Analgesic effects of adenylyl cyclase inhibitor NB001 on bone cancer pain in a mouse model.
Cancer pain, especially the one caused by metastasis in bones, is a severe type of pain. Pain becomes chronic unless its causes and consequences are resolved. With improvements in cancer detection and survival among patients, pain has been considered as a great challenge because traditional therapies are partially effective in terms of providing relief. Cancer pain mechanisms are more poorly understood than neuropathic and inflammatory pain states. Chronic inflammatory pain and neuropathic pain are influenced by NB001, an adenylyl cyclase 1 (AC1)-specific inhibitor with analgesic effects. In this study, the analgesic effects of NB001 on cancer pain were evaluated.



Pain was induced by injecting osteolytic murine sarcoma cell NCTC 2472 into the intramedullary cavity of the femur of mice. The mice injected with sarcoma cells for four weeks exhibited significant spontaneous pain behavior and mechanical allodynia. The continuous systemic application of NB001 (30 mg/kg, intraperitoneally, twice daily for three days) markedly decreased the number of spontaneous lifting but increased the mechanical paw withdrawal threshold. NB001 decreased the concentrations of cAMP and the levels of GluN2A, GluN2B, p-GluA1 (831), and p-GluA1 (845) in the anterior cingulate cortex, and inhibited the frequency of presynaptic neurotransmitter release in the anterior cingulate cortex of the mouse models.



NB001 may serve as a novel analgesic to treat bone cancer pain. Its analgesic effect is at least partially due to the inhibition of AC1 in anterior cingulate cortex.
Department of Orthopedics, Nanjing General