[Dmt1]N/OFQ(1–13)‐NH2: a potent nociceptin/orphanin FQ and opioid receptor universal agonist. (18th December 2012)

• Record Type: Journal Article
• Authors: Molinari, S; Camarda, V; Rizzi, A; Marzola, G; Salvadori, S; Marzola, E; Molinari, P; McDonald, J; Ko, MC; Lambert, DG; Calo', G; Guerrini, R
• Is Part Of: British journal of pharmacology. Volume 168:Number 1(2013:Jan.)
• Page Start: 151
• Page End: 162
• Publication Date: 2012-12-18
• Subjects: Pharmacology -- Periodicals; Chemotherapy -- Periodicals; Drug Therapy -- Periodicals; Pharmacology -- Periodicals; 615.1
• DOI: 10.1111/j.1476-5381.2012.02115.x
• Languages: English
• ISSNs: 0007-1188

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="bph2115-sec-0001" sec-type="section"> <title>Background and Purpose</title> <p>Intrathecally (i.t.) administered nociceptin/orphanin FQ (N/OFQ) evokes antinociceptive effects in rodents. Recent studies in monkeys demonstrated that i.t. co‐application of N/OFQ and morphine elicits synergistic antinociceptive actions suggesting mixed N/OFQ peptide (NOP) and μ opioid receptor agonists as innovative spinal analgesics. Thus, novel N/OFQ related peptides were synthesized in order to identify and pharmacologically characterize a mixed NOP/ μ opioid receptor agonist.</p> </sec> <sec id="bph2115-sec-0002" sec-type="section"> <title>Experimental Approach</title> <p>The following <italic>in vitro</italic> assays were used: calcium mobilization in cells expressing the human NOP or classical opioid receptors and chimeric G proteins, receptor and [<sup>35</sup>S]‐GTPγS binding, [<sup>35</sup>S]‐GTPγS binding in rat spinal cord membranes, guinea pig ileum bioassay. <italic>In vivo</italic> experiments were performed in monkeys using the tail withdrawal assay.</p> </sec> <sec id="bph2115-sec-0003" sec-type="section"> <title>Key Results</title> <p>From calcium mobilization studies [Dmt<sup>1</sup>]N/OFQ(1–13)‐NH<sub>2</sub> was selected as the most potent and least selective compound. The mixed NOP/opioid full agonist activity and high affinity of [Dmt<sup>1</sup>]N/OFQ(1–13)‐NH<sub>2</sub> was confirmed at human recombinant receptors in receptor binding, calcium mobilization and/or [<sup>35</sup>S]‐GTPγS binding studies, at rat spinal cord receptors in [<sup>35</sup>S]‐GTPγS binding experiments, and at guinea pig receptors inhibiting neurogenic contractions in the ileum. <italic>In vivo</italic> in the tail withdrawal assay in monkeys i.t. [Dmt<sup>1</sup>]N/OFQ(1–13)‐NH<sub>2</sub> was able to elicit robust and long‐lasting antinociceptive effects.</p> </sec> <sec id="bph2115-sec-0004" sec-type="section"> <title>Conclusions and Implications</title> <p>Collectively, these results demonstrate that [Dmt<sup>1</sup>]N/OFQ(1–13)‐NH<sub>2</sub> behaves as NOP/opioid receptor universal agonist and substantiate the suggestion that such mixed ligands are worthy of development as innovative spinal analgesics.</p> </sec> </abstract>