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Research ArticleNEUROPHARMACOLOGY

The Antitussive Activity of δ-Opioid Receptor Stimulation in Guinea Pigs

Charles J. Kotzer, Douglas W. P. Hay, Giulio Dondio, Giuseppe Giardina, Paola Petrillo and David C. Underwood
Journal of Pharmacology and Experimental Therapeutics February 2000, 292 (2) 803-809;
Charles J. Kotzer
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Douglas W. P. Hay
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Giulio Dondio
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Giuseppe Giardina
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Paola Petrillo
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David C. Underwood
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Abstract

In this study, the activity of the δ-opioid receptor subtype-selective agonist, SB 227122, was investigated in a guinea pig model of citric acid-induced cough. Parenteral administration of selective agonists of the δ-opioid receptor (SB 227122), μ-opioid receptor (codeine and hydrocodone), and κ-opioid receptor (BRL 52974) produced dose-related inhibition of citric acid-induced cough with ED50 values of 7.3, 5.2, 5.1, and 5.3 mg/kg, respectively. The nonselective opioid receptor antagonist, naloxone (3 mg/kg, i.m.), attenuated the antitussive effects of codeine or SB 227122, indicating that the antitussive activity of both compounds is opioid receptor-mediated. The δ-receptor antagonist, SB 244525 (10 mg/kg, i.p.), inhibited the antitussive effect of SB 227122 (20 mg/kg, i.p.). In contrast, combined pretreatment with β-funaltrexamine (μ-receptor antagonist; 20 mg/kg, s.c.) and norbinaltorphimine (κ-receptor antagonist; 20 mg/kg, s.c.), at doses that inhibited the antitussive activity of μ- and κ-receptor agonists, respectively, was without effect on the antitussive response of SB 227122 (20 mg/kg, i.p.). The ς-receptor antagonist rimcazole (3 mg/kg, i.p.) inhibited the antitussive effect of dextromethorphan (30 mg/kg, i.p.), a ς-receptor agonist, but not that of SB 227122. These studies provide compelling evidence that the antitussive effects of SB 227122 in this guinea pig cough model are mediated by agonist activity at the δ-opioid receptor.

Footnotes

  • Send reprint requests to: Dr. David C. Underwood, Department of Pulmonary Pharmacology, UW2532, SmithKline Beecham Pharmaceuticals, 709 Swedeland Rd., King of Prussia, PA 19406. E-mail:david_c_underwood{at}sbphrd.com

  • Abbreviations:
    DAMGO
    d-Ala2-Me-Phe4-Gly-ol5-enkephalin
    h-DOR
    human δ-opioid receptor
    h-MOR
    human μ-opioid receptor
    h-KOR
    human κ-opioid receptor
    β-FNA
    β-funaltrexamine
    Nor-BNI
    norbinaltorphimine
    CHO
    Chinese hamster ovary
    HEK-293
    human embryonic kidney 293
    RT-PCR
    reverse-transcription polymerase chain reaction
    DADLE
    d-Ala2-d-Leu5-enkephalin
    S.A.
    specific activity
    PLSD
    protected least-squares difference
    • Received July 30, 1999.
    • Accepted November 1, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 292 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 292, Issue 2
1 Feb 2000
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Research ArticleNEUROPHARMACOLOGY

The Antitussive Activity of δ-Opioid Receptor Stimulation in Guinea Pigs

Charles J. Kotzer, Douglas W. P. Hay, Giulio Dondio, Giuseppe Giardina, Paola Petrillo and David C. Underwood
Journal of Pharmacology and Experimental Therapeutics February 1, 2000, 292 (2) 803-809;

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Research ArticleNEUROPHARMACOLOGY

The Antitussive Activity of δ-Opioid Receptor Stimulation in Guinea Pigs

Charles J. Kotzer, Douglas W. P. Hay, Giulio Dondio, Giuseppe Giardina, Paola Petrillo and David C. Underwood
Journal of Pharmacology and Experimental Therapeutics February 1, 2000, 292 (2) 803-809;
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