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Research Article

Identification of a high‐affinity orphanin FQ/nociceptin(1–11) binding site in mouse brain

John P. Mathis

The Cotzias Laboratory of Neuro‐Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10021

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Ira E. Goldberg

The Cotzias Laboratory of Neuro‐Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10021

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Sharon R. Letchworth

The Cotzias Laboratory of Neuro‐Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10021

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Jennifer P. Ryan‐Moro

The Cotzias Laboratory of Neuro‐Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10021

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Gavril W. Pasternak

Corresponding Author

E-mail address: [email protected]

The Cotzias Laboratory of Neuro‐Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10021

Department of Neurology, Memorial Sloan‐Kettering Cancer Center, 1275 York Avenue, New York, NY 10021.
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Abstract

The presence of pairs of basic amino acids within the orphanin FQ/Nociceptin (OFQ/N) sequence has raised the possibility that truncated versions of the peptide might be physiologically important. OFQ/N(1–11) is pharmacologically active in mice, despite its poor affinity in binding assays (Ki > 250 nM) for the OFQ/N receptor. Using an analog of OFQ/N(1–11), [125I][Tyr10]OFQ/N(1–11), we identified a high‐affinity binding site (KD 234 pM; Bmax 43 fmol/mg protein) with a selectivity profile distinct from the OFQ/N receptor and all the traditional opioid receptors. This site had very high affinity for OFQ/N and its related peptides. The most striking differences between the new site and the OFQ/N receptor previously observed in brain were seen with traditional opioids. Dynorphin A analogs and α‐neoendorphin competed with [125I][Tyr10]OFQ/N(1–11) binding in mouse brain with Ki values below 10 nM, while naloxone benzoylhydrazone (Ki 3.9 nM) labeled the [125I][Tyr10]OFQ/N(1–11) binding site as potently as many traditional opioid receptors. Several other opioids, including fentanyl, (−)cyclazocine, levallorphan, naltrindole, and diprenorphine, also displayed moderate affinities for this site. Finally, the [125I][Tyr10]OFQ/N(1–11) site had a unique regional distribution consistent with a distinct receptor. Thus, [125I][Tyr10]OFQ/N(1–11) labels a novel site in brain with a selectivity profile intermediate between that of either opioid or OFQ/N receptors. Synapse 34:181–186, 1999. © 1999 Wiley‐Liss, Inc.

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