NOCICEPTIN ORPHANIN FQ METABOLISM - ROLE OF AMINOPEPTIDASE AND ENDOPEPTIDASE-24.15/

The endogenous opioid receptor-like(1) (ORL(1)) ligand, nociceptin/orp hanin FQ (FGGFTGARKSARKLANQ), a heptadecapeptide structurally resembli ng dynorphin A, has recently been identified. The wide distribution of ORL(1) mRNA and nociceptin/orphanin FQ precursor in the CNS, particul arly in the limbic system regions and in several areas known to be inv olved in pain perception, suggests that nociceptin/orphanin FQ is pote ntially endowed with various central functions. In general, activation and/or inactivation of regulatory peptides occur through the action o f cell surface peptidases. The physiological mechanisms under which no ciceptin/orphanin FQ is metabolized should lead to a better understand ing of its physiological functions. Mouse brain cortical slices were i ncubated in medium containing the heptadecapeptide in the presence or in the absence of peptidase inhibitors. The critical sites of enzymati c cleavage are Phe(1)-Gly(2), Ala(7)-Arg(8), Ala(11)-Arg(12), and Arg( 12)-Lys(13) bonds. The major role played by metallopeptidases was conf irmed by the complete protection of metabolism in the presence of EDTA . Aminopeptidase N and endopeptidase 24.15 are the two main enzymes in volved in nociceptin/orphanin FQ metabolism, whereas endopeptidase 24. 11 (involved in enkephalin [YGGFM(L)] catabolism) does not appear crit ically involved in nociceptin/orphanin FQ metabolism. The physiologica l relevance of aminopeptidase N and endopeptidase 24.15 in the heptade capeptide metabolism remains to be determined.