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

THE ORL 1 receptor, an orphan receptor whose human 1 and murine 2-8 complementary DNAs have recently been characterized, structurally resembles opioid receptors and is negatively coupled with adenylate cyclase 1 . ORL 1 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(ORL 1 + ) cell line, of a neuropeptide that resembles dynorphin A 9 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(ORL 1 + ) 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 ORL 1 receptor and that it may be endowed with pro-nociceptive properties.