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

Abstract

Ting Yang1 1, Yaqun Zhou1 1, Wen Zhang1 1, Longqing Zhang1 1, Shuping Chen1 1, Chao Chen1 1, Feng Gao1 1, Hui Yang1 1, Anne Manyande2 2, Jie Wang3 3, Yuke Tian1 1, Xuebi Tian1 1 1Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 2School of Human and Social Sciences, University of West London, London, UK; 3State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, Key Laboratory of Magnetic Resonance in Biological Systems, Wuhan Center for Magnetic Resonance, Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, Wuhan, Hubei, People’s Republic of ChinaCorrespondence: Xuebi TianDepartment of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1095#, Wuhan, Hubei, 430030, People’s Republic of ChinaTel [phone]Fax [phone]Email [email protected]: 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 α 7-nAChRs exerts analgesic effects in some chronic pain models. However, the role of spinal α 7-nAChRs in CIBP remains unknown. This study was designed to investigate the role of α 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 α 7-nAChRs and NF-κB were measured with Western blotting analysis. Immunofluorescence was employed to detect the expression of α 7-nAChRs and co-expressed of α 7-nAChRs with NeuN or GFAP or Iba1.Results: Experiment results showed that the expression of spinal α 7-nAChRs was significantly downregulated over time in CIBP rats, and in both CIBP rats and sham rats, most of the α 7-nAChRs located in neurons. Behavioral data suggested PNU-282,987, a selective α 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 α 7-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 α 7-nAChRs contributes to the maintenance of CIBP by upregulating NF-κB expression, which implying a novel pharmacological therapeutic target for the treatment of CIBP.Keywords: cancer-induced bone pain, α 7-nAChR, NF-κB, PNU-282,987

Keywords

• cancer-induced bone pain
• α7-nachr
• nf-κb
• pnu-282987