[Dmt(1) ]N/OFQ(1-13)-NH(2) , a potent nociceptin/orphanin FQ and opioid receptor universal agonist.

Background and purpose. Intrathecally (i.t.) administered nociceptin/orphanin FQ (N/OFQ) evokes antinociceptive effects in rodents. Recent studies in monkeys demonstrated that i.t. coapplication of N/OFQ and morphine elicits synergistic antinociceptive actions suggesting mixed N/OFQ peptide (NOP) and mu opioid (MOP) receptor agonists as innovative spinal analgesics. Thus novel N/OFQ related peptides were synthesised in order to identify and pharmacologically characterize a mixed NOP/MOP agonist. Experimental approach. The following in vitro assays were used: calcium mobilization in cells expressing the human NOP or classical opioid receptors and chimeric G proteins, receptor and [(35) S]GTPgammaS binding, [(35) S]GTPgammaS binding in rat spinal cord membranes, guinea pig ileum bioassay. In vivo experiments were performed in monkeys using the tail withdrawal assay. Key results. From calcium mobilization studies [Dmt(1) ]N/OFQ(1-13)-NH(2) was selected as the most potent and least selective compound. The mixed NOP/opioid full agonist activity and high affinity of [Dmt(1) ]N/OFQ(1-13)-NH(2) was confirmed at human recombinant receptors in receptor binding, calcium mobilization and/or [(35) S]GTPgammaS binding studies, at rat spinal cord receptors in [(35) S]GTPgammaS binding experiments, and at guinea pig receptors inhibiting neurogenic contractions in the ileum. In vivo in the tail withdrawal assay in monkeys i.t. [Dmt(1) ]N/OFQ(1-13)-NH(2) was able to elicit robust and long lasting antinociceptive effects. Conclusions and Implications. Collectively these results demonstrate that [Dmt(1) ]N/OFQ(1-13)-NH(2) behaves as NOP/opioid receptor universal agonist and substantiate the suggestion that such mixed ligands are worthy of development as innovative spinal analgesics.