title: Neuron-glia crosstalk gets serious: role in pain hypersensitivity.
abstract: OBJECTIVE
  Recent studies show that peripheral injury activates both neuronal and nonneuronal or glial components of the peripheral and central cellular circuitry. The subsequent neuron-glia interactions contribute to pain hypersensitivity. This review will briefly discuss novel findings that have shed light on the cellular mechanisms of neuron-glia interactions in persistent pain.
  
  
  RESULTS
  Two fundamental questions related to neuron-glia interactions in pain mechanisms have been addressed: what are the signals that lead to central glial activation after injury and how do glial cells affect central nervous system neuronal activity and promote hyperalgesia?
  
  
  CONCLUSIONS
  Evidence indicates that central glial activation depends on nerve inputs from the site of injury and release of chemical mediators. Hematogenous immune cells may migrate to/infiltrate the brain and circulating inflammatory mediators may penetrate the blood-brain barrier to participate in central glial responses to injury. Inflammatory cytokines such as interleukin-1beta released from glia may facilitate pain transmission through its coupling to neuronal glutamate receptors. This bidirectional neuron-glia signaling plays a key role in glial activation, cytokine production and the initiation and maintenance of hyperalgesia. Recognition of the contribution of the mutual neuron-glia interactions to central sensitization and hyperalgesia prompts new treatment for chronic pain.
authors.affiliation: Department of Neural and Pain Sciences, Dental School and Program in Neuroscience, University of Maryland, Baltimore, Maryland 21201-1586, USA.
authors.forename: Ke
authors.initials: K
authors.lastname: Ren
authors.forename: Ronald
authors.initials: R
authors.lastname: Dubner
mesh_terms: D001253:Astrocytes / Q000502:physiology; D002450:Cell Communication / Q000502:physiology*; D016207:Cytokines / Q000502:physiology; D006801:Humans; D006930:Hyperalgesia / Q000378:metabolism / Q000503:physiopathology*; D009457:Neuroglia / Q000378:metabolism / Q000502:physiology*; D009474:Neurons / Q000502:physiology*; D059348:Peripheral Nerve Injuries; D020239:Receptor Cross-Talk; D015398:Signal Transduction
chemical_list: D016207:Cytokines
references.citation: Pain. 2007 Apr;128(3):215-224
references.pmid: 17110040
references.citation: J Neurosci. 2007 Aug 8;27(32):8699-708
references.pmid: 17687047
references.citation: Brain Pathol. 2007 Apr;17(2):243-50
references.pmid: 17388955
references.citation: Brain Res. 2005 Feb 9;1034(1-2):172-9
references.pmid: 15713269
references.citation: Nat Neurosci. 1999 Feb;2(2):139-43
references.pmid: 10195197
references.citation: J Neurosci. 2007 Aug 22;27(34):9068-76
references.pmid: 17715343
references.citation: J Physiol. 2004 Aug 15;559(Pt 1):3-15
references.pmid: 15218071
references.citation: J Neurochem. 2006 Nov;99(3):924-36
references.pmid: 17076659
references.citation: Acta Physiol (Oxf). 2006 May-Jun;187(1-2):321-7
references.pmid: 16734769
references.citation: Pain. 1993 Feb;52(2):127-136
references.pmid: 8455960
references.citation: Neuroscience. 1995 Apr;65(3):815-26
references.pmid: 7609880
references.citation: Cell Signal. 2007 Feb;19(2):330-40
references.pmid: 16935468
references.citation: Exp Eye Res. 2007 Aug;85(2):280-8
references.pmid: 17604021
references.citation: Pain. 2005 May;115(1-2):60-70
references.pmid: 15836970
references.citation: J Neurosci. 2007 May 30;27(22):6006-18
references.pmid: 17537972
references.citation: J Biol Chem. 2007 May 18;282(20):14975-83
references.pmid: 17355971
references.citation: Neuroscience. 2006 Jul 7;140(3):1003-10
references.pmid: 16600520
references.citation: Expert Opin Investig Drugs. 2007 Jul;16(7):935-50
references.pmid: 17594181
references.citation: J Neurosci Methods. 2007 Aug 30;164(2):207-17
references.pmid: 17553569
references.citation: Exp Neurol. 1994 Oct;129(2):237-43
references.pmid: 7957738
references.citation: J Neurochem. 1996 Nov;67(5):1840-5
references.pmid: 8863488
references.citation: Eur J Neurosci. 2007 Sep;26(6):1387-98
