A heptadecapeptide (Phe-Gly-Gly-Phe-Thr-Gly-Ala-Arg-Lys-Ser-Ala-Arg-Lys-Leu-Ala-Asn-Gln) was identified from rat brain and from porcine brain as a ligand for OP4, a new G-protein coupled receptor that is similar in sequence to opioid receptors. The OP4 receptor is widely expressed in the nervous system where it mediates a broad range of physiological functions. The new peptide, nociceptin (NC), has a primary sequence recalling that of opioid peptides. Despite the homologies (a) of the OP4 receptor with known opioid receptors, especially the OP2 (kappa) receptor, and (b) of NC with opioid peptides, particularly dynorphin A, the two biological systems have different anatomical locations and chemical requirements for activation. NC does not bind to opioid receptors, and mammalian opioid peptides do not interact with the OP4 receptor. The presence of Phe in position 1 and Arg in position 8, appear to be instrumental to exclude NC from interacting with the opioid receptors. Contrary to opioid peptides which strikly require Tyr in position 1, the active core that activates the OP4 appears to be towards the centre of the peptide molecule and includes Phe4. Based on the message/address model, several changes have been made in the N-terminal tetrapeptide Phe-Gly-Gly-Phe (message) and a few also in the C-terminal of the template NC(1-13)-NH2, a fragment that acts as a full agonist both in vitro and in vivo. Subtle changes of the N-terminal sequence, especially at Phe1, led to the discovery of peptide antagonists ([Phe1 psi (CH2-NH)Gly2[-NC(1-13)-NH2 and [Nphe1[-NC(1-13)-NH2). The first compound has been widely used to characterize NC actions in the periphery and in the central nervous system. It has been shown to act mainly as an antagonist outside the brain and as an agonist in the central nervous system. [Nphe1[-NC(1-13)-NH2- on the contrary, acts as antagonist both in the periphery and in the brain. These first peptide prototypes may soon be followed by non-peptide compounds, some of which, are already described in patient literature.