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Research ArticleNEUROPHARMACOLOGY

Protein Kinase C-Mediated Acute Tolerance to Peripheral μ-Opioid Analgesia in the Bradykinin-Nociception Test in Mice

Makoto Inoue and Hiroshi Ueda
Journal of Pharmacology and Experimental Therapeutics May 2000, 293 (2) 662-669;
Makoto Inoue
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Hiroshi Ueda
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Abstract

We studied the acute tolerance liability of peripheral opioid analgesia in mice. The analgesia was assessed by the inhibition of bradykinin (BK)-induced nociceptive action by using a newly developed flexor reflex paradigm. Morphine [intraplantarly (i.pl.)] given ipsilaterally to BK showed a dose-dependent reduction of the BK (2 pmol) responses, whereas the administration of 10 nmol of morphine into the contralateral side failed to show any significant analgesic effects. Furthermore, DAMGO ([d-Ala2,MePhe4,Gly-ol5]-enkephalin), a μ-opioid receptor (MOR) agonist, and U-69593, a κ-opioid receptor (KOR) agonist, but not DSLET ([d-Ser2]Leu-enkephalin-Thr6), a δ-opioid receptor agonist, showed similar analgesia on the BK responses. The morphine- or U-69593 [(5α,7α,8β)-(+)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4,5]dec-8yl] benzeneacetamide]-induced analgesia was markedly attenuated by the intrathecal injection of each antisense oligodeoxynucleotide for the MOR or KOR, respectively, suggesting that these peripheral analgesia are mediated through MORs and KORs located on nociceptor endings, respectively. As BK response was completely recovered to the control level 4 h after morphine (3 nmol i.pl.) or U-69593 (10 nmol i.pl.) administration, these compounds were challenged again to see the inhibition of BK responses. Although morphine analgesia by the second challenge was markedly attenuated, U-69593 analgesia was not. The attenuated morphine analgesia was completely reversed by the pretreatment of calphostin C, Go6976, or HBDDE, a protein kinase C inhibitor, but not by KT-5720, a protein kinase A inhibitor. These results suggest that selective acute tolerance of peripheral morphine analgesia, but not U-69593 analgesia, through MORs and KORs located on polymodal nociceptors, respectively, in the bradykinin-nociception test in mice was mediated through protein kinase C activation.

Footnotes

  • Send reprint requests to: Hiroshi Ueda, Ph.D., Dept. 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 Parts of this study were supported by Grants-in-Aid from the Ministry of Education, Science, Culture and Sports of Japan, and a grant from The Suzuken Memorial Foundation. M.I. is a Research Fellow of the Japan Society for the Promotion of Science.

  • Abbreviations:
    BK
    bradykinin
    nor-BNI
    nor-binaltorphimine
    AUC
    area under the analgesic curve
    CTOP
    d-Phe-Cys-Tyr-d-Trp-Orn-Thr-Pen-Thr-amide
    DAMGO
    [d-Ala2,MePhe4,Gly-ol5]-enkephalin
    DSLET
    [d-Ser2]Leu-enkephalin-Thr6
    DRGs
    dorsal root ganglions
    HBDDE
    2,2′,3,3′,4,4′-hexahydroxy-1,1′-biphenyl-6,6′-dimethanol dimethyl ether
    U-69593
    (5α,7α,8β)-(+)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4,5]dec-8yl] benzeneacetamide
    AS-ODN
    antisense oligodeoxynucleotide
    MS-ODN
    missense oligodeoxynucleotide
    i.pl.
    intraplantar(ly)
    MOR
    μ-opioid receptor
    KOR
    κ-opioid receptor
    i.t.
    intrathecal
    AD50
    median analgesic dose
    DOR
    δ-opioid receptor
    PKC
    protein kinase C
    PKA
    cyclic AMP-dependent protein kinase
    • Received August 31, 1999.
    • Accepted January 25, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 293 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 293, Issue 2
1 May 2000
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Research ArticleNEUROPHARMACOLOGY

Protein Kinase C-Mediated Acute Tolerance to Peripheral μ-Opioid Analgesia in the Bradykinin-Nociception Test in Mice

Makoto Inoue and Hiroshi Ueda
Journal of Pharmacology and Experimental Therapeutics May 1, 2000, 293 (2) 662-669;

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Research ArticleNEUROPHARMACOLOGY

Protein Kinase C-Mediated Acute Tolerance to Peripheral μ-Opioid Analgesia in the Bradykinin-Nociception Test in Mice

Makoto Inoue and Hiroshi Ueda
Journal of Pharmacology and Experimental Therapeutics May 1, 2000, 293 (2) 662-669;
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