The actions of naloxazone on the binding and analgesic properties of morphiceptin (NH2Tyr-Pro-Phe-Pro-CONH2), a selective mu-receptor ligand |
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Authors: | A Z Zhang J K Chang G W Pasternak |
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Institution: | 1. The George C. Cotzias Laboratory of Neuro-Oncology, Memorial Sloan-Kettering Cancer Center, and The Departments of Neurology and Pharmacology Cornell University Medical College New York, New York 10021, USA;2. Peninsula Laboratories San Carlos, California 94070, USA |
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Abstract: | Active in both binding and biological assays, morphiceptin (NH2 Tyr-Pro-Phe-Pro-CONH2), a potent opioid peptide derivative of β-casamorphine, binds specifically and selectively to mu or morphine-type receptors with little affinity for delta sites. Displacement studies of a variety of 3H-labeled opiates and enkephalins show biphasic curves. Naloxazone, which blocks irreversibly and selectively high affinity opiate and enkephalin binding, abolishes morphiceptin's inhibition of binding at low concentrations, suggesting that the high affinity binding of enkephalins and opiates represents a mu or morphine-type receptor. Unlike the reversible antagonist naloxone, naloxazone treatment inhibits for over 24 hours the analgesic activity of morphiceptin like it inhibits morphine, β-endorphin and enkephalin analgesia. Together, these studies imply that opiates and enkephalins bind with highest affinity to a mu receptor which mediates their analgesic activity. The 3H-D-ala2-D-leu5-enkephalin binding remaining after naloxazone treatment, representing a lower affinity site (KD 4 nM), is quite insensitive to morphiceptin inhibition and has the characteristics of a delta receptor. However, the 3H-dihydromorphine binding present after naloxazone treatment, which also represents a lower affinity site (KD 6 nM), is far more sensitive to both morphine and morphiceptin and may represent a second morphine-like, or mu, receptor. |
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Keywords: | Address all Correspondence to Dr G W Pasternak Sloan-Kettering Institute 1275 York Avenue New York NY 10021 USA |
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