The Spinal α7-Nicotinic Acetylcholine Receptor Contributes to the Maintenance of Cancer-Induced Bone Pain

Abstract

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 α7-nAChRs exerts analgesic effects in some chronic pain models. However, the role of spinal α7-nAChRs in CIBP remains unknown. This study was designed to investigate the role of α7-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 α7-nAChRs and NF-κB were measured with Western blotting analysis. Immunofluorescence was employed to detect the expression of α7-nAChRs and co-expressed of α7-nAChRs with NeuN or GFAP or Iba1. Results Experiment results showed that the expression of spinal α7-nAChRs was significantly downregulated over time in CIBP rats, and in both CIBP rats and sham rats, most of the α7-nAChRs located in neurons. Behavioral data suggested PNU-282,987, a selective α7-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 α7-nAChRs, inhibited the nuclear factor kappa B (NF-κB) signaling pathway, and attenuates CIBP-induced mechanical allodynia state as well. Conclusion These results suggest that the reduced expression of spinal α7-nAChRs contributes to the maintenance of CIBP by upregulating NF-κB expression, which implying a novel pharmacological therapeutic target for the treatment of CIBP.