title: TNF-alpha and neuropathic pain--a review.
abstract: Tumor necrosis factor alpha (TNF-alpha) was discovered more than a century ago, and its known roles have extended from within the immune system to include a neuro-inflammatory domain in the nervous system. Neuropathic pain is a recognized type of pathological pain where nociceptive responses persist beyond the resolution of damage to the nerve or its surrounding tissue. Very often, neuropathic pain is disproportionately enhanced in intensity (hyperalgesia) or altered in modality (hyperpathia or allodynia) in relation to the stimuli. At time of this writing, there is as yet no common consensus about the etiology of neuropathic pain - possible mechanisms can be categorized into peripheral sensitization and central sensitization of the nervous system in response to the nociceptive stimuli. Animal models of neuropathic pain based on various types of nerve injuries (peripheral versus spinal nerve, ligation versus chronic constrictive injury) have persistently implicated a pivotal role for TNF-alpha at both peripheral and central levels of sensitization. Despite a lack of success in clinical trials of anti-TNF-alpha therapy in alleviating the sciatic type of neuropathic pain, the intricate link of TNF-alpha with other neuro-inflammatory signaling systems (e.g., chemokines and p38 MAPK) has indeed inspired a systems approach perspective for future drug development in treating neuropathic pain.
authors.affiliation: Centre for Neurosciences Studies, 18, Stuart Street, Queen's University, Kingston, Ontario K7L 3N6, Canada. leungl@queensu.ca
authors.forename: Lawrence
authors.initials: L
authors.lastname: Leung
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Cahill
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000473:pathology; D009457:Neuroglia / Q000502:physiology; D009473:Neuronal Plasticity / Q000502:physiology; D010146:Pain / Q000209:etiology / Q000473:pathology*; D059348:Peripheral Nerve Injuries; D010523:Peripheral Nervous System Diseases / Q000150:complications / Q000473:pathology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D016207:Cytokines; D014409:Tumor Necrosis Factor-alpha; D000255:Adenosine Triphosphate; D048051:p38 Mitogen-Activated Protein Kinases
references.citation: Nature. 1983 Aug 25-31;304(5928):730-3
references.pmid: 6888539
references.citation: Purinergic Signal. 2007 Sep;3(4):311-6
references.pmid: 18404444
references.citation: Pain. 2006 Aug;123(3):264-274
references.pmid: 16644129
references.citation: Brain Res. 1999 Sep 11;841(1-2):70-7
references.pmid: 10546989
references.citation: Neurosci Lett. 2008 May 9;436(2):210-3
references.pmid: 18394803
references.citation: Curr Opin Anaesthesiol. 2008 Oct;21(5):570-9
references.pmid: 18784481
references.citation: Acta Physiol (Oxf). 2006 May-Jun;187(1-2):321-7
references.pmid: 16734769
references.citation: Arthritis Rheum. 1989 Apr;32(4):370-7
references.pmid: 2784964
references.citation: Pain. 1990 Nov;43(2):205-218
references.pmid: 1982347
references.citation: Brain Res. 2000 Feb 7;855(1):83-9
references.pmid: 10650133
references.citation: J Peripher Nerv Syst. 2001 Jun;6(2):67-72
references.pmid: 11446385
references.citation: Neurosci Lett. 2004 May 6;361(1-3):184-7
references.pmid: 15135924
references.citation: Brain Res Rev. 2006 Aug;51(2):240-64
references.pmid: 16388853
references.citation: J Physiol. 2009 May 15;587(Pt 10):2111-2
