Synergistic interaction between the agonism of cebranopadol at nociceptin/orphanin FQ and classical opioid receptors in the rat spinal nerve ligation model

Autor:	Wolfgang P. Schröder, Thomas Christoph, Jean De Vry, Robert B. Raffa
Rok vydání:	2018
Předmět:	Agonist Male Indoles medicine.drug_class Narcotic Antagonists NOP Pharmacology Rats Sprague-Dawley 03 medical and health sciences cebranopadol 0302 clinical medicine nociceptin/orphanin FQ Piperidines 030202 anesthesiology Opioid receptor Naltrindole synergism medicine Animals Humans Spiro Compounds rat General Pharmacology Toxicology and Pharmaceutics Opioid peptide Ligation Pain Measurement Chemistry Cebranopadol Drug Synergism Original Articles Rats Analgesics Opioid Nociceptin receptor Disease Models Animal Spinal Nerves Neurology Opioid Opioid Peptides spinal nerve ligation Receptors Opioid Neuralgia Benzimidazoles Original Article 030217 neurology & neurosurgery medicine.drug
Zdroj:	Pharmacology Research & Perspectives
ISSN:	2052-1707
Popis:	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 opioid peptide (NOP) and classical opioid receptor (MOP, DOP, and KOP) agonist with highly efficacious and potent activity in a broad range of rodent models of nociceptive, inflammatory, and neuropathic pain as well as limited opioid‐type side effects such as respiratory depression. This study was designed to explore contribution and interaction of NOP and classical opioid receptor agonist components to cebranopadol analgesia in the rat spinal nerve ligation (SNL) model. Assessing antihypersensitive activity in SNL rats intraperitoneal (IP) administration of cebranopadol resulted in ED 50 values of 3.3 and 3.58 μg/kg in two independent experiments. Pretreatment (IP) with J‐113397 (4.64 mg/kg) a selective antagonist for the NOP receptor or naloxone (1 mg/kg), naltrindole (10 mg/kg), or nor‐BNI (10 mg/kg), selective antagonists for MOP, DOP, and KOP receptors, yielded ED 50 values of 14.1, 16.9, 17.3, and 15 μg/kg, respectively. This 4‐5 fold rightward shift of the dose‐response curves suggested agonistic contribution of all four receptors to the analgesic activity of cebranopadol. Combined pretreatment with a mixture of the antagonists for the three classical opioid receptors resulted in an 18‐fold potency shift with an ED 50 of 65.5 μg/kg. The concept of dose equivalence was used to calculate the expected additive effects of the parent compound for NOP and opioid receptor contribution and to compare them with the observed effects, respectively. This analysis revealed a statistically significant difference between the expected additive and the observed effects suggesting intrinsic synergistic analgesic interaction of the NOP and the classical opioid receptor components of cebranopadol. Together with the observation of limited respiratory depression in rats and humans the synergistic interaction of NOP and classical opioid receptor components in analgesia described in the current study may contribute to the favorable therapeutic index of cebranopadol observed in clinical trials.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e107c4baa57898f653a920a5c0e811c9 https://pubmed.ncbi.nlm.nih.gov/30519474 Zobrazit plný text záznamu Plný text ve formátu PDF Plný text ve formátu HTML
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