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

Orphanin FQ/nociceptin (OFQ/N), the endogenous ligand for the ORL-1/KOR-3 r eceptor, produces a wide variety of behavioral responses. Its precursor pro tein, prepro-OFQ/N (ppOFQ/N) contains several series of amino acids bounded by pairs of basic amino acids. raising the possibility that additional fun ctional neuropeptides could be generated by proteolytic posttranslational p rocessing. Several of these processing products have been shown to have pha rmacological activity, including the 17 amino acid peptide OFQ/N (mppOFQ/N1 40-157) which is a major product of this precursor in the hypothalamus. Her e wt: have used a newly developed radioimmunoassay and RP-HPLC to detect mp pOFQ/N160-187 in mouse hypothalamic extracts, Murine ppOFQ/N160-187 has pot ent analgesic activity supraspinally (3.3 nmol, i.c.v,) and spinally (4.3 n mol, i.t.). This analgesic activity was reversed by the opioid antagonist n aloxone (5 mg/kg, s.c.) and kappa(1)-selective opioid antagonist nor-BNI (6 0 mug. i.c.v.), despite the inability of ppOFQ/N160-187 to compete binding in mu, delta, kappa(1), kappa(3). or OFQ/N binding assays. These findings s uggest that murine ppOFQ/N160-187 may be a physiologically relevant neurope ptide with a novel mechanism of action. (C) 2001 Elsevier Science B.V. All rights reserved.