RT Journal Article SR Electronic T1 Cebranopadol: a Novel Potent Analgesic Nociceptin/Orphanin FQ Peptide and Opioid Receptor Agonist JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP jpet.114.213694 DO 10.1124/jpet.114.213694 A1 Klaus Linz A1 Thomas Christoph A1 Thomas M. Tzschentke A1 Thomas Koch A1 Klaus Schiene A1 Michael Gautrois A1 Wolfgang Schroder A1 Babette Y. Kogel A1 Horst Beier A1 Werner Englberger A1 Stefan Schunk A1 Jean De Vry A1 Ulrich Jahnel A1 Stefanie Frosch YR 2014 UL http://jpet.aspetjournals.org/content/early/2014/04/08/jpet.114.213694.abstract AB Cebranopadol (trans-6'-fluoro-4',9'-dihydro-N,N-dimethyl-4-phenyl-spiro[cyclohexane-1,1'(3'H)-pyrano[3,4-b]indol]-4-amine) is a novel analgesic nociceptin/orphanin FQ peptide (NOP) and opioid receptor agonist (Ki [nM]/EC50 [nM]/relative efficacy [%]: human NOP receptor 0.9/13.0/89; human mu opioid peptide [MOP] receptor 0.7/1.2/104; human kappa opioid peptide receptor 2.6/17/67; human delta opioid peptide receptor 18/110/105). Cebranopadol exhibits highly potent and efficacious antinociceptive and antihypersensitive effects in several rat models of acute and chronic pain (tail-flick, rheumatoid arthritis, bone cancer, spinal nerve ligation, diabetic neuropathy) with ED50 values of 0.5-5.6 μg/kg after intravenous and 25.1 μg/kg after oral administration. In comparison to selective MOP receptor agonists, cebranopadol was more potent in models of chronic neuropathic than acute nociceptive pain. Cebranopadol's duration of action is long (up to 7 h after intravenous 12 μg/kg; >9 h after oral 55 μg/kg in the rat tail-flick test). The antihypersensitive activity of cebranopadol in the spinal nerve ligation model was partially reversed by pretreatment with the selective NOP receptor antagonist J-113397 (1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one) or the opioid receptor antagonist naloxone, indicating that both NOP and opioid receptor agonism are involved in this activity. Development of analgesic tolerance in the chronic constriction injury model was clearly delayed compared with that from an equi-analgesic dose of morphine (complete tolerance on day 26 versus day 11, respectively). Unlike morphine, cebranopadol did not disrupt motor coordination and respiration at doses within and exceeding the analgesic dose range. Cebranopadol, by its combination of agonism at NOP and opioid receptors, affords highly potent and efficacious analgesia in various pain models with a favorable side-effect profile.