title: Microglia in the spinal cord and neuropathic pain.
abstract: In contrast to physiological pain, pathological pain is not dependent on the presence of tissue-damaging stimuli. One type of pathological pain - neuropathic pain - is often a consequence of nerve injury or of diseases such as diabetes. Neuropathic pain can be agonizing, can persist over long periods and is often resistant to known painkillers. A growing body of evidence shows that many pathological processes within the central nervous system are mediated by complex interactions between neurons and glial cells. In the case of painful peripheral neuropathy, spinal microglia react and undergo a series of changes that directly influence the establishment of neuropathic pain states. After nerve damage, purinergic P2X4 receptors (non-selective cation channels activated by extracellular adenosine triphosphate) are upregulated in spinal microglia in a manner that depends on the transcription factors interferon regulatory factor 8 and 5, both of which are expressed in microglia after peripheral nerve injury. P2X4 receptor expression on the cell surface of microglia is also regulated at the post-translational level by signaling from CC chemokine receptor chemotactic cytokine receptor 2. Furthermore, spinal microglia in response to extracellular stimuli results in signal transduction through intracellular signaling cascades, such as mitogen-activated protein kinases, p38 and extracellular signal-regulated protein kinase. Importantly, inhibiting the function or expression of these microglial molecules suppresses the aberrant excitability of dorsal horn neurons and neuropathic pain. These findings show that spinal microglia are a central player in mechanisms for neuropathic pain, and might be a potential target for treating the chronic pain state.
authors.affiliation: Department of Life Innovation Graduate School of Pharmaceutical Sciences Kyushu University Fukuoka Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Tsuda
mesh_terms: D000818:Animals; D048909:Diabetes Complications / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D017628:Microglia / Q000378:metabolism* / Q000473:pathology; D009437:Neuralgia / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology; D013116:Spinal Cord / Q000378:metabolism* / Q000473:pathology
keywords: Microglia; Painful diabetic neuropathy; Purinergic receptors
references.citation: Proc Natl Acad Sci U S A. 2007 Jun 19;104(25):10655-60
references.pmid: 17551020
references.citation: J Neurol Sci. 2004 May 15;220(1-2):137-9
references.pmid: 15140623
references.citation: Neurosci Res. 2004 Apr;48(4):463-9
references.pmid: 15041200
references.citation: Proc Natl Acad Sci U S A. 2009 May 12;106(19):8032-7
references.pmid: 19380717
references.citation: Glia. 2008 Apr;56(5):579-85
references.pmid: 18240312
references.citation: Eur J Pain. 2000;4(3):247-57
references.pmid: 10985868
references.citation: J Neurosci. 2009 May 27;29(21):6945-54
references.pmid: 19474321
references.citation: Brain. 2011 Apr;134(Pt 4):1127-39
references.pmid: 21371995
references.citation: Neurosci Bull. 2014 Feb;30(1):53-66
references.pmid: 24194231
references.citation: Neuron Glia Biol. 2007 Aug;3(3):255-68
references.pmid: 18504511
references.citation: J Biol Chem. 2007 May 18;282(20):14975-83
references.pmid: 17355971
references.citation: J Peripher Nerv Syst. 2005 Mar;10(1):47-57
references.pmid: 15703018
references.citation: J Cell Sci. 2007 Nov 1;120(Pt 21):3838-49
references.pmid: 17940064
references.citation: Lancet. 1999 Jun 5;353(9168):1959-64
references.pmid: 10371588
references.citation: J Neurosci. 2012 Aug 15;32(33):11285-98
references.pmid: 22895712
