. 2014 Jan;32(1):40-51
references.pmid: 24406927
references.citation: Biochim Biophys Acta. 2011 Aug;1813(8):1554-60
references.pmid: 21640764
references.citation: Eur J Pharmacol. 2004 Nov 28;505(1-3):1-9
references.pmid: 15556131
references.citation: J Neurochem. 2005 Oct;95(2):437-45
references.pmid: 16086683
references.citation: Gut. 2008 Aug;57(8):1140-55
references.pmid: 18397936
references.citation: N Engl J Med. 2014 Jun 5;370(23):2219-27
references.pmid: 24897085
references.citation: Nat Rev Cancer. 2003 Oct;3(10):745-55
references.pmid: 14570037
references.citation: Eur J Pharmacol. 2006 Aug 7;542(1-3):100-5
references.pmid: 16781706
references.citation: Chem Biol. 2011 Aug 26;18(8):1053-64
references.pmid: 21867920
references.citation: FEBS Lett. 2005 Sep 12;579(22):5084-8
references.pmid: 16139274
references.citation: Pharmacol Rev. 2002 Jun;54(2):161-202
references.pmid: 12037135
references.citation: J Neurosci. 2003 Aug 27;23(21):7767-75
references.pmid: 12944505
references.citation: Proc Natl Acad Sci U S A. 2008 Jul 1;105(26):9099-104
references.pmid: 18574142
references.citation: Curr Opin Cell Biol. 2001 Apr;13(2):139-45
references.pmid: 11248546
references.citation: Psychopharmacology (Berl). 2013 Oct;229(4):591-601
references.pmid: 23652588
references.citation: Br J Pharmacol. 2007 Aug;151(7):1061-70
references.pmid: 17549048
references.citation: Clin J Pain. 2011 Oct;27(8):668-76
references.pmid: 21540741
references.citation: Trends Pharmacol Sci. 2014 Jul;35(7):308-16
references.pmid: 24878326
references.citation: Exp Cell Res. 2006 Jul 1;312(11):2121-31
references.pmid: 16624285
references.citation: Eur J Biochem. 1996 May 1;237(3):704-11
references.pmid: 8647116
references.citation: J Pharmacol Exp Ther. 2005 Nov;315(2):828-38
references.pmid: 16081674
references.citation: Br J Pharmacol. 2008 Jan;153(2):286-9
references.pmid: 17952109
references.citation: Br J Pharmacol. 2012 Mar;165(6):1773-1788
references.pmid: 21951063
references.citation: Recent Pat CNS Drug Discov. 2013 Apr;8(1):42-69
references.pmid: 23477308
references.citation: Proc Natl Acad Sci U S A. 2007 Oct 16;104(42):16657-62
references.pmid: 17925438
references.citation: Pharmacol Rev. 2010 Dec;62(4):588-631
references.pmid: 21079038
references.citation: Neuroscience. 2005;135(1):235-45
references.pmid: 16084654
references.citation: Recent Pat CNS Drug Discov. 2012 Apr 1;7(1):41-8
references.pmid: 22280340
references.citation: Pain. 2001 Sep;93(3):239-245
references.pmid: 11514083