title: An antinociceptive role for substance P in acid-induced chronic muscle pain.
abstract: Release of substance P (SP) from nociceptive nerve fibers and activation of its receptor neurokinin 1 (NK1) are important effectors in the transmission of pain signals. Nonetheless, the role of SP in muscle pain remains unknown. Here we show that a single i.m. acid injection in mice lacking SP signaling by deletion of the tachykinin precursor 1 (Tac1) gene or coadministration of NK1 receptor antagonists produces long-lasting hyperalgesia rather than the transient hyperalgesia seen in control animals. The inhibitory effect of SP was found exclusively in neurons expressing acid-sensing ion channel 3, where SP enhances M-channel-like potassium currents through the NK1 receptor in a G protein-independent but tyrosine kinase-dependent manner. Furthermore, the SP signaling could alter action potential thresholds and modulate the expression of TTX-resistant sodium currents in medium-sized muscle nociceptors. Thus, i.m. SP mediates an unconventional NK1 receptor signal pathway to inhibit acid activation in muscle nociceptors, resulting in an unexpected antinociceptive effect against chronic mechanical hyperalgesia, here induced by repeated i.m. acid injection.
authors.affiliation: Molecular Medicine Program, Taiwan International Graduate Program, Institute of Biomedical Sciences,  Academia Sinica, Section 2, Nankang, Taipei 115,  Taiwan.
authors.forename: Chia-Ching John
authors.initials: CC
authors.lastname: Lin
authors.forename: Wei-Nan
authors.initials: WN
authors.lastname: Chen
authors.forename: Chien-Ju
authors.initials: CJ
authors.lastname: Chen
authors.forename: Yi-Wen
authors.initials: YW
authors.lastname: Lin
authors.forename: Andreas
authors.initials: A
authors.lastname: Zimmer
authors.forename: Chih-Cheng
authors.initials: CC
authors.lastname: Chen
mesh_terms: D062565:Acid Sensing Ion Channels; D000200:Action Potentials / Q000502:physiology; D000700:Analgesics / Q000378:metabolism*; D000818:Animals; D059350:Chronic Pain / Q000139:chemically induced / Q000378:metabolism*; D004594:Electrophysiology; D005727:Ganglia, Spinal / Q000378:metabolism; D017353:Gene Deletion; D051379:Mice; D008810:Mice, Inbred C57BL; D059352:Musculoskeletal Pain / Q000139:chemically induced / Q000378:metabolism*; D015288:Neurokinin A / Q000235:genetics; D064729:Neurokinin-1 Receptor Antagonists; D010147:Pain Measurement; D018408:Patch-Clamp Techniques; D011498:Protein Precursors / Q000172:deficiency / Q000235:genetics; D018040:Receptors, Neurokinin-1 / Q000378:metabolism*; D015222:Sodium Channels / Q000235:genetics; D013373:Substance P / Q000378:metabolism*; D015320:Tachykinins / Q000172:deficiency / Q000235:genetics
chemical_list: C508378:ASIC3 protein, mouse; D062565:Acid Sensing Ion Channels; D000700:Analgesics; D064729:Neurokinin-1 Receptor Antagonists; D011498:Protein Precursors; D018040:Receptors, Neurokinin-1; D015222:Sodium Channels; D015320:Tachykinins; C054618:protachykinin; D013373:Substance P; D015288:Neurokinin A
references.citation: J Anat. 2002 Jan;200(Pt 1):69-79
references.pmid: 11837252
references.citation: Trends Neurosci. 2003 Dec;26(12):696-705
references.pmid: 14624855
references.citation: Nature. 1998 Mar 26;392(6674):390-4
references.pmid: 9537322
references.citation: J Pain. 2010 Mar;11(3):210-8
references.pmid: 20015700
references.citation: Mol Pharmacol. 2002 Sep;62(3):554-65
references.pmid: 12181432
references.citation: Exp Neurol. 2007 May;205(1):92-100
references.pmid: 17362934
references.citation: Neurosci Lett. 1996 Apr 26;208(3):191-4
references.pmid: 8733302
references.citation: Exp Brain Res. 1998 Jul;121(2):174-80
references.pmid: 9696386
references.citation: Science. 1975 Nov 28;190(4217):889-90
references.pmid: 242075
references.citation: J Neurosci. 2004 Oct 20;24(42):9405-13
references.pmid: 15496676
references.citation: J Neurochem. 1998 Jul;71(1):106-11
references.pmid: 9648856
references.citation: J Clin Invest. 2010 Apr;120(4):1240-52
references.pmid: 20335661
references.citation: Dtsch Arztebl Int. 2008 Mar;105(12):214-9
references.pmid: 19629211
references.citation: Pharmacol Ther. 2010 Dec;128(3):549-58
references.pmid: 20807551
references.citation: Pain. 2003 Dec;106(3):229-239