references.pmid: 19332492
references.citation: J Neurol Sci. 1998 Jun 11;158(1):1-4
references.pmid: 9667770
references.citation: Pflugers Arch. 2006 Aug;452(5):645-52
references.pmid: 16767466
references.citation: Spine (Phila Pa 1976). 2005 Dec 15;30(24):2724-8
references.pmid: 16371894
references.citation: J Neurosci. 2008 May 7;28(19):5072-81
references.pmid: 18463260
references.citation: J Neurosci. 2002 Apr 15;22(8):3025-32
references.pmid: 11943805
references.citation: J Neuropathol Exp Neurol. 1991 Jan;50(1):63-72
references.pmid: 1985154
references.citation: J Neurosci. 2008 Aug 20;28(34):8489-501
references.pmid: 18716207
references.citation: Expert Opin Investig Drugs. 2007 Jul;16(7):935-50
references.pmid: 17594181
references.citation: J Infect Dis. 1997 Dec;176 Suppl 2:S173-9
references.pmid: 9396706
references.citation: Br J Pharmacol. 1978 Apr;62(4):573-7
references.pmid: 656702
references.citation: J Neurosci. 2006 Jan 4;26(1):246-55
references.pmid: 16399694
references.citation: Neurosci Lett. 1992 Nov 9;146(2):176-8
references.pmid: 1337194
references.citation: Proc Natl Acad Sci U S A. 1975 Sep;72(9):3666-70
references.pmid: 1103152
references.citation: J Biosci. 2008 Sep;33(3):405-21
references.pmid: 19005240
references.citation: Neuroscience. 2008 Nov 19;157(2):414-23
references.pmid: 18838115
references.citation: J Neuropathol Exp Neurol. 1989 Jan;48(1):33-47
references.pmid: 2908897
references.citation: J Neurosci. 2002 Sep 15;22(18):8139-47
references.pmid: 12223568
references.citation: Exp Neurol. 1999 Nov;160(1):124-32
references.pmid: 10630197
references.citation: J Physiol. 1959 Mar 12;145(3):494-504
references.pmid: 13642316
references.citation: Neurosci Lett. 2004 Dec 6;372(3):215-9
references.pmid: 15542243
references.citation: Glia. 2008 Sep;56(12):1312-9
references.pmid: 18615568
references.citation: J Pharmacol Sci. 2004 Feb;94(2):112-4
references.pmid: 14978347
references.citation: Neuropharmacology. 2007 Mar;52(3):708-15
references.pmid: 17084420
references.citation: J Neurophysiol. 2006 Dec;96(6):3551-5
references.pmid: 17021023
references.citation: Gene Ther. 2007 Jul;14(13):1010-6
references.pmid: 17443214
references.citation: Ann Rheum Dis. 2004 Sep;63(9):1120-3
references.pmid: 15115710
references.citation: J Neurosci. 1996 Aug 15;16(16):5095-105
references.pmid: 8756439
references.citation: J Exp Med. 1993 Jun 1;177(6):1675-80
references.pmid: 8496685
references.citation: J Neuroimmunol. 2001 Mar 1;114(1-2):48-56
references.pmid: 11240015
references.citation: Nature. 2006 Apr 20;440(7087):1054-9
references.pmid: 16547515
references.citation: J Exp Med. 1987 Apr 1;165(4):1218-23
references.pmid: 3559478
references.citation: Psychopharmacology (Berl). 2007 Jul;193(1):97-105
references.pmid: 17393145
references.citation: Glia. 2009 Apr 15;57(6):583-91
references.pmid: 18837052
references.citation: Nucleic Acids Res. 2004 Mar 16;32(5):e49
references.pmid: 15026538
references.citation: J Control Release. 2008 Aug 7;129(3):179-86
references.pmid: 18547669
references.citation: J Neurosci. 2002 Apr 15;22(8):3052-60
references.pmid: 11943808
references.citation: J Neuropathol Exp Neurol. 1991 Mar;50(2):118-25
references.pmid: 1849173
references.citation: Nature. 2003 Aug 14;424(6950):778-83
references.pmid: 12917686
references.citation: Pharmacoeconomics. 2009;27(2):95-112
references.pmid: 19254044
