[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: [Dmt1]N/OFQ(1–13)‐NH2 -- NOP receptor -- opioid receptors -- calcium mobilization -- receptor and [35S]‐GTPγS binding -- guinea pig ileum -- spinal cord -- tail withdrawal assay -- monkey; 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 : 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. 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. 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]‐GTPγS binding, [ 35 S]‐GTPγS 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)‐NH2 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)‐NH2 was confirmed at human recombinant receptors in receptor binding, calcium mobilization and/or [ 35 S]‐GTPγS binding studies, at rat spinal cord receptors in [ 35 S]‐GTPγS 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)‐NH2 was able to elicit robust and long‐lasting antinociceptive effects. Conclusions and Implications: Collectively, these results demonstrate that [Dmt 1 ]N/OFQ(1–13)‐NH2 behaves as NOP/opioid receptor universal agonist and substantiate the suggestion that such mixed ligands are worthy of development as innovative spinal analgesics.