Supraspinal and spinal effects of [Phe(1)psi(CH2-NH)Gly(2)]-nociceptin(1-13)-NH2 on nociception in the rat

A new derivative of the neuropeptide nociceptin CNC) has recently been deve loped. This molecule, the pseudopeptide [Phe(1)Psi(CH2-NH)Gly(2)] nocicepti n(1-13)-NH2 was found to antagonize NC inhibitory effects in peripheral smo oth muscle preparations in vitro. However, contrasting results have appeare d as regards its pharmacodynamic profile in the CNS. Here, we investigated the pseudopeptide effects, in vivo, on nociceptive responses in the rat. [P he(1)Psi(CH2-NH) Gly(2)] -nociceptin(1 - 13)-NH2 was administered intracere broventricularly (i.c.v.) or intrathecally (i.t.) (alone or in combination with,NC), and tail-flick latencies (TFL) to radiant heat were assessed. I.c .v. [Phe(1)Psi(CH2-NH)Gly(2)]nociceptin(1-13)-NH2 (1-10 nmol/rat) caused a short-lasting decrease (5 min) of TFL and did not antagonize the threshold lowering effect of i.c.v. NC (1 nmol/rat). At the spinal level, the i.t, ad ministration (0.2-10 nmol/rat) of [Phe(1)Psi(CH2-NH)Gly(2)]-nociceptin(1-13 )-NH2 produced a dose-dependent and long-lasting antinociceptive effect tha t was not modified by the administration of a high dose (30 nmol/rat i.t.) of the opioid antagonist naloxone. The i.t. co-administration of the pseudo peptide (10 nmol/rat) did not block the antinociceptive effect of i.t. NC ( 10 nmol/rat). These data indicate that the pseudopeptide behaves as an NC a gonist at supraspinal and spinal levels in the rat tail-flick test of nocic eption. These different profiles in the periphery and the CNS could suggest differences between central and peripheral NC receptor/s and provide a bas is for further development of antagonist molecules suitable for their chara cterization.