references.pmid: 14659506
references.citation: Pain. 1993 Sep;54(3):241-289
references.pmid: 8233542
references.citation: Pharmacol Rev. 2001 Mar;53(1):1-24
references.pmid: 11171937
references.citation: J Pain. 2007 May;8(5):422-9
references.pmid: 17293165
references.citation: Nature. 1996 Nov 28;384(6607):360-4
references.pmid: 8934522
references.citation: Neuron. 2010 Nov 18;68(4):739-49
references.pmid: 21092862
references.citation: Z Rheumatol. 1998;57 Suppl 2:63-6
references.pmid: 10025086
references.citation: Neuroscience. 2008 Jun 2;153(4):1020-33
references.pmid: 18440151
references.citation: Pain. 2006 Jan;120(1-2):53-68
references.pmid: 16359792
references.citation: PLoS One. 2010 Dec 21;5(12):e15162
references.pmid: 21200438
references.citation: Pain. 2005 Mar;114(1-2):168-76
references.pmid: 15733642
references.citation: J Appl Physiol (1985). 2005 Nov;99(5):1977-84
references.pmid: 16037403
references.citation: PLoS Biol. 2008 Jan;6(1):e13
references.pmid: 18232734
references.citation: J Intern Med. 2001 Jan;249(1):27-40
references.pmid: 11168782
references.citation: Mol Pain. 2005 Nov 23;1:35
references.pmid: 16305749
references.citation: Nature. 1998 Mar 26;392(6674):394-7
references.pmid: 9537323
references.citation: Proc Natl Acad Sci U S A. 2002 Jun 25;99(13):8992-7
references.pmid: 12060708
references.citation: Science. 1978 Mar 24;199(4335):1359-62
references.pmid: 204012
references.citation: Trends Pharmacol Sci. 2000 Dec;21(12):462-4; author reply 465
references.pmid: 11229417
references.citation: J Physiol. 1984 Jan;346:203-17
references.pmid: 6199493
references.citation: Science. 1980 Apr 18;208(4441):305-7
references.pmid: 6154313
references.citation: Exp Brain Res. 2009 Jun;196(1):89-100
references.pmid: 19139871
references.citation: Cell. 2009 Oct 16;139(2):267-84
references.pmid: 19837031
references.citation: J Neurosci. 2007 Oct 24;27(43):11533-42
references.pmid: 17959796
references.citation: Muscle Nerve. 2001 Jan;24(1):37-46
references.pmid: 11150964
references.citation: Neurosci Lett. 1984 Dec 21;52(3):235-40
references.pmid: 6084209
references.citation: Nature. 2009 Feb 5;457(7230):741-4
references.pmid: 19092807
references.citation: Br J Pharmacol. 2009 Apr;156(8):1185-95
references.pmid: 19298256
references.citation: J Appl Physiol (1985). 1998 Jun;84(6):1827-33
references.pmid: 9609773
references.citation: J Neurosci. 2002 Jul 1;22(13):5687-93
references.pmid: 12097520
references.citation: Nat Neurosci. 2001 Sep;4(9):869-70
references.pmid: 11528414
references.citation: Mol Pain. 2009 Jul 14;5:39
references.pmid: 19602228
references.citation: Pain. 2003 Aug;104(3):579-588
references.pmid: 12927630
references.citation: Pain. 2007 May;129(1-2):102-12
references.pmid: 17134831
references.citation: Eur J Pharmacol. 2004 Mar 8;487(1-3):93-103
references.pmid: 15033380
references.citation: Neuropeptides. 1997 Dec;31(6):537-63
references.pmid: 9574822
references.citation: Nat Protoc. 2010 Apr;5(4):714-24
references.pmid: 20360766
references.citation: Pflugers Arch. 2008 Aug;456(5):857-66
references.pmid: 18228037
references.citation: J Physiol. 1996 May 15;493 ( Pt 1):157-66
references.pmid: 8735701
references.citation: Nature. 1976 Aug 26;262(5571):784-5
references.pmid: 958450
references.citation: Expert Opin Investig Drugs. 2009 Oct;18(10):1479-93
references.pmid: 19732029
references.citation: J Neurosci. 2001 Oct 15;21(20):8026-33
references.pmid: 11588175
references.citation: Trends Pharmacol Sci. 2000 Jul;21(7):244-6
references.pmid: 10871891
references.citation: J Neurosci. 2010 Mar 10;30(10):3752-61
references.pmid: 20220009
references.citation: Science. 2003 Feb 21;299(5610):1237-40
references.pmid: 12595694
references.citation: Proc Natl Acad Sci U S A. 1998 Mar 3;95(5):2630-5
references.pmid: 9482938
references.citation: Mol Pain. 2009 Jan 07;5:1
references.pmid: 19126241
references.citation: Neuroscience. 2008 Jan 24;151(2):544-57
references.pmid: 18082972
references.citation: J Neurosci. 2008 Oct 29;28(44):11240-9
references.pmid: 18971466
references.citation: Science. 1997 Oct 10;278(5336):275-9
references.pmid: 9323204
references.citation: J Physiol. 2005 Apr 1;564(Pt 1):259-68
references.pmid: 15677691