references.pmid: 17880383
references.citation: Pain. 2006 Sep;124(1-2):211-21
references.pmid: 16806707
references.citation: Nat Neurosci. 2007 Nov;10(11):1387-94
references.pmid: 17965659
references.citation: Open Pain J. 2010 Mar 1;2010(3):144-152
references.pmid: 21170295
references.citation: Neuroscience. 2006;138(4):1351-60
references.pmid: 16426766
references.citation: Nat Neurosci. 2002 Dec;5(12):1319-26
references.pmid: 12402039
references.citation: Br J Pharmacol. 2008 Feb;153(4):775-83
references.pmid: 18059318
references.citation: Glia. 2006 Aug 15;54(3):193-203
references.pmid: 16819765
references.citation: Neurosci Lett. 2004 Nov 16;371(1):24-9
references.pmid: 15500960
references.citation: J Neurochem. 2007 Nov;103(4):1273-84
references.pmid: 17727631
references.citation: Gene Ther. 2007 Jul;14(13):1010-6
references.pmid: 17443214
references.citation: J Pain. 2004 Sep;5(7):392-405
references.pmid: 15501197
references.citation: J Pain. 2005 Jul;6(7):434-8
references.pmid: 15993821
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: Eur J Pharmacol. 2007 Apr 10;560(2-3):142-9
references.pmid: 17307159
references.citation: Brain Behav Immun. 2007 Jul;21(5):642-51
references.pmid: 17174525
references.citation: J Physiol. 2007 Jun 15;581(Pt 3):1057-81
references.pmid: 17412766
references.citation: Pain. 1994 Jun;57(3):375-382
references.pmid: 7936715
references.citation: J Neurosci. 2005 Apr 6;25(14):3701-11
references.pmid: 15814801
references.citation: Open Pain J. 2009 Jan 1;2:76-83
references.pmid: 20221418
references.citation: Pain. 2008 Apr;135(3):232-239
references.pmid: 17689191
references.citation: Reg Anesth Pain Med. 2007 May-Jun;32(3):209-16
references.pmid: 17543815
references.citation: Nat Neurosci. 2007 Mar;10(3):331-9
references.pmid: 17310248
references.citation: Glia. 2008 Jan 1;56(1):50-8
references.pmid: 17918263
references.citation: J Neurosci. 2008 Mar 12;28(11):2892-902
references.pmid: 18337420
references.citation: Eur J Neurosci. 2004 Nov;20(9):2294-302
references.pmid: 15525271
references.citation: Neuron Glia Biol. 2006 Nov;2(4):259-69
references.pmid: 17710215
references.citation: J Neurosci. 2007 Mar 7;27(10):2570-81
references.pmid: 17344394
references.citation: Pain. 2007 May;129(1-2):64-75
references.pmid: 17123734
references.citation: Brain Res. 2007 Jun 11;1153:52-7
references.pmid: 17459345
references.citation: Biochem Biophys Res Commun. 2006 Feb 24;340(4):1264-72
references.pmid: 16406240
references.citation: J Neuroimmunol. 2006 Feb;171(1-2):72-85
references.pmid: 16278020
references.citation: Neuron. 2007 May 24;54(4):611-26
references.pmid: 17521573
references.citation: Brain Res. 1992 Dec 18;599(1):13-8
references.pmid: 1283556
references.citation: Proc Natl Acad Sci U S A. 2007 Jun 19;104(25):10655-60
references.pmid: 17551020
references.citation: Brain Res. 2006 Aug 2;1102(1):135-44
references.pmid: 16806114
references.citation: Brain Res. 2007 Nov 14;1180:140-54
references.pmid: 17919462
references.citation: J Neurosci. 2007 Feb 28;27(9):2357-68
references.pmid: 17329433
references.citation: Proc Natl Acad Sci U S A. 2007 Dec 18;104(51):20151-8
references.pmid: 18083844
references.citation: Physiol Rev. 2006 Jul;86(3):1009-31
references.pmid: 16816144
references.citation: Brain Behav Immun. 2007 Jul;21(5):624-33
references.pmid: 17267172
references.citation: FEBS Lett. 2006 Aug 7;580(18):4306-10
references.pmid: 16842787
references.citation: Neurochem Int. 2007 Jul-Sep;51(2-4):185-91
references.pmid: 17669557
references.citation: Neuroscience. 2007 Nov 9;149(3):706-14
references.pmid: 17870246
references.citation: J Neurosci. 2007 Jun 13;27(24):6473-7
references.pmid: 17567808
references.citation: Neuroreport. 2003 Jun 11;14(8):1153-7
references.pmid: 12821799
references.citation: J Neurosci. 2006 Mar 8;26(10):2673-83
references.pmid: 16525046
references.citation: Nature. 2005 Dec 15;438(7070):1017-21
references.pmid: 16355225
references.citation: Nat Med. 2008 Mar;14(3):331-6
references.pmid: 18264108
references.citation: J Neurochem. 2007 Sep;102(5):1447-1458
references.pmid: 17697046
references.citation: J Neurochem. 2008 Jun 1;105(6):2249-59
