title: Opioid-type Respiratory Depressant Side Effects of Cebranopadol in Rats Are Limited by Its Nociceptin/Orphanin FQ Peptide Receptor Agonist Activity.
abstract: Cebranopadol is a first-in-class analgesic with agonist activity at classic opioid peptide receptors and the nociceptin/orphanin FQ peptide receptor. The authors compared the antinociceptive and respiratory depressant effects of cebranopadol and the classic opioid fentanyl and used selective antagonists to provide the first mechanistic evidence of the contributions of the nociceptin/orphanin FQ peptide and μ-opioid peptide receptors to cebranopadol's respiratory side-effect profile.
  
  
  
  Antinociception was assessed in male Sprague-Dawley rats using the low-intensity tail-flick model (n = 10 per group). Arterial blood gas tensions (PaCO2 and PaO2) were measured over time in samples from unrestrained, conscious rats after intravenous administration of cebranopadol or fentanyl (n = 6 per group).
  
  
  
  The ED50 for peak antinociceptive effect in the tail-flick model was 7.4 μg/kg for cebranopadol (95% CI, 6.6 to 8.2 μg/kg) and 10.7 μg/kg for fentanyl citrate (9 to 12.7 μg/kg). Fentanyl citrate increased PaCO2 levels to 45 mmHg (upper limit of normal range) at 17.6 μg/kg (95% CI, 7.6 to 40.8 μg/kg) and to greater than 50 mmHg at doses producing maximal antinociception. In contrast, with cebranopadol, PaCO2 levels remained less than 35 mmHg up to doses producing maximal antinociception. The nociceptin/orphanin FQ peptide receptor antagonist J-113397 potentiated the respiratory depressant effects of cebranopadol; these changes in PaCO2 and PaO2 were fully reversible with the μ-opioid peptide receptor antagonist naloxone.
  
  
  
  The therapeutic window between antinociception and respiratory depression in rats is larger for cebranopadol than that for fentanyl because the nociceptin/orphanin FQ peptide receptor agonist action of cebranopadol counteracts side effects resulting from its μ-opioid peptide receptor agonist action.
authors.affiliation: From the Department of Preclinical Drug Development (K.L., S.F.) and Department of Pharmacology and Biomarker Development (W.S., T.C.), Grünenthal GmbH, Aachen, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Linz
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Schröder
authors.forename: Stefanie
authors.initials: S
authors.lastname: Frosch
authors.forename: Thomas
authors.initials: T
authors.lastname: Christoph
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D005283:Fentanyl / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D023421:Models, Animal; D051381:Rats; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid / Q000819:agonists*; D012119:Respiration / Q000187:drug effects*; D013141:Spiro Compounds / Q000494:pharmacology*; D000094942:Nociceptin Receptor
chemical_list: D000701:Analgesics, Opioid; D005283:Fentanyl; D007211:Indoles; D011957:Receptors, Opioid; D013141:Spiro Compounds; D000094942:Nociceptin Receptor; C000589289:6'-fluoro-4',9'-dihydro-N,N-dimethyl-4-phenylspiro(cyclohexane-1,1'(3'H)-pyrano(3,4-b)indol)-4-amine; C000722285:Oprl1 protein, rat