title: [Dmt1]N/OFQ(1-13)-NH2: a potent nociceptin/orphanin FQ and opioid receptor universal agonist.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  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]-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)-NH(2) was able to elicit robust and long-lasting antinociceptive effects.
  
  
  CONCLUSIONS
  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.
authors: Department of Experimental and Clinical Medicine, Section of Pharmacology, University of Ferrara, Italy.
authors: S
authors: S
authors: Molinari
authors: V
authors: V
authors: Camarda
authors: A
authors: A
authors: Rizzi
authors: G
authors: G
authors: Marzola
authors: S
authors: S
authors: Salvadori
authors: E
authors: E
authors: Marzola
authors: P
authors: P
authors: Molinari
authors: J
authors: J
authors: McDonald
authors: M C
authors: MC
authors: Ko
authors: D G
authors: DG
authors: Lambert
authors: G
authors: G
authors: Calo'
authors: R
authors: R
authors: Guerrini
mesh_terms: D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D005260:Female; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000737:chemistry / Q000378:metabolism; D006168:Guinea Pigs; D006801:Humans; D007082:Ileum / Q000187:drug effects* / Q000378:metabolism*; D066298:In Vitro Techniques; D007278:Injections, Spinal; D008253:Macaca mulatta; D008297:Male; D009842:Oligopeptides / Q000494:pharmacology*; D018847:Opioid Peptides / Q000819:agonists*; D011485:Protein Binding; D051381:Rats; D011957:Receptors, Opioid / Q000819:agonists*; D000094942:Nociceptin Receptor; D000097629:Nociceptin
chemical_list: D000700:Analgesics; D002118:Calcium; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D009842:Oligopeptides; D018847:Opioid Peptides; D011957:Receptors, Opioid; D000094942:Nociceptin Receptor; D000097629:Nociceptin; C584786:(Dmt(1))N-OFQ(1-13)-NH(2)