references.pmid: 18363823
references.citation: Science. 2007 Aug 24;317(5841):1083-6
references.pmid: 17717185
references.citation: Neuroscience. 2001;103(2):529-39
references.pmid: 11246166
references.citation: Pain. 2005 Nov;118(1-2):125-36
references.pmid: 16154703
references.citation: J Neurosci. 2003 Sep 24;23(25):8692-700
references.pmid: 14507968
references.citation: J Neurochem. 2006 Nov;99(3):868-80
references.pmid: 16942597
references.citation: J Neurosci. 2000 Jan 1;20(1):251-8
references.pmid: 10627602
references.citation: Mol Pain. 2007 Dec 12;3:38
references.pmid: 18076762
references.citation: Nat Neurosci. 2007 Nov;10(11):1361-8
references.pmid: 17965656
references.citation: Physiol Res. 1998;47(5):365-75
references.pmid: 10052606
references.citation: J Mol Histol. 2007 Jun;38(3):245-51
references.pmid: 17503193
references.citation: Brain Res Mol Brain Res. 1995 Dec 28;34(2):209-20
references.pmid: 8750824
references.citation: Pain. 2004 Aug;110(3):517-530
references.pmid: 15288392
references.citation: Neuroscience. 2007 Jun 29;147(2):445-55
references.pmid: 17543465
references.citation: Pain. 2005 Mar;114(1-2):149-59
references.pmid: 15733640
references.citation: Nat Rev Neurosci. 2006 Jun;7(6):423-36
references.pmid: 16715052
references.citation: Pain. 2006 May;122(1-2):17-21
references.pmid: 16564626
references.citation: Eur J Neurosci. 2005 Dec;22(11):2775-82
references.pmid: 16324111
references.citation: Brain Res. 1993 Apr 30;610(1):32-8
references.pmid: 8518929
references.citation: J Neurosci. 2004 Aug 18;24(33):7353-65
references.pmid: 15317861
references.citation: J Neurosci. 2004 Sep 29;24(39):8595-605
references.pmid: 15456833
references.citation: Eur J Neurosci. 2004 Jul;20(2):467-73
references.pmid: 15233755
references.citation: Eur J Immunol. 2008 Feb;38(2):448-58
references.pmid: 18196515
references.citation: J Neurosci. 2007 Nov 7;27(45):12396-406
references.pmid: 17989304
references.citation: Neuroscience. 2007 Mar 16;145(2):530-8
references.pmid: 17303338
references.citation: J Neurosci. 2006 May 3;26(18):4930-9
references.pmid: 16672668
references.citation: Anesthesiology. 2007 Aug;107(2):312-21
references.pmid: 17667577
references.citation: Brain Behav Immun. 2007 Jul;21(5):617-23
references.pmid: 17158026
references.citation: Nature. 1994 Jun 30;369(6483):744-7
references.pmid: 7911978
references.citation: J Neurosci. 2007 Aug 15;27(33):8893-902
references.pmid: 17699671
references.citation: Eur J Neurosci. 2004 Sep;20(5):1150-60
references.pmid: 15341587
references.citation: Brain Res Rev. 2007 Nov;56(1):148-69
references.pmid: 17706291
references.citation: Glia. 2007 Apr 15;55(6):595-603
references.pmid: 17299772
references.citation: Proc Natl Acad Sci U S A. 2005 Apr 19;102(16):5856-61
references.pmid: 15809417
references.citation: Eur J Neurosci. 2007 Mar;25(5):1297-306
references.pmid: 17425556
references.citation: J Neurosci. 2003 Apr 1;23(7):2899-910
references.pmid: 12684477
references.citation: Nature. 2001 Mar 22;410(6827):471-5
references.pmid: 11260714
references.citation: Neuroreport. 2007 May 7;18(7):713-7
references.pmid: 17426605
references.citation: J Neurochem. 2005 Mar;92(6):1508-20
references.pmid: 15748168
references.citation: J Neurochem. 2006 Jun;97(5):1337-48
references.pmid: 16606373
references.citation: Pain. 2006 Feb;120(3):315-324
references.pmid: 16426759
references.citation: Mol Ther. 2007 Apr;15(4):687-97
references.pmid: 17299402
references.citation: J Neurochem. 2006 May;97(3):772-83
references.pmid: 16524371
references.citation: Neurochem Int. 2004 Jul-Aug;45(2-3):397-407
references.pmid: 15145554
references.citation: Prog Neurobiol. 1993 Apr;40(4):477-506
references.pmid: 8095350
references.citation: Pain. 2008 Aug 15;138(1):130-142
references.pmid: 18215468
references.citation: Proc Natl Acad Sci U S A. 1961 Jan 15;47:129-36
references.pmid: 13703008
references.citation: Neurosci Lett. 1994 Dec 5;182(2):185-7
references.pmid: 7536313
references.citation: Brain Behav Immun. 2007 Feb;21(2):238-46
references.pmid: 16949251
references.citation: Nat Neurosci. 2007 Nov;10(11):1377-86
references.pmid: 17965658