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The Journal of Neuroscience, September 17, 2008, 28(38):9486-9494; doi:10.1523/JNEUROSCI.1857-08.2008

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Behavioral/Systems/Cognitive
Reactive Oxygen Species Derived from NOX1/NADPH Oxidase Enhance Inflammatory Pain

Masakazu Ibi,¹ Kuniharu Matsuno,¹ Dai Shiba,² Masato Katsuyama,¹ Kazumi Iwata,¹ Tomoko Kakehi,¹ Takayuki Nakagawa,³ Kazunori Sango,⁴ Yasuhito Shirai,⁵ Takahiko Yokoyama,² Shuji Kaneko,³ Naoaki Saito,⁵ and Chihiro Yabe-Nishimura¹

Departments of ¹Pharmacology and ²Anatomy and Developmental Biology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan, ³Department of Molecular Pharmacology, Graduate School of Pharmaceutical Science, Kyoto University, Kyoto 606-8501, Japan, ⁴Department of Developmental Morphology, Tokyo Metropolitan Institute for Neuroscience, Tokyo 183-8526, Japan, and ⁵Laboratory of Molecular Pharmacology, Biosignal Research Center, Kobe University, Kobe 657-8501, Japan

Correspondence should be addressed to Dr. Chihiro Yabe-Nishimura, Department of Pharmacology, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto 602-8566, Japan. E-mail address: Email: nchihiro{at}koto.kpu-m.ac.jp

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 PKC was markedly perturbed in Nox1^–/Y or Nox1^+/Y DRG neurons treated with ROS-scavenging agents. In cells transfected with tagged PKC, hydrogen peroxide induced translocation and a reduction in free sulfhydryls of full-length PKC but not of the deletion mutant lacking the C1A domain. These findings indicate that NOX1/NADPH oxidase accelerates the translocation of PKC in DRG neurons, thereby enhancing the TRPV1 activity and the sensitivity to painful stimuli.

Key words: NOX1; NADPH oxidase; PKC; TRPV1; hyperalgesia; inflammation

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Received April 28, 2008; revised Aug. 4, 2008; accepted Aug. 4, 2008.

Correspondence should be addressed to Dr. Chihiro Yabe-Nishimura, Department of Pharmacology, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto 602-8566, Japan. E-mail address: Email: nchihiro{at}koto.kpu-m.ac.jp

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