Involvement of RVM-expressed P2X7 receptor in bone cancer pain: mechanism of descending facilitation.
Patients with bone cancer commonly experience bone pain that is severe, intolerable, and difficult to manage. The rostral ventromedial medulla (RVM) plays an important role in the development of chronic pain via descending facilitation of spinal nociception. The compelling evidence shows that glial P2X7 receptor (P2X7R) is involved in the induction and maintenance of chronic pain syndromes. The present study explored the mechanism of glial activation and P2X7R expression underlying the induction of bone cancer pain. The results demonstrated that microglia and astrocytes in the RVM were markedly activated in bone cancer rats, and the expression of P2X7R was significantly upregulated. Injection of Brilliant Blue G (BBG), an inhibitor of P2X7R, into the RVM significantly alleviated pain behaviors of cancer rats, which was supported by intra-RVM injection of RNA interference targeting the P2X7R in the RVM. It is suggested that activation of microglia-expressed P2X7R in the RVM contributes to bone cancer pain. Given that 5-HT in the RVM is involved in modulating spinal nociception, changes in 5-HT and Fos expression were addressed in the spinal cord. Inhibition of P2X7R by BBG or small-interference RNA targeting P2X7 in the RVM markedly reduced 5-HT level and Fos expression in the spinal cord. The data clearly suggest that the activation of microglial P2X7R in the RVM contributes to the development of bone cancer pain via upregulation of spinal 5HT levels by the descending pain facilitatory system.
Department of Anesthesiology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China Department of Anesthesiology, Kunming General Hospital of Chengdu Military Command, Yunnan, China Unit of Pain Research, Institute of Neurobiology, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China.
Zhang Xiang
ZX
Huang
Zhi Jie
ZJ
Lu
Wei Qing
WQ
Ma
Fei Xiang
FX
Wu
Yu Qiu
YQ
Zhang
Wei-Feng
WF
Yu
Zhi Qi
ZQ
Zhao
D000344:Afferent Pathways / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D001859:Bone Neoplasms / Q000150:complications*; D039481:CD11b Antigen / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D008526:Medulla Oblongata / Q000187:drug effects / Q000378:metabolism*; D009020:Morphine / Q000627:therapeutic use; D009294:Narcotics / Q000627:therapeutic use; D010146:Pain / Q000188:drug therapy / Q000209:etiology* / Q000473:pathology*; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D058486:Receptors, Purinergic P2X7 / Q000235:genetics / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism
D039481:CD11b Antigen; D005904:Glial Fibrillary Acidic Protein; D009294:Narcotics; D058486:Receptors, Purinergic P2X7; D012701:Serotonin; D009020:Morphine; D010751:Phosphopyruvate Hydratase
Bone cancer pain; Descending facilitation; P2X7; RVM