Christoph, Thomas;
Raffa, Robert;
De Vry, Jean;
Schröder, Wolfgang
Synergistic interaction between the agonism of cebranopadol at nociceptin/orphanin FQ and classical opioid receptors in the rat spinal nerve ligation model
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Medientyp:
E-Artikel
Titel:
Synergistic interaction between the agonism of cebranopadol at nociceptin/orphanin FQ and classical opioid receptors in the rat spinal nerve ligation model
Beteiligte:
Christoph, Thomas;
Raffa, Robert;
De Vry, Jean;
Schröder, Wolfgang
Erschienen:
Wiley, 2018
Erschienen in:Pharmacology Research & Perspectives
Beschreibung:
<jats:title>Abstract</jats:title><jats:p>Cebranopadol (trans‐6′‐fluoro‐4′,9′‐dihydro‐<jats:italic>N,N</jats:italic>‐dimethyl‐4‐phenyl‐spiro[cyclohexane‐1,1′(3′H)‐pyrano[3,4‐b]indol]‐4‐amine) is a novel analgesic nociceptin/orphanin <jats:styled-content style="fixed-case">FQ</jats:styled-content> opioid peptide (<jats:styled-content style="fixed-case">NOP</jats:styled-content>) and classical opioid receptor (<jats:styled-content style="fixed-case">MOP</jats:styled-content>,<jats:styled-content style="fixed-case"> DOP</jats:styled-content>, and <jats:styled-content style="fixed-case">KOP</jats:styled-content>) 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 <jats:styled-content style="fixed-case">NOP</jats:styled-content> and classical opioid receptor agonist components to cebranopadol analgesia in the rat spinal nerve ligation (<jats:styled-content style="fixed-case">SNL</jats:styled-content>) model. Assessing antihypersensitive activity in <jats:styled-content style="fixed-case">SNL</jats:styled-content> rats intraperitoneal (<jats:styled-content style="fixed-case">IP</jats:styled-content>) administration of cebranopadol resulted in <jats:styled-content style="fixed-case">ED</jats:styled-content><jats:sub>50</jats:sub> values of 3.3 and 3.58 μg/kg in two independent experiments. Pretreatment (<jats:styled-content style="fixed-case">IP</jats:styled-content>) with J‐113397 (4.64 mg/kg) a selective antagonist for the <jats:styled-content style="fixed-case">NOP</jats:styled-content> receptor or naloxone (1 mg/kg), naltrindole (10 mg/kg), or nor‐BNI (10 mg/kg), selective antagonists for <jats:styled-content style="fixed-case">MOP</jats:styled-content>,<jats:styled-content style="fixed-case"> DOP</jats:styled-content>, and <jats:styled-content style="fixed-case">KOP</jats:styled-content> receptors, yielded <jats:styled-content style="fixed-case">ED</jats:styled-content><jats:sub>50</jats:sub> 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 <jats:styled-content style="fixed-case">ED</jats:styled-content><jats:sub>50</jats:sub> of 65.5 μg/kg. The concept of dose equivalence was used to calculate the expected additive effects of the parent compound for <jats:styled-content style="fixed-case">NOP</jats:styled-content> 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 <jats:styled-content style="fixed-case">NOP</jats:styled-content> and the classical opioid receptor components of cebranopadol. Together with the observation of limited respiratory depression in rats and humans the synergistic interaction of <jats:styled-content style="fixed-case">NOP</jats:styled-content> 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.</jats:p>