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Medientyp:
E-Artikel
Titel:
The nociceptin/orphanin FQ receptor system as a target to alleviate cancer‐induced bone pain in rats: Model validation and pharmacological evaluation
Beteiligte:
Sliepen, Sonny H.J.;
Korioth, Johanna;
Christoph, Thomas;
Tzschentke, Thomas M.;
Diaz‐delCastillo, Marta;
Heegaard, Anne‐Marie;
Rutten, Kris
Beschreibung:
<jats:sec><jats:title>Background and Purpose</jats:title><jats:p>Cancer‐induced bone pain remains inadequately controlled, and current standard of care analgesics is accompanied by several side effects. Nociceptin/orphanin FQ peptide (NOP) receptor agonists have demonstrated broad analgesic properties in rodent neuropathic and inflammatory pain models. Here, we investigate the analgesic potential of NOP receptor activation in a rodent cancer‐induced bone pain model.</jats:p></jats:sec><jats:sec><jats:title>Experimental Approach</jats:title><jats:p>Model validation by intratibial inoculation in male Sprague Dawley rats was performed with varying MRMT‐1/Luc2 cell quantities (0.5–1.5 × 10<jats:sup>6</jats:sup>·ml<jats:sup>−1</jats:sup>) and a behavioural battery (>14 days post‐surgery) including evoked and non‐evoked readouts: paw pressure test, cold plate, von Frey, open field, and weight distribution. Anti‐allodynic potential of the endogenous NOP receptor ligand nociceptin (i.t.) and NOP receptor agonist Ro65‐6570 ( i.p.) was tested using von Frey filaments, followed by a combination experiment with Ro65‐6570 and the NOP receptor antagonist J‐113397 (i.p.). Plasma cytokine levels and NOP receptor gene expression in dorsal root ganglion (DRG, L4‐L6) and bone marrow were examined.</jats:p></jats:sec><jats:sec><jats:title>Key Results</jats:title><jats:p>Inoculation with 1.5 × 10<jats:sup>6</jats:sup>·ml<jats:sup>−1</jats:sup> of MRMT‐1/Luc2 cells resulted in a robust and progressive pain‐related phenotype. Nociceptin and Ro65‐6570 treatment inhibited cancer‐induced mechanical allodynia. J‐113397 selectively antagonized the effect of Ro65‐6570. MRMT‐1/Luc2‐bearing animals demonstrated elevated plasma cytokine levels of IL‐4, IL‐5, IL‐6 and IL‐10 plus unaltered NOP‐r gene expression in DRG and reduced expression in bone marrow.</jats:p></jats:sec><jats:sec><jats:title>Conclusion and Implications</jats:title><jats:p>Nociceptin and Ro65‐6570 selectively and dose‐dependently reversed cancer‐induced bone pain‐like behaviour. The NOP receptor system may be a potential target for cancer‐induced bone pain treatment.</jats:p></jats:sec><jats:sec><jats:title>LINKED ARTICLES</jats:title><jats:p>This article is part of a themed issue on The molecular pharmacology of bone and cancer‐elated bone diseases. To view the other articles in this section visit <jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.9/issuetoc">http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.9/issuetoc</jats:ext-link></jats:p></jats:sec>