title: Spinal antinociceptive effects of the novel NOP receptor agonist PWT2-nociceptin/orphanin FQ in mice and monkeys.
abstract: OBJECTIVE
  Using an innovative chemical approach, peptide welding technology (PWT), a tetrabranched derivative of nociceptin/orphanin FQ (N/OFQ) has been generated and pharmacologically characterized. Both in vitro and in vivo PWT2-N/OFQ displayed the same pharmacological profile to the natural ligand. It was more potent and produced longer-lasting effects. The aim of the present study was to investigate the spinal effects of PWT2-N/OFQ in nociceptive and neuropathic pain models in mice and non-human primates.
  
  
  METHODS
  Tail withdrawal assay in mice and monkeys was used as a nociceptive pain model and mechanical threshold in mice subjected to chronic constriction injury was used as a neuropathic pain model. The antinociceptive effects of spinally administered N/OFQ and PWT2-N/OFQ were assessed in these models.
  
  
  RESULTS
  PWT2-N/OFQ mimicked the spinal antinociceptive effects of N/OFQ both in nociceptive and neuropathic pain models in mice as well as in non-human primates displaying 40-fold higher potency and a markedly prolonged duration of action. The effects of N/OFQ and PWT2-N/OFQ were sensitive to the N/OFQ receptor (NOP) antagonist SB-612111, but not to opioid receptor antagonists.
  
  
  CONCLUSIONS
  The present study has demonstrated that PWT2-N/OFQ mimicked the antinociceptive effects of the natural peptide in rodents and non-human primates acting as a potent and longer-lasting NOP-selective agonist. More generally, PWT derivatives of biologically active peptides can be viewed as innovative pharmacological tools for investigating those conditions and states in which selective and prolonged receptor stimulation promotes beneficial effects.
authors.affiliation: Department of Medical Sciences, Section of Pharmacology and National Institute of Neuroscience, University of Ferrara, Ferrara, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Rizzi
authors.affiliation: Department of Anesthesiology, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
authors.forename: D D
authors.initials: DD
authors.lastname: Sukhtankar
authors.affiliation: Department of Anesthesiology, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
authors.forename: H
authors.initials: H
authors.lastname: Ding
authors.affiliation: Department of Chemical and Pharmaceutical Sciences and LTTA, University of Ferrara, Ferrara, Italy.
authors.forename: K
authors.initials: K
authors.lastname: Hayashida
authors.affiliation: Department of Medical Sciences, Section of Pharmacology and National Institute of Neuroscience, University of Ferrara, Ferrara, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Ruzza
authors.affiliation: Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
authors.forename: R
authors.initials: R
authors.lastname: Guerrini
authors.affiliation: Department of Medical Sciences, Section of Pharmacology and National Institute of Neuroscience, University of Ferrara, Ferrara, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Calò
authors.affiliation: Department of Anesthesiology, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
authors.forename: M C
authors.initials: MC
authors.lastname: Ko
mesh_terms: D000700:Analgesics / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D003508:Cycloheptanes / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D009292:Narcotic Antagonists / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D018847:Opioid Peptides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology; D011957:Receptors, Opioid / Q000819:agonists*; D013127:Spinal Nerves / Q000187:drug effects* / Q000293:injuries; D000094942:Nociceptin Receptor; D000097629:Nociceptin
chemical_list: D000700:Analgesics; D003508:Cycloheptanes; D009292:Narcotic Antagonists; D018847:Opioid Peptides; D010880:Piperidines; D011957:Receptors, Opioid; D000094942:Nociceptin Receptor; D000097629:Nociceptin; C000607555:PWT2 nociceptin; C482404:cis-1-methyl-7-((4-(2,6-dichlorophenyl)piperidin-1-yl)methyl)-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol
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