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Research ArticleArticle

Dose-Related Opposite Modulation by Nociceptin/Orphanin FQ of Substance P Nociception in the Nociceptors and Spinal Cord

Makoto Inoue, Ichiro Shimohira, Akira Yoshida, Andreas Zimmer, Hiroshi Takeshima, Tsukasa Sakurada and Hiroshi Ueda
Journal of Pharmacology and Experimental Therapeutics October 1999, 291 (1) 308-313;
Makoto Inoue
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Ichiro Shimohira
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Akira Yoshida
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Andreas Zimmer
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Hiroshi Takeshima
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Tsukasa Sakurada
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Hiroshi Ueda
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Abstract

We previously reported that the intraplantar (i.pl.) application of nociceptin/orphanin FQ (N/OFQ) at extremely low doses elicited a nociception through a substance P (SP) release from nociceptor endings. In the present study, the nociception induced by SP (and N/OFQ) was abolished by intrathecal (i.t.) injection of neurokinin1(SP receptor) antagonist, suggesting the involvement of the stimulation of nociceptive primary SP neuron and SP release into spinal synapses. On the other hand, similar low doses of N/OFQ (i.t.) exerted nociceptive responses, characterized by scratching, biting, and licking, and these responses were blocked by an neurokinin1antagonist (i.t.) or capsaicin pretreatment or in tachykinin 1 gene knockout mice (tac1−/− mice), suggesting that N/OFQ receptor (NOR) also exists on the spinal terminals of SP neurons. When wide ranges of N/OFQ doses were used, a typical bell-shaped dose-response relationship was observed in both peripheral and central nociception tests. Furthermore, N/OFQ (1 nmol) administered i.pl. blocked SP (i.pl.)-induced flexor responses, which were abolished by pertussis toxin pretreatment or in NOR gene knockout (NOR−/− ) mice. On the other hand, N/OFQ administered i.t. blocked SP (i.t.)-induced scratching, biting, and licking in capsaicin-pretreated and tac1−/− mice, and this antinociception was abolished in NOR−/− mice. All these findings suggest that N/OFQ has biphasic actions depending on doses in the nociceptors and spinal synapses and has postsynaptic antinociceptive actions in spinal cord by modulating SP signaling.

Footnotes

  • Send reprint requests to: Dr. Hiroshi Ueda, Department of Molecular Pharmacology and Neuroscience, Nagasaki University School of Pharmaceutical Sciences, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan. E-mail: ueda{at}net.nagasaki-u.ac.jp

  • ↵1 JSPS research fellow.

  • Abbreviations:
    N/OFQ
    nociceptin/orphanin FQ
    SP
    substance P
    i.pl.
    intraplantar
    i.t.
    intrathecally
    SBL responses
    scratching, biting, and licking
    tac1−/− mice
    tachykinin 1 gene knockout mice
    PLC
    phospholipase C
    PTX
    pertussis toxin
    • Received March 15, 1999.
    • Accepted June 21, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 291 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 291, Issue 1
1 Oct 1999
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Research ArticleArticle

Dose-Related Opposite Modulation by Nociceptin/Orphanin FQ of Substance P Nociception in the Nociceptors and Spinal Cord

Makoto Inoue, Ichiro Shimohira, Akira Yoshida, Andreas Zimmer, Hiroshi Takeshima, Tsukasa Sakurada and Hiroshi Ueda
Journal of Pharmacology and Experimental Therapeutics October 1, 1999, 291 (1) 308-313;

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Research ArticleArticle

Dose-Related Opposite Modulation by Nociceptin/Orphanin FQ of Substance P Nociception in the Nociceptors and Spinal Cord

Makoto Inoue, Ichiro Shimohira, Akira Yoshida, Andreas Zimmer, Hiroshi Takeshima, Tsukasa Sakurada and Hiroshi Ueda
Journal of Pharmacology and Experimental Therapeutics October 1, 1999, 291 (1) 308-313;
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