C-Terminal glycine is crucial for hyperalgesic activity of nociceptin/orphanin FQ-(1-6).

A C-terminal analog of the hexapeptide orphanin FQ/nociceptin-(1-6), [Ala(6)]-orphanin FQ/nociceptin-(1-6), and a pentapeptide orphanin FQ/nociceptin-(1-5) were tested in vivo for their analgesic/hyperalgesic activity in the hot-plate test with rats. Replacement of the C-terminal glycine by L-alanine (Phe-Gly-Gly-Phe-Thr-Ala) in orphanin FQ/nociceptin-(1-6) abolished the hyperalgesic potency of native orphanin FQ/nociceptin-(1-6) (Phe-Gly-Gly-Phe-Thr-Gly), but analgesic activity was retained and was diminished by naloxone. Removal of the C-terminal amino acid (glycine or alanine) from orphanin FQ/nociceptin-(1-6) caused a significant loss of analgesic activity. It is anticipated that glycine plays a crucial role in the biphasic activity of orphanin FQ/nociceptin-(1-6). This may suggest the existence of a mechanism for terminating the biological action of orphanin FQ/nociceptin.