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Letters to Nature
Nature 377, 532 - 535 (12 October 2002); doi:10.1038/377532a0

Isolation and structure of the endogenous agonist of opioid receptor-like ORL1 receptor

Jean-Claude Meunier*, Catherine Mollereau*, Lawrence Toll*, Charles Suaudeauᤠ, Christiane Moisand*, Paul Alvinerie*, Jean-Luc Butour*, Jean-Claude Guillemotᤡ, Pascual Ferraraᤡ, Bernard Monsarrat*, Honoré Mazarguil*, Gilbert Vassart§, Marc Parmentier§ & Jean Costentiná¤

*Laboratoire de Pharmacologie et de Toxicologie Fondamentales, CNRS UPR 8221, 205 Route de Narbonne, 31077 Toulouse Cedex, France
ᤠIFRMP, Unité de Neuropsychopharmacologie Expérimentale, CNRS URA 1969, Faculté de Médecine et de Pharmacie, Avenue de I'Université, BP 97, 76803 Saint Etienne du Rouvray, France
ᤡ Unité de Biochimie des Protéines, Sanofi Recherche, Labège Innopole voie 1, BP 137, 31676 Labege Cedex, France
§IRIBHN, Université Libre, Campus Hospital Erasme, 808 route de Lennik, 1070 Bruxelles, Belgique

THE ORL1 receptor, an orphan receptor whose human1and murine2á¤-8 complementary DNAs have recently been characterized, structurally resembles opioid receptors and is negatively coupled with adenylate cyclase1. ORL1 transcripts are particularly abundant in the central nervous system. Here we report the isolation, on the basis of its ability to inhibit the cyclase in a stable recombinant CHO(ORL1 +) cell line, of a neuropeptide that resembles dynorphin A9 and whose amino acid sequence is Phe-Gly-Gly-Phe-Thr-Gly-Ala-Arg-Lys-Ser-Ala-Arg-Lys-Leu-Ala-Asn-Gln. A rat-brain cDNA encodes the peptide flanked by Lys-Arg proteolytic cleavage motifs. The synthetic heptadecapeptide potently inhibits adenylate cyclase in CHO(ORL1 +) cells in culture and induces hyperalgesia when administered intracerebroventricularly to mice. Taken together, these data indicate that the newly discovered heptadecapeptide is an endogenous agonist of the ORL1 receptor and that it may be endowed with pro-nociceptive properties.

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