Opioid-type Respiratory Depressant Side Effects of Cebranopadol in Rats Are Limited by Its Nociceptin/Orphanin FQ Peptide Receptor Agonist Activity. 2017

Klaus Linz, and Wolfgang Schröder, and Stefanie Frosch, and Thomas Christoph
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.

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.

UI MeSH Term Description Entries
D007211 Indoles Benzopyrroles with the nitrogen at the number one carbon adjacent to the benzyl portion, in contrast to ISOINDOLES which have the nitrogen away from the six-membered ring.
D008297 Male Males
D011957 Receptors, Opioid Cell membrane proteins that bind opioids and trigger intracellular changes which influence the behavior of cells. The endogenous ligands for opioid receptors in mammals include three families of peptides, the enkephalins, endorphins, and dynorphins. The receptor classes include mu, delta, and kappa receptors. Sigma receptors bind several psychoactive substances, including certain opioids, but their endogenous ligands are not known. Endorphin Receptors,Enkephalin Receptors,Narcotic Receptors,Opioid Receptors,Receptors, Endorphin,Receptors, Enkephalin,Receptors, Narcotic,Receptors, Opiate,Endorphin Receptor,Enkephalin Receptor,Normorphine Receptors,Opiate Receptor,Opiate Receptors,Opioid Receptor,Receptors, Normorphine,Receptors, beta-Endorphin,beta-Endorphin Receptor,Receptor, Endorphin,Receptor, Enkephalin,Receptor, Opiate,Receptor, Opioid,Receptor, beta-Endorphin,Receptors, beta Endorphin,beta Endorphin Receptor,beta-Endorphin Receptors
D012119 Respiration The act of breathing with the LUNGS, consisting of INHALATION, or the taking into the lungs of the ambient air, and of EXHALATION, or the expelling of the modified air which contains more CARBON DIOXIDE than the air taken in (Blakiston's Gould Medical Dictionary, 4th ed.). This does not include tissue respiration ( Breathing
D005283 Fentanyl A potent narcotic analgesic, abuse of which leads to habituation or addiction. It is primarily a mu-opioid agonist. Fentanyl is also used as an adjunct to general anesthetics, and as an anesthetic for induction and maintenance. (From Martindale, The Extra Pharmacopoeia, 30th ed, p1078) Phentanyl,Duragesic,Durogesic,Fentanest,Fentanyl Citrate,Fentora,R-4263,Sublimaze,Transmucosal Oral Fentanyl Citrate,R 4263,R4263
D000094942 Nociceptin Receptor A member of the opioid subfamily of the G PROTEIN-COUPLED RECEPTORS. It is the receptor for the endogenous neuropeptide nociceptin. It functions in modulating NOCICEPTION and the perception of pain. KOR-3 Protein,Kappa3-Related Opioid Receptor,MOR-C Protein,Nociceptin Receptors,OFQ Receptor,OFQ Receptors,ORL1 Receptor,ORL1 Receptors,Opiate Receptor-Like 1,Opioid Receptor-Like Protein,Opioid-Receptor-Like 1 Protein,Orphanin FQ Receptor,Orphanin FQ Receptors,Receptor, Nociceptin,Receptor, OFQ,Receptor, Orphanin FQ,Receptors, ORL1,Noci-R,1 Protein, Opioid-Receptor-Like,1, Opiate Receptor-Like,FQ Receptor, Orphanin,FQ Receptors, Orphanin,MOR C Protein,Noci R,Opioid Receptor Like 1 Protein,Protein, KOR-3,Protein, MOR-C,Protein, Opioid Receptor-Like,Protein, Opioid-Receptor-Like 1,Receptor, Kappa3-Related Opioid,Receptor-Like 1, Opiate,Receptor-Like Protein, Opioid,Receptors, Nociceptin,Receptors, Orphanin FQ
D000701 Analgesics, Opioid Compounds with activity like OPIATE ALKALOIDS, acting at OPIOID RECEPTORS. Properties include induction of ANALGESIA or NARCOSIS. Opioid,Opioid Analgesic,Opioid Analgesics,Opioids,Full Opioid Agonists,Opioid Full Agonists,Opioid Mixed Agonist-Antagonists,Opioid Partial Agonists,Partial Opioid Agonists,Agonist-Antagonists, Opioid Mixed,Agonists, Full Opioid,Agonists, Opioid Full,Agonists, Opioid Partial,Agonists, Partial Opioid,Analgesic, Opioid,Full Agonists, Opioid,Mixed Agonist-Antagonists, Opioid,Opioid Agonists, Full,Opioid Agonists, Partial,Opioid Mixed Agonist Antagonists,Partial Agonists, Opioid
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D013141 Spiro Compounds Cyclic compounds that include two rings which share a single atom (usually a carbon). The simplest example of this type of compound is Spiro[2.2]pentane, which looks like a bow tie. Compounds, Spiro
D017207 Rats, Sprague-Dawley A strain of albino rat used widely for experimental purposes because of its calmness and ease of handling. It was developed by the Sprague-Dawley Animal Company. Holtzman Rat,Rats, Holtzman,Sprague-Dawley Rat,Rats, Sprague Dawley,Holtzman Rats,Rat, Holtzman,Rat, Sprague-Dawley,Sprague Dawley Rat,Sprague Dawley Rats,Sprague-Dawley Rats

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