references.citation: J Pharmacol Exp Ther. 2000 Feb;292(2):497-504
references.pmid: 10640285
references.citation: Diabetes Obes Metab. 2011 Feb;13(2):150-9
references.pmid: 21199267
references.citation: Neuroscience. 1986 Sep;19(1):297-312
references.pmid: 3785668
references.citation: J Neurosci. 2009 Mar 18;29(11):3518-28
references.pmid: 19295157
references.citation: J Diabetes Investig. 2016 Jan;7(1):17-26
references.pmid: 26813032
references.citation: J Clin Endocrinol Metab. 2005 Aug;90(8):4936-45
references.pmid: 15899953
references.citation: J Pharmacol Sci. 2013;121(2):89-94
references.pmid: 23337437
references.citation: J Neurosci. 2006 Mar 29;26(13):3551-60
references.pmid: 16571763
references.citation: Nature. 2003 Aug 14;424(6950):778-83
references.pmid: 12917686
references.citation: Annu Rev Neurosci. 2009;32:1-32
references.pmid: 19400724
references.citation: Eur J Pharmacol. 2011 Jul 1;661(1-3):15-21
references.pmid: 21536024
references.citation: J Neurosci. 2003 May 15;23(10):4017-22
references.pmid: 12764087
references.citation: Spine (Phila Pa 1976). 2007 Jan 15;32(2):159-67
references.pmid: 17224809
references.citation: Pain. 2001 Feb 1;90(1-2):1-6
references.pmid: 11166964
references.citation: Brain. 2013 Mar;136(Pt 3):828-43
references.pmid: 23364351
references.citation: Pharmacol Rev. 2006 Sep;58(3):281-341
references.pmid: 16968944
references.citation: Mol Pain. 2007 Nov 01;3:33
references.pmid: 17974036
references.citation: Glia. 2008 Jan 1;56(1):50-8
references.pmid: 17918263
references.citation: Eur J Pain. 2009 Mar;13(3):263-72
references.pmid: 18554968
references.citation: J Neurosci. 2008 Mar 12;28(11):2892-902
references.pmid: 18337420
references.citation: Cell Rep. 2012 Apr 19;1(4):334-340
references.pmid: 22832225
references.citation: J Neuroinflammation. 2012 Sep 28;9:227
references.pmid: 23020843
references.citation: Exp Neurol. 2007 Mar;204(1):355-65
references.pmid: 17258708
references.citation: Neuron Glia Biol. 2006 Nov;2(4):259-69
references.pmid: 17710215
references.citation: J Neurosci. 2008 May 14;28(20):5189-94
references.pmid: 18480275
references.citation: Clin Ther. 2005 Aug;27(8):1278-94
references.pmid: 16199253
references.citation: Nat Neurosci. 2014 Feb;17(2):183-91
references.pmid: 24473266
references.citation: Glia. 2008 Mar;56(4):378-86
references.pmid: 18186080
references.citation: J Neurosci. 2007 Feb 28;27(9):2357-68
references.pmid: 17329433
references.citation: Glia. 2008 May;56(7):723-33
references.pmid: 18293403
references.citation: Trends Neurosci. 2001 Aug;24(8):450-5
references.pmid: 11476884
references.citation: Proc Natl Acad Sci U S A. 2007 Dec 18;104(51):20151-8
references.pmid: 18083844
references.citation: Neuroscience. 2008 Jun 2;153(4):1245-55
references.pmid: 18440713
references.citation: Science. 2010 Nov 5;330(6005):841-5
references.pmid: 20966214
references.citation: Nature. 2006 Aug 3;442(7102):527-32
references.pmid: 16885977
references.citation: Eur J Pain. 2009 Sep;13(8):807-11
references.pmid: 18977160
references.citation: Nat Rev Drug Discov. 2008 Jul;7(7):575-90
references.pmid: 18591979
references.citation: Nat Med. 2008 Mar;14(3):331-6
references.pmid: 18264108
references.citation: Nat Rev Neurosci. 2010 Dec;11(12):823-36
references.pmid: 21068766
references.citation: Nat Rev Neurosci. 2005 Jul;6(7):521-32
references.pmid: 15995723
references.citation: J Biol Chem. 2012 Apr 27;287(18):14734-48
references.pmid: 22393055
references.citation: J Neurochem. 2008 Jun 1;105(6):2249-59
references.pmid: 18363823
references.citation: J Biol Chem. 2009 May 15;284(20):13446-54
references.pmid: 19304656
references.citation: Nat Neurosci. 2007 Dec;10(12):1538-43
