Sensitization of TRPV1 by protein kinase C in rats with mono-iodoacetate-induced joint pain

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• 作者：K. Koda^&dagger ; ; ^a ; ^{ken.koda@shionogi.co.jp" class="auth_mail" title="E-mail the corresponding author} ; K. Hyakkoku^&dagger ; ; ^a ; ^{kana.hyakkoku@shionogi.co.jp" class="auth_mail" title="E-mail the corresponding author} ; K. Ogawa^&dagger ; ; ^{kouichi.ogawa@shionogi.co.jp" class="auth_mail" title="E-mail the corresponding author} ; K. Takasu^&dagger ; ; ^{keiko.takasu@shionogi.co.jp" class="auth_mail" title="E-mail the corresponding author} ; S. Imai^&Dagger ; ; ^{sunao.imai@shionogi.co.jp" class="auth_mail" title="E-mail the corresponding author} ; Y. Sakurai^&dagger ; ; ^{yusuke.sakurai@shionogi.co.jp" class="auth_mail" title="E-mail the corresponding author} ; M. Fujita^&dagger ; ; ^{masahide.fujita@shionogi.co.jp" class="auth_mail" title="E-mail the corresponding author} ; H. Ono^&dagger ; ; ^{hiroko_ono@shionogi.co.jp" class="auth_mail" title="E-mail the corresponding author} ; M. Yamamoto^&dagger ; ; ^{miyuki.yamamoto@shionogi.co.jp" class="auth_mail" title="E-mail the corresponding author} ; I. Fukuda^§ ; ; ^{isao.fukuda@shionogi.co.jp" class="auth_mail" title="E-mail the corresponding author} ; S. Yamane^&Dagger ; ; ^{shoji.yamane@shionogi.co.jp" class="auth_mail" title="E-mail the corresponding author} ; A. Morita^§ ; ; ^{atsushi.morita@shionogi.co.jp" class="auth_mail" title="E-mail the corresponding author} ; T. Asaki^&dagger ; ; ^{toshiyuki.asaki@shionogi.co.jp" class="auth_mail" title="E-mail the corresponding author} ; T. Kanemasa^&dagger ; ; ^{toshiyuki.kanemasa@shionogi.co.jp" class="auth_mail" title="E-mail the corresponding author} ; G. Sakaguchi^&dagger ; ; ^{gaku.sakaguchi@shionogi.co.jp" class="auth_mail" title="E-mail the corresponding author} ; Y. Morioka^&dagger ; ; ^{yasuhide.morioka@shionogi.co.jp" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Mono-iodoacetate ; Dorsal root ganglion ; TRPV1 ; Protein kinase C ; Joint pain
• 刊名：Osteoarthritis and Cartilage
• 出版年：2016
• 出版时间：July 2016
• 年：2016
• 卷：24
• 期：7
• 页码：1254-1262
• 全文大小：1031 K

文摘

To assess the functional changes of Transient receptor potential vanilloid 1 (TRPV1) receptor and to clarify its mechanism in a rat mono-iodoacetate (MIA)-induced joint pain model (MIA rats), which has joint degeneration with cartilage loss similar to osteoarthritis.

Methods

Sensitization of TRPV1 in MIA rats was assessed by transient spontaneous pain behavior induced by capsaicin injection in knee joints and electrophysiological changes of dorsal root ganglion (DRG) neurons innervating knee joints in response to capsaicin. Mechanisms of TRPV1 sensitization were analyzed by a newly developed sandwich enzyme-linked immunosorbent assay that detects phosphorylated TRPV1, followed by functional and expression analyses of protein kinase C (PKC) in vivo and in vitro, which involves TRPV1 phosphorylation.

Results

Pain-related behavior induced by intra-articular injection of capsaicin was significantly increased in MIA rats compared with sham rats. In addition, capsaicin sensitivity, evaluated by capsaicin-induced inward currents, was significantly increased in DRG neurons of MIA rats. Protein levels of TRPV1 remained unchanged, but phosphorylated TRPV1 at Ser800 increased in DRG neurons of MIA rats. Phosphorylated-PKCɛ (p-PKCɛ) increased and co-localized with TRPV1 in DRG neurons of MIA rats. Capsaicin-induced pain-related behavior in MIA rats was inhibited by intra-articular pretreatment of the PKC inhibitor bisindolylmaleimide I. In addition, intra-articular injection of the PKC activator phorbol 12-myristate 13-acetate increased capsaicin-induced pain-related behavior in normal rats.

Conclusion

TRPV1 was sensitized at the knee joint and at DRG neurons of MIA rats through PKC activation. Thus, TRPV1 sensitization might be involved in chronic pain caused by osteoarthritis.