THE ORL₁ receptor, an orphan receptor whose human¹and murine^2-8 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.