Reactive oxygen species derived from NOX1/NADPH oxidase enhance inflammatory pain.
The involvement of reactive oxygen species (ROS) in an augmented sensitivity to painful stimuli (hyperalgesia) during inflammation has been suggested, yet how and where ROS affect the pain signaling remain unknown. Here we report a novel role for the superoxide-generating NADPH oxidase in the development of hyperalgesia. In mice lacking Nox1 (Nox1(-/Y)), a catalytic subunit of NADPH oxidase, thermal and mechanical hyperalgesia was significantly attenuated, whereas no change in nociceptive responses to heat or mechanical stimuli was observed. In dorsal root ganglia (DRG) neurons of Nox1(+/Y), pretreatment with chemical mediators bradykinin, serotonin, or phorbol 12-myristate 13-acetate (PMA) augmented the capsaicin-induced calcium increase, whereas this increase was significantly attenuated in DRG neurons of Nox1(-/Y). Concomitantly, PMA-induced translocation of PKCepsilon was markedly perturbed in Nox1(-/Y) or Nox1(+/Y) DRG neurons treated with ROS-scavenging agents. In cells transfected with tagged PKCepsilon, hydrogen peroxide induced translocation and a reduction in free sulfhydryls of full-length PKCepsilon but not of the deletion mutant lacking the C1A domain. These findings indicate that NOX1/NADPH oxidase accelerates the translocation of PKCepsilon in DRG neurons, thereby enhancing the TRPV1 activity and the sensitivity to painful stimuli.
Ibi
Masakazu
M
Department of Pharmacology and Anatomy and Developmental Biology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
Matsuno
Kuniharu
K
Shiba
Dai
D
Katsuyama
Masato
M
Iwata
Kazumi
K
Kakehi
Tomoko
T
Nakagawa
Takayuki
T
Sango
Kazunori
K
Shirai
Yasuhito
Y
Yokoyama
Takahiko
T
Kaneko
Shuji
S
Saito
Naoaki
N
Yabe-Nishimura
Chihiro
C
D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D016166:Free Radical Scavengers / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000166:cytology / Q000378:metabolism / Q000503:physiopathology; D006930:Hyperalgesia / Q000378:metabolism / Q000503:physiopathology; D007249:Inflammation / Q000378:metabolism* / Q000503:physiopathology; D018836:Inflammation Mediators / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009247:NADH, NADPH Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D000074624:NADPH Oxidase 1; D009475:Neurons, Afferent / Q000378:metabolism; D009619:Nociceptors / Q000378:metabolism* / Q000503:physiopathology; D018384:Oxidative Stress / Q000502:physiology*; D010146:Pain / Q000378:metabolism* / Q000503:physiopathology; D051744:Protein Kinase C-epsilon / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D050916:TRPV Cation Channels / Q000187:drug effects / Q000378:metabolism
D016166:Free Radical Scavengers; D018836:Inflammation Mediators; D017382:Reactive Oxygen Species; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D009247:NADH, NADPH Oxidoreductases; D000074624:NADPH Oxidase 1; C000614711:NOX1 protein, mouse; D051744:Protein Kinase C-epsilon
Neuron. 1999 Sep;24(1):253-60
10677042
J Physiol. 2006 Nov 1;576(Pt 3):809-22
16901936
J Neurosci. 2004 Jan 14;24(2):565-75
14724257
Neuron. 1999 Jul;23(3):617-24
10433272
J Neurochem. 2005 Dec;95(6):1689-703
16283857
Free Radic Biol Med. 2006 May 15;40(10):1785-95
16678016
Eur J Pharmacol. 2006 Oct 24;548(1-3):167-73
16973155
Nature. 2001 Jun 21;411(6840):957-62
11418861
Pain. 2008 Sep 15;138(3):514-524
18375065
J Neurosci. 2002 Sep 1;22(17):7444-52
12196566
J Neurosci. 2002 Jun 1;22(11):4740-5
12040081
J Neurosci. 2002 Mar 1;22(5):1763-71
11880505
Proc Natl Acad Sci U S A. 2005 Mar 22;102(12):4536-41
15764707
Pain. 2004 Sep;111(1-2):96-103
15327813
Neuron. 2002 Aug 15;35(4):721-31
12194871
J Physiol. 2006 Sep 1;575(Pt 2):555-71
16793902
Jpn J Pharmacol. 1977 Feb;27(1):117-26
864872
J Biol Chem. 2005 Apr 8;280(14):13682-93
15642736
J Biol Chem. 2001 Nov 2;276(44):40591-8
11509553
Circulation. 2005 Oct 25;112(17):2677-85
16246966
J Biol Chem. 2002 May 17;277(20):18037-45
11877428
Pain. 2000 May;86(1-2):95-101
10779666
J Biol Chem. 2002 Sep 20;277(38):35752-9
12095983
J Pathol. 2005 Oct;207(2):164-76
16086438
Pain. 2008 Jan;134(1-2):216-31
18063312
J Biol Chem. 2002 Apr 19;277(16):13375-8
11884385
Eur J Neurosci. 2004 Jan;19(1):55-64
14750963
Proc Natl Acad Sci U S A. 1996 Dec 24;93(26):15435-9
8986829
Neuron. 1998 Sep;21(3):531-43
9768840
Pain. 1997 Jul;71(3):225-35
9231865
Brain. 2005 Jul;128(Pt 7):1634-41
15817518
Pain. 1988 Jan;32(1):77-88
3340425
Proc Natl Acad Sci U S A. 1997 Oct 14;94(21):11233-7
9326592
Science. 2000 Apr 14;288(5464):306-13
10764638
Eur J Pharmacol. 1996 May 15;303(3):217-20
8813572
Proc Natl Acad Sci U S A. 2006 Aug 8;103(32):12132-7
16877542
Nat Rev Immunol. 2004 Mar;4(3):181-9
15039755
J Biol Chem. 2000 Aug 4;275(31):24136-45
10823825
Nat Chem Biol. 2006 Nov;2(11):596-607
16998480
J Pharmacol Exp Ther. 2004 Jun;309(3):869-78
14988418