PT  - JOURNAL ARTICLE
AU  - Klaus Linz
AU  - Thomas Christoph
AU  - Thomas M. Tzschentke
AU  - Thomas Koch
AU  - Klaus Schiene
AU  - Michael Gautrois
AU  - Wolfgang Schroder
AU  - Babette Y. Kogel
AU  - Horst Beier
AU  - Werner Englberger
AU  - Stefan Schunk
AU  - Jean De Vry
AU  - Ulrich Jahnel
AU  - Stefanie Frosch
TI  - Cebranopadol: a Novel Potent Analgesic Nociceptin/Orphanin FQ Peptide and Opioid Receptor Agonist
AID  - 10.1124/jpet.114.213694
DP  - 2014 Jan 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - jpet.114.213694
4099  - http://jpet.aspetjournals.org/content/early/2014/04/08/jpet.114.213694.short
4100  - http://jpet.aspetjournals.org/content/early/2014/04/08/jpet.114.213694.full
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.