Nociceptin (NC) and some of its fragments as well as nociceptin-(1−13)-peptide amide [NC(1−13)-NH₂] and a series of its analogues were prepared and tested in the mouse vas deferens in an attempt to identify the sequences involved in the activation (message) and in the binding (address) of nociceptin to its receptor. The NC receptor that inhibits the electrically evoked twitches of the mouse vas deferens was demonstrated to be distinct from the δ opioid receptor, since naloxone and Dmt-Tic-OH (a selective δ opioid receptor antagonist) block the δ opioid receptor but have no effect on the nociceptin receptor. Results from structure−activity experiments suggest that (a) the entire sequence of NC may not be required for full biological activities, since NC(1−13)-NH₂ is as active as NC; (b) fragments of NC have however to be amidated as in NC(1−13)-NH₂ in order to be protected from degradation by proteases; (c) cationic residues (as Arg^8,12, Lys^9,13) appear to play a functional role, since their replacement with Ala in the sequence of NC(1−13)-NH₂ leads to inactivity; (d) the N-terminal tetrapeptide Phe-Gly-Gly-Phe is essential for activity:  its full length and flexibility appear to be required for NC receptor activation and/or occupation; (e) Phe⁴ and not Phe appears to be the residue involved in receptor activation, since the replacement of Phe¹ with Leu has no effect, while that of Phe⁴ leads to inactivity. Results summarized in this paper indicate that the structural requirements of NC for occupation and activation of its receptor are different from that of opioids, particularly δ agonists.