references.citation: Purinergic Signal. 2007 Mar;3(1-2):135-44
references.pmid: 18404427
references.citation: Br J Clin Pharmacol. 2008 Dec;66(6):792-801
references.pmid: 19032723
references.citation: J Neurophysiol. 1997 Oct;78(4):1973-82
references.pmid: 9325365
references.citation: Nature. 1993 Jan 7;361(6407):31-9
references.pmid: 8421494
references.citation: Neurosci Lett. 2008 Apr 4;434(3):293-8
references.pmid: 18314270
references.citation: Neuron. 2006 Oct 5;52(1):77-92
references.pmid: 17015228
references.citation: Brain Res Mol Brain Res. 1998 Nov 20;62(2):228-35
references.pmid: 9813345
references.citation: Neuron Glia Biol. 2006 Nov;2(4):279-91
references.pmid: 18176632
references.citation: Exp Neurol. 2002 May;175(1):23-34
references.pmid: 12009757
references.citation: Neuroreport. 1996 Nov 25;7(18):2897-901
references.pmid: 9116205
references.citation: Reg Anesth Pain Med. 2002 Jul-Aug;27(4):357-66
references.pmid: 12132059
references.citation: Glia. 2010 Apr;58(5):599-610
references.pmid: 19908283
references.citation: J Pain. 2007 Feb;8(2):161-7
references.pmid: 17010673
references.citation: Brain Res Rev. 2009 Apr;60(1):135-48
references.pmid: 19150373
references.citation: Cell Mol Neurobiol. 2008 Dec;28(8):1049-56
references.pmid: 18379870
references.citation: Exp Neurol. 2005 Apr;192(2):444-62
references.pmid: 15755561
references.citation: J Peripher Nerv Syst. 2000 Jun;5(2):96-100
references.pmid: 10905468
references.citation: Brain Res. 2002 May 24;937(1-2):94-9
references.pmid: 12020867
references.citation: Pain. 2002 Sep;99(1-2):11-9
references.pmid: 12237180
references.citation: Neurosci Lett. 1990 Jul 17;115(1):62-7
references.pmid: 2216058
references.citation: Sheng Li Xue Bao. 2004 Oct 25;56(5):591-6
references.pmid: 15497039
references.citation: Mol Pain. 2007 Nov 01;3:33
references.pmid: 17974036
references.citation: Expert Rev Neurother. 2007 Nov;7(11):1613-27
references.pmid: 17997707
references.citation: J Neuropathol Exp Neurol. 1993 May;52(3):223-33
references.pmid: 8492140
references.citation: Exp Neurol. 2001 Jun;169(2):386-91
references.pmid: 11358451
references.citation: Anesthesiology. 2007 Jul;107(1):99-105
references.pmid: 17585221
references.citation: Eur J Pain. 2009 Mar;13(3):263-72
references.pmid: 18554968
references.citation: Pain. 1995 Dec;63(3):289-302
references.pmid: 8719529
references.citation: Spine (Phila Pa 1976). 2004 Oct 1;29(19):2115-9
references.pmid: 15454701
references.citation: Brain Res Rev. 2009 Apr;60(1):125-34
references.pmid: 19146875
references.citation: Anesthesiology. 2009 May;110(5):1116-26
references.pmid: 19387178
references.citation: Eur J Neurosci. 2003 Feb;17(4):791-804
references.pmid: 12603269
references.citation: Acta Neurol Scand. 1967;43(3):365-74
references.pmid: 6049789
references.citation: J Pharmacol Exp Ther. 2004 Mar;308(3):1158-64
references.pmid: 14634040
references.citation: Neuron Glia Biol. 2006 Nov;2(4):259-69
references.pmid: 17710215
references.citation: Neuroscience. 1996 Aug;73(3):625-9
references.pmid: 8809782
references.citation: Gut. 2002 Feb;50(2):196-200
references.pmid: 11788559
references.citation: Neurosci Lett. 1991 Dec 9;133(2):199-202
references.pmid: 1816497
references.citation: Neuroscience. 1993 Aug;55(4):1003-13
references.pmid: 8232895
references.citation: Neurosci Lett. 1995 May 19;191(1-2):43-6
references.pmid: 7659287
