Introduction: Cancer-induced bone pain (CIBP) is acknowledged as a multifactorial chronic pain that tortures advanced cancer patients, but existing treatment strategies for CIBP have not been satisfactory yet. Investigators have demonstrated that the activation of alpha 7-nAChRs exerts analgesic effects in some chronic pain models. However, the role of spinal alpha 7-nAChRs in CIBP remains unknown. This study was designed to investigate the role of alpha 7-nAChRs in a well-established CIBP model induced by Walker 256 rat mammary gland carcinoma cells. Methods: The paw withdrawal threshold (PWT) of the ipsilateral hind paw was measured using von Frey filament The expressions of spinal alpha 7-nAChRs and NF-kappa B were measured with Western blotting analysis. Immunofluorescence was employed to detect the expression of alpha 7-nAChRs and co-expressed of alpha 7-nAChRs with NeuN or GFAP or Iba1. Results: Experiment results showed that the expression of spinal alpha 7-nAChRs was significantly downregulated over time in CIBP rats, and in both CIBP rats and sham rats, most of the alpha 7-nAChRs located in neurons. Behavioral data suggested PNU-282,987, a selective alpha 7-nAChRs agonist, dose-dependently produced analgesic effect and positive allosteric modulator could intensify its effects. Further, repeated administration of PNU-282,987 reversed the expression of alpha 7-nAChRs, inhibited the nuclear factor kappa B (NF-kappa B) signaling pathway, and attenuates CIBP-induced mechanical allodynia state as well. Conclusion: These results suggest that the reduced expression of spinal alpha 7-nAChRs contributes to the maintenance of CIBP by upregulating NF-kappa B expression, which implying a novel pharmacological therapeutic target for the treatment of CIBP.