Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
8528959 | European Journal of Pharmacology | 2018 | 23 Pages |
Abstract
Cebranopadol is a novel, first-in-class analgesic with agonist activity at the nociceptin/orphanin FQ opioid peptide (NOP) receptor as well as the classical opioid peptide receptors. This study investigated the anti-hypersensitive effect of cebranopadol in a rat model of arthritic pain. Selective antagonists were used to probe the involvement of the NOP receptor and the µ-opioid peptide (MOP) receptors. Experimental mono-arthritis was induced by intra-articular injection of complete Freund's adjuvant into the left hind knee joint. Intravenous (i.v.) administration of cebranopadol 0.8-8.0â¯Âµg/kg to rats 5 days after induction of arthritis elicited dose-dependent increases in weight bearing on the affected limb. The quarter-maximal effective dose (ED25) for this anti-hypersensitive effect of cebranopadol was 1.6â¯Âµg/kg i.v. (95% confidence interval [CI]: 0.8, 1.6). The ED25 increased to 3.2â¯Âµg/kg i.v. (95% CI: 2.4, 4.0) following pretreatment with the selective NOP receptor antagonist J-113397 and to 18.3â¯Âµg/kg i.v. (95% CI: 9.6, 146.0) following pretreatment with the MOP receptor antagonist naloxone (at intraperitoneal antagonist doses of 4.64â¯mg/kg and 1.0â¯mg/kg, respectively). The MOP receptor agonist morphine and the NOP receptor agonist Ro65-6570 also elicited increases in weight bearing on the affected limb. The anti-hypersensitive effect of morphine 2.15â¯mg/kg i.v. was inhibited by naloxone but not by J-113397. Conversely, the anti-hypersensitive effect of Ro65-6570 0.464â¯mg/kg i.v. was inhibited by J-113397 but not by naloxone. In conclusion, cebranopadol evoked potent anti-hypersensitive efficacy in a rat model of arthritic pain, and this involved agonist activity at both the NOP and MOP receptors.
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Authors
Klaus Schiene, Wolfgang Schröder, Klaus Linz, Stefanie Frosch, Thomas M. Tzschentke, Ulla Jansen, Thomas Christoph,