references.citation: Physiol Rev. 2007 Apr;87(2):659-797
references.pmid: 17429044
references.citation: Arch Dermatol. 1984 Mar;120(3):338-41
references.pmid: 6703734
references.citation: J Neurosci. 2004 Jan 7;24(1):1-7
references.pmid: 14715932
references.citation: J Neurosci. 2008 Oct 15;28(42):10482-95
references.pmid: 18923025
references.citation: Phys Med Rehabil Clin N Am. 2001 May;12(2):447-59
references.pmid: 11345017
references.citation: J Neuroimmunol. 1992 Aug;39(3):261-8
references.pmid: 1644899
references.citation: Pain. 2000 Aug;87(2):159-169
references.pmid: 10924809
references.citation: Pain. 2006 May;122(1-2):156-62
references.pmid: 16545908
references.citation: Exp Neurol. 2008 Oct;213(2):257-67
references.pmid: 18590729
references.citation: Brain Res. 1994 Jan 28;635(1-2):75-80
references.pmid: 8173981
references.citation: Prog Biochem Pharmacol. 1980;16:141-54
references.pmid: 6108568
references.citation: Adv Exp Med Biol. 2003;521:1-21
references.pmid: 12617561
references.citation: Isr Med Assoc J. 2002 Jun;4(6):471-2
references.pmid: 12073431
references.citation: Cochrane Database Syst Rev. 2003;(2):CD002853
references.pmid: 12804440
references.citation: Novartis Found Symp. 2004;261:55-64; discussion 64-7, 149-54
references.pmid: 15469044
references.citation: Physiol Rev. 2006 Jul;86(3):1009-31
references.pmid: 16816144
references.citation: Brain Res. 1998 Feb 16;784(1-2):154-62
references.pmid: 9518588
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: Expert Opin Ther Targets. 2007 Mar;11(3):307-20
references.pmid: 17298290
references.citation: Exp Physiol. 2005 Sep;90(5):663-70
references.pmid: 15944202
references.citation: Mol Cell Neurosci. 1998 Nov;12(4-5):256-68
references.pmid: 9828090
references.citation: Neuroscience. 2008 Jun 2;153(4):1245-55
references.pmid: 18440713
references.citation: Pain. 1977 Aug;3(4):367-377
references.pmid: 198725
references.citation: Yakugaku Zasshi. 2000 May;120(5):455-62
references.pmid: 10825809
references.citation: Trends Biochem Sci. 2002 Jan;27(1):19-26
references.pmid: 11796220
references.citation: Brain Res. 2000 Mar 17;859(1):113-22
references.pmid: 10720620
references.citation: Cell. 2003 Jul 25;114(2):181-90
references.pmid: 12887920
references.citation: Neurosci Lett. 2008 Jun 6;437(3):194-8
references.pmid: 18403115
references.citation: Nature. 2005 Dec 15;438(7070):1017-21
references.pmid: 16355225
references.citation: Pain Med. 2009 Jul-Aug;10(5):918-29
references.pmid: 19594844
references.citation: Brain Res. 1998 Nov 23;812(1-2):97-104
references.pmid: 9813261
references.citation: Nat Rev Drug Discov. 2008 Jul;7(7):575-90
references.pmid: 18591979
references.citation: Neurol Res. 2008 Jul;30(6):623-31
references.pmid: 18489817
references.citation: Exp Neurol. 1998 May;151(1):138-42
references.pmid: 9582261
references.citation: Nat Rev Neurosci. 2005 Jul;6(7):521-32
references.pmid: 15995723
references.citation: Arthritis Rheum. 2000 Mar;43(3):656-63
references.pmid: 10728760
references.citation: J Neurosurg Spine. 2008 Aug;9(2):221-8
references.pmid: 18764758
references.citation: Nat Rev Drug Discov. 2003 Dec;2(12):973-85
references.pmid: 14654796
references.citation: Curr Pain Headache Rep. 2007 Feb;11(1):38-43
references.pmid: 17214920
references.citation: Int J Biochem Cell Biol. 2005 Jan;37(1):17-21
references.pmid: 15381143
references.citation: Exp Mol Pathol. 1990 Dec;53(3):211-22