references.pmid: 18026097
references.citation: Neuron. 2014 May 7;82(3):522-36
references.pmid: 24811377
references.citation: Trends Neurosci. 2005 Feb;28(2):101-7
references.pmid: 15667933
references.citation: J Neurosci. 2008 Oct 29;28(44):11263-8
references.pmid: 18971468
references.citation: Science. 2000 Jun 9;288(5472):1765-9
references.pmid: 10846153
references.citation: Front Cell Neurosci. 2013 Oct 28;7:191
references.pmid: 24191146
references.citation: Nat Neurosci. 2002 Nov;5 Suppl:1062-7
references.pmid: 12403987
references.citation: J Neurosci. 2003 Sep 24;23(25):8692-700
references.pmid: 14507968
references.citation: Mol Pain. 2009 Sep 22;5:53
references.pmid: 19772627
references.citation: Annu Rev Immunol. 2008;26:535-84
references.pmid: 18303999
references.citation: Nat Neurosci. 2007 Nov;10(11):1361-8
references.pmid: 17965656
references.citation: J Gen Physiol. 2010 Apr;135(4):333-53
references.pmid: 20231374
references.citation: Pain. 2005 Mar;114(1-2):149-59
references.pmid: 15733640
references.citation: J Pharmacol Exp Ther. 2003 Aug;306(2):624-30
references.pmid: 12734393
references.citation: J Neurocytol. 1989 Feb;18(1):77-86
references.pmid: 2496205
references.citation: Nat Commun. 2014 May 13;5:3771
references.pmid: 24818655
references.citation: Nat Neurosci. 2005 Jun;8(6):752-8
references.pmid: 15895084
references.citation: Mol Pain. 2010 Mar 17;6:16
references.pmid: 20236533
references.citation: Proc Natl Acad Sci U S A. 1993 Jun 1;90(11):5113-7
references.pmid: 7685114
references.citation: Nat Clin Pract Neurol. 2006 Feb;2(2):95-106
references.pmid: 16932531
references.citation: Pharmacol Rev. 1972 Sep;24(3):509-81
references.pmid: 4404211
references.citation: J Neurosci. 2007 Nov 7;27(45):12396-406
references.pmid: 17989304
references.citation: Anesthesiology. 2007 Aug;107(2):312-21
references.pmid: 17667577
references.citation: Mol Pharmacol. 2006 Oct;70(4):1246-54
references.pmid: 16868181
references.citation: Nat Neurosci. 2012 Jul 26;15(8):1068-73
references.pmid: 22837036
references.citation: Pharmacol Ther. 2006 Jan;109(1-2):210-26
references.pmid: 16169595
references.citation: Proc Natl Acad Sci U S A. 2005 Apr 19;102(16):5856-61
references.pmid: 15809417
references.citation: Mol Pain. 2007 Sep 27;3:27
references.pmid: 17900333
references.citation: FEBS Lett. 1993 Jun 14;324(2):219-25
references.pmid: 8508924
references.citation: Pain. 2006 Apr;121(3):219-31
references.pmid: 16495005
references.citation: J Neurosci. 2006 Apr 19;26(16):4308-17
references.pmid: 16624951
references.citation: J Neuroimmunol. 2013 Sep 15;262(1-2):35-45
references.pmid: 23870534
references.citation: Eur J Neurosci. 2007 Mar;25(5):1297-306
references.pmid: 17425556
references.citation: Purinergic Signal. 2012 Jun;8(2):301-10
references.pmid: 22222817
references.citation: Anesth Analg. 2011 Oct;113(4):941-6
references.pmid: 21788310
references.citation: J Neurochem. 2006 Jun;97(5):1337-48
references.pmid: 16606373
references.citation: Glia. 2013 Jun;61(6):929-42
references.pmid: 23483680
references.citation: Mol Pain. 2009 Jun 11;5:28
references.pmid: 19515262
references.citation: Eur J Pain. 2014 Feb;18(2):162-73
references.pmid: 23868758
references.citation: J Neurochem. 2006 May;97(3):772-83
references.pmid: 16524371
references.citation: Science. 2005 May 27;308(5726):1314-8
references.pmid: 15831717
references.citation: J Neurosci. 2003 Apr 1;23(7):2517-21
references.pmid: 12684435
references.citation: Glia. 2004 Jan 1;45(1):89-95
references.pmid: 14648549
references.citation: Muscle Nerve. 1995 Jun;18(6):574-84
references.pmid: 7753119
references.citation: J Cell Mol Med. 2009 Sep;13(9B):3251-9
references.pmid: 19298529