Opiate receptor knockout mice define μ receptor roles in endogenous nociceptive responses and morphine-induced analgesia

DOI Web Site 被引用文献35件
  • Ichiro Sora
    Molecular Neurobiology Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD 21224; and Departments of Neurology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21224
  • Nobuyuki Takahashi
    Molecular Neurobiology Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD 21224; and Departments of Neurology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21224
  • Masahiko Funada
    Molecular Neurobiology Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD 21224; and Departments of Neurology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21224
  • Hiroshi Ujike
    Molecular Neurobiology Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD 21224; and Departments of Neurology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21224
  • Randal S. Revay
    Molecular Neurobiology Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD 21224; and Departments of Neurology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21224
  • David M. Donovan
    Molecular Neurobiology Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD 21224; and Departments of Neurology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21224
  • Lucinda L. Miner
    Molecular Neurobiology Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD 21224; and Departments of Neurology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21224
  • George R. Uhl
    Molecular Neurobiology Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD 21224; and Departments of Neurology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21224

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<jats:p>Morphine produces analgesia at opiate receptors expressed in nociceptive circuits. μ, δ, and κ opiate receptor subtypes are expressed in circuits that can modulate nociception and receive inputs from endogenous opioid neuropeptide ligands. The roles played by each receptor subtype in nociceptive processing in drug-free and morphine-treated states have not been clear, however. We produced homologous, recombinant μ, opiate receptor, heterozygous and homozygous knockout animals that displayed ≈54% and 0% of wild-type levels of μ receptor expression, respectively. These mice expressed κ receptors and δ receptors at near wild-type levels. Untreated knockout mice displayed shorter latencies on tail flick and hot plate tests for spinal and supraspinal nociceptive responses than wild-type mice. These findings support a significant role for endogenous opioid–peptide interactions with μ opiate receptors in normal nociceptive processing. Morphine failed to significantly reduce nociceptive responses in hot plate or tail flick tests of homozygous μ receptor knockout mice, and heterozygote mice displayed right and downward shifts in morphine analgesia dose–effect relationships. These results implicate endogenous opioid–peptide actions at μ opiate receptors in several tests of nociceptive responsiveness and support μ receptor mediation of morphine-induced analgesia in tests of spinal and supraspinal analgesia.</jats:p>

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