references.pmid: 2257929
references.citation: Eur J Neurosci. 2004 Dec;20(11):2896-902
references.pmid: 15579143
references.citation: Exp Brain Res. 1992;91(1):73-8
references.pmid: 1338718
references.citation: Cell Signal. 2004 Feb;16(2):139-44
references.pmid: 14636884
references.citation: J Neurosci. 2008 Oct 29;28(44):11263-8
references.pmid: 18971468
references.citation: Pain. 2007 Apr;128(3):215-224
references.pmid: 17110040
references.citation: Pharmacol Res. 2007 Feb;55(2):158-66
references.pmid: 17207636
references.citation: Pain. 2007 Oct;131(3):262-271
references.pmid: 17317010
references.citation: Neurosci Lett. 2003 Aug 28;347(3):179-82
references.pmid: 12875915
references.citation: Neurochem Int. 2004 Jul-Aug;45(2-3):389-95
references.pmid: 15145553
references.citation: J Inflamm (Lond). 2007 Mar 16;4:5
references.pmid: 17367517
references.citation: Pain. 1993 Dec;55(3):297-304
references.pmid: 8121690
references.citation: J Clin Invest. 1948 Jul;27(4):524
references.pmid: 18939147
references.citation: Curr Pain Headache Rep. 2007 Apr;11(2):109-14
references.pmid: 17367589
references.citation: J Neurosci. 2004 Jan 28;24(4):964-71
references.pmid: 14749441
references.citation: Int Immunopharmacol. 2008 Feb;8(2):188-96
references.pmid: 18182225
references.citation: Eur Spine J. 2009 Dec;18(12):1978-85
references.pmid: 19543754
references.citation: Alzheimer Dis Assoc Disord. 1998;12 Suppl 2:S29-35
references.pmid: 9769027
references.citation: J Neurocytol. 1992 May;21(5):382-90
references.pmid: 1607881
references.citation: Psychoneuroendocrinology. 2005 Nov;30(10):959-64
references.pmid: 15963655
references.citation: J Neuroinflammation. 2010 Feb 10;7:11
references.pmid: 20146792
references.citation: Exp Neurol. 2004 Jan;185(1):160-8
references.pmid: 14697327
references.citation: Neurosci Lett. 2005 May 13;379(3):209-13
references.pmid: 15843065
references.citation: Exp Neurol. 2008 Oct;213(2):303-14
references.pmid: 18601922
references.citation: J Immunol. 2007 Oct 1;179(7):4307-12
references.pmid: 17878324
references.citation: J Neuroimmunol. 2008 Jul 31;198(1-2):113-20
references.pmid: 18547654
references.citation: Annu Rev Psychol. 2000;51:29-57
references.pmid: 10751964
references.citation: Nat Rev Neurosci. 2009 Jan;10(1):23-36
references.pmid: 19096368
references.citation: Pain. 2006 Aug;123(3):306-321
references.pmid: 16675114
references.citation: J Neurosci. 2003 Apr 1;23(7):3028-38
references.pmid: 12684490
references.citation: Science. 2002 Mar 22;295(5563):2282-5
references.pmid: 11910117
references.citation: J Anat. 1997 Feb;190 ( Pt 2):161-200
references.pmid: 9061442
references.citation: Pain. 2006 May;122(1-2):17-21
references.pmid: 16564626
references.citation: Anesthesiology. 2009 Jan;110(1):155-65
references.pmid: 19104183
references.citation: Br Med Bull. 1991 Jul;47(3):644-66
references.pmid: 1794077
references.citation: Neurosci Lett. 2008 Jun 6;437(3):209-13
references.pmid: 18403116
references.citation: Neuroscience. 1999;94(2):587-94
references.pmid: 10579219
references.citation: Spine (Phila Pa 1976). 2003 Apr 15;28(8):750-3; discussion 753-4
references.pmid: 12698115
references.citation: J Neurochem. 1995 Feb;64(2):850-8
references.pmid: 7830079
references.citation: J Interferon Cytokine Res. 1996 Sep;16(9):695-700
references.pmid: 8887053
references.citation: Cell. 2001 Feb 23;104(4):487-501
references.pmid: 11239407
