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.

Cancer-induced Bone Pain Impairs Burrowing Behaviour in Mouse and Rat.

BACKGROUND: Cancer-induced bone pain remains a serious public health concern, with a need for translational behavioural tests in order to assess nociception in preclinical models of this condition. Burrowing is an innate, ethologically relevant rodent behaviour that has been proven sensitive to chronic pain conditions. Herein, we studied for the first time whether burrowing performance is altered in preclinical models of cancer-induced bone pain. MATERIALS AND METHODS: Mice and rats were inoculated with syngeneic breast cancer cells. Bone degradation was radiographically evaluated and nociception was assessed in limb-use and burrowing tests. RESULTS: Cancer-bearing rodents showed reduced relative bone density and limb-use scores, confirming disease development. Burrowing performance decreased over time in both rodent models. CONCLUSION: Burrowing performance was reduced in both rodent models, indicating that the burrowing test is a relevant and reproducible behavioural test for assessing disease development in both mouse and rat models of cancer-induced bone pain.