The nociceptin/orphanin FQ receptor system as a target to alleviate cancer‐induced bone pain in rats: Model validation and pharmacological evaluation

Background and Purpose 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. Experimental Approach Model validation by intratibial inoculation in male Sprague Dawley rats was performed with varying MRMT‐1/Luc2 cell quantities (0.5–1.5 × 106·ml−1) 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. Key Results Inoculation with 1.5 × 106·ml−1 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. Conclusion and Implications 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. LINKED ARTICLES 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 http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.9/issuetoc