Association of aminopeptidase N and endopeptidase 24.15 inhibitors potentiate behavioral effects mediated by nociceptin/orphanin FQ in mice.

The behavioral effects induced by central administration in mice of the endogenous ORL1 (opioid receptor-like1) ligand, nociceptin/orphanin FQ, were investigated in the absence or presence of inhibitors of aminopeptidase N (bestatin) and endopeptidase 24.15 (Z-(L,D)Phe psi(PO2CH2)(L,D)Ala-Arg-Phe) recently shown to be involved in the metabolism of the heptadecapeptide in vitro. A severe reduction in motor activity induced by nociceptin/orphanin FQ was measured in two tests (spontaneous motor activity and open field). This pharmacological effect was shown to be potentiated by the association of bestatin and Z-(L,D)Phe psi(PO2CH2)(L,D)Ala-Arg-Phe, confirming in vivo the involvement of these peptidases in nociceptin/orphanin FQ inactivation. In our conditions, these inhibitors were devoid of intrinsic effects, suggesting a low tonic regulation by the heptadecapeptide of the measured behaviour.