Carboxyl terminal peptides derived from prepro-orphanin FQ/nociceptin (ppOFQ/N) are produced in the hypothalamus and possess analgesic bioactivities

• Published in: Brain research 2001-03, Vol.895 (1), p.89-94
• Main Authors: Mathis, John P., Rossi, Grace C., Pellegrino, Michael J., Jimenez, Charles, Pasternak, Gavril W., Allen, Richard G.
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence - physiology; Analgesics, Opioid - pharmacology; Animals; Biological and medical sciences; Central nervous system; Central neurotransmission. Neuromudulation. Pathways and receptors; Dose-Response Relationship, Drug; Fundamental and applied biological sciences. Psychology; Hypothalamus - drug effects; Hypothalamus - metabolism; Mice; Molecular Sequence Data; Narcotic Antagonists - pharmacology; Nociceptin; OFQ2; Opioid Peptides - analysis; Opioid Peptides - chemistry; Opioid Peptides - metabolism; Opioid Peptides - pharmacology; ORL1; Pain - drug therapy; Pain - metabolism; Pain - physiopathology; Pain Threshold - drug effects; Pain Threshold - physiology; Peptide Fragments - analysis; Peptide Fragments - chemistry; Peptide Fragments - pharmacology; Peptide processing; Protein Structure, Tertiary - physiology; Radioimmunoassay; Receptors, Opioid - drug effects; Receptors, Opioid - metabolism; Sequence Homology, Amino Acid; Spinal Cord - drug effects; Spinal Cord - physiology; Vertebrates: nervous system and sense organs
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/S0006-8993(01)02035-2

Orphanin FQ/nociceptin (OFQ/N), the endogenous ligand for the ORL-1/KOR-3 receptor, produces a wide variety of behavioral responses. Its precursor protein, prepro-OFQ/N (ppOFQ/N) contains several series of amino acids bounded by pairs of basic amino acids, raising the possibility that additional functional neuropeptides could be generated by proteolytic posttranslational processing. Several of these processing products have been shown to have pharmacological activity, including the 17 amino acid peptide OFQ/N (mppOFQ/N 140-157) which is a major product of this precursor in the hypothalamus. Here we have used a newly developed radioimmunoassay and RP-HPLC to detect mppOFQ/N 160-187 in mouse hypothalamic extracts. Murine ppOFQ/N 160-187 has potent analgesic activity supraspinally (3.4 nmol, i.c.v.) and spinally (4.3 nmol, i.t.). This analgesic activity was reversed by the opioid antagonist naloxone (5 mg/kg, s.c.) and kappa 1-selective opioid antagonist nor-BNI (60 μg, i.c.v.), despite the inability of ppOFQ/N 160-187 to compete binding in mu, delta, kappa 1, kappa 3, or OFQ/N binding assays. These findings suggest that murine ppOFQ/N 160-187 may be a physiologically relevant neuropeptide with a novel mechanism of action.