references.citation: Pain. 1999 Mar;80(1-2):273-82
references.pmid: 10204740
references.citation: Neurol Res. 1998 Jan;20(1):41-5
references.pmid: 9471102
references.citation: Phys Biol. 2007 Jan 09;4(1):1-9
references.pmid: 17406080
references.citation: Brain Res. 2000 Jun 2;866(1-2):15-22
references.pmid: 10825476
references.citation: Pain. 1998 Jan;74(1):83-91
references.pmid: 9514564
references.citation: J Invest Dermatol. 1990 Nov;95(5 Suppl):27S-28S
references.pmid: 16788625
references.citation: Brain Res. 1999 May 22;829(1-2):209-21
references.pmid: 10350552
references.citation: Brain Nerve. 2007 Sep;59(9):953-9
references.pmid: 17886477
references.citation: Neurosci Lett. 1995 Jan 16;184(1):5-8
references.pmid: 7739805
references.citation: Eur J Pain. 2009 Aug;13(7):673-81
references.pmid: 18849175
references.citation: Arthritis Rheum. 2007 May;56(5):1440-5
references.pmid: 17469101
references.citation: Neurology. 2001 May 22;56(10):1371-7
references.pmid: 11376190
references.citation: Neurosci Res. 2009 Jun;64(2):133-6
references.pmid: 19428692
references.citation: Pain. 1988 Apr;33(1):87-107
references.pmid: 2837713
references.citation: Brain Res Rev. 2007 Nov;56(1):148-69
references.pmid: 17706291
references.citation: Pain. 2005 Aug;116(3):257-263
references.pmid: 15964142
references.citation: J Neurophysiol. 1995 May;73(5):1811-20
references.pmid: 7623082
references.citation: Brain Res Bull. 2008 Nov 25;77(5):233-6
references.pmid: 18824078
references.citation: Pain. 2004 Aug;110(3):578-587
references.pmid: 15288398
references.citation: Spine (Phila Pa 1976). 2008 Sep 1;33(19):2041-6
references.pmid: 18758358
references.citation: Neurosci Lett. 2002 Mar 1;320(1-2):99-101
references.pmid: 11849773
references.citation: Neurosignals. 2008;16(4):278-88
references.pmid: 18635944
references.citation: Exp Neurol. 2005 Mar;192(1):163-6
references.pmid: 15698630
references.citation: J Biol Regul Homeost Agents. 2002 Apr-Jun;16(2):105-9
references.pmid: 12144121
references.citation: Gen Pharmacol. 1985;16(5):433-40
references.pmid: 2996968
references.citation: Exp Brain Res. 1997 Feb;113(2):200-6
references.pmid: 9063706
references.citation: Eur J Pain. 2006 Feb;10(2):127-35
references.pmid: 16310716
references.citation: Exp Neurol. 2006 Jun;199(2):397-407
references.pmid: 16478624
references.citation: Pain. 2000 Dec 1;88(3):267-275
references.pmid: 11068114
references.citation: J Physiol. 1954 Oct 28;126(1):124-40
references.pmid: 13212735
references.citation: J Pharmacol Exp Ther. 2001 Jun;297(3):1210-7
references.pmid: 11356948
references.citation: Brain Res. 2001 Sep 14;913(1):86-9
references.pmid: 11532251
references.citation: Pharmacol Ther. 2010 Apr;126(1):56-68
references.pmid: 20117131
references.citation: J Neurosci. 2003 Apr 1;23(7):2517-21
references.pmid: 12684435
references.citation: Pain. 1993 Jul;54(1):57-69
references.pmid: 8378104
references.citation: Pain Med. 2009 Oct;10(7):1229-36
references.pmid: 19818033
references.citation: Spine (Phila Pa 1976). 2006 Nov 15;31(24):2759-66
references.pmid: 17108825
references.citation: J Neurosci. 2006 Dec 13;26(50):12852-60
references.pmid: 17167076
references.citation: Brain Res. 1991 Nov 22;565(1):1-7
references.pmid: 1723019
references.citation: Eur J Pharmacol. 2007 Mar 29;560(1):1-8
references.pmid: 17316606
references.citation: Brain Behav Immun. 2007 Feb;21(2):238-46
references.pmid: 16949251