Microglia-neuronal signalling in neuropathic pain hypersensitivity 2.0.
Microglia are increasingly recognized as critical in the pathogenesis of pain hypersensitivity caused by injury to peripheral nerves. The core signalling pathway is through P2X4 purinergic receptors on the microglia which, via the release of brain-derived neurotrophic factor, cause disinhibition of nociceptive dorsal horn neurons by raising intracellular chloride levels. This disinhibition works in synergy with enhanced excitatory synaptic transmission in the dorsal horn to transform the output of the nociceptive network. There is increased discharge output, unmasking of responses to innocuous peripheral inputs and spontaneous activity in neurons that otherwise only signal nociception. Together the changes caused by microglia-neuron signalling may account for the main symptoms of neuropathic pain in humans.
Beggs
Simon
S
Program in Neurosciences & Mental Health, Hospital for Sick Children, 555 University Avenue, Toronto, ON M6H 2X6, Canada.
Salter
Michael W
MW
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002450:Cell Communication / Q000502:physiology*; D002712:Chlorides / Q000378:metabolism; D006801:Humans; D017628:Microglia / Q000502:physiology*; D008954:Models, Biological; D009437:Neuralgia / Q000473:pathology* / Q000503:physiopathology; D009474:Neurons / Q000502:physiology*; D017288:Pain Threshold / Q000502:physiology; D058848:Receptors, Purinergic P2X4 / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D009435:Synaptic Transmission / Q000502:physiology
D019208:Brain-Derived Neurotrophic Factor; D002712:Chlorides; D058848:Receptors, Purinergic P2X4
Nature. 2003 Aug 21;424(6951):938-42
12931188
Neuropathol Appl Neurobiol. 1994 Apr;20(2):177
8072647
Adv Exp Med Biol. 2003;521:1-21
12617561
Nat Med. 2008 Mar;14(3):331-6
18264108
Mol Pain. 2009 Sep 22;5:53
19772627
Nat Med. 2008 Dec;14(12):1325-32
19011637
Nat Neurosci. 2005 Jun;8(6):752-8
15895084
EMBO J. 2010 Jul 21;29(14):2290-300
20562826
J Neurosci. 2007 Nov 7;27(45):12396-406
17989304
Mol Pain. 2007 Sep 27;3:27
17900333
Mol Pain. 2009 Jun 11;5:28
19515262
Proc Natl Acad Sci U S A. 2009 May 12;106(19):8032-7
19380717
Glia. 2008 Apr;56(5):579-85
18240312
J Comp Neurol. 2005 Aug 15;489(1):59-68
15977164
Eur J Neurosci. 2010 Jul;32(2):278-89
20629726
Nat Neurosci. 2007 Nov;10(11):1387-94
17965659
J Neurosci. 2009 Mar 18;29(11):3518-28
19295157
Nature. 2003 Aug 14;424(6950):778-83
12917686
Annu Rev Neurosci. 2009;32:1-32
19400724
Proc Natl Acad Sci U S A. 2004 Apr 20;101(16):6237-42
15069201
J Neurosci. 2003 May 15;23(10):4017-22
12764087
Pain. 2001 Feb 1;90(1-2):1-6
11166964
Annu Rev Immunol. 2009;27:119-45
19302036
J Neurosci. 2009 Nov 18;29(46):14415-22
19923276
Glia. 2008 Jan 1;56(1):50-8
17918263
Brain Behav Immun. 2007 Jul;21(5):624-33
17267172
Nat Rev Immunol. 2009 Jun;9(6):429-39
19461673
Glia. 2006 May;53(7):769-75
16534777
Nature. 2005 Dec 15;438(7070):1017-21
16355225
Trends Neurosci. 2005 Feb;28(2):101-7
15667933
J Neurosci. 2008 Oct 29;28(44):11263-8
18971468
Science. 2000 Jun 9;288(5472):1765-9
10846153
Nat Rev Neurosci. 2009 Jan;10(1):23-36
19096368
Pain. 2005 Mar;114(1-2):149-59
15733640
J Neurosci. 2009 Apr 1;29(13):4096-108
19339605
Science. 2005 May 27;308(5726):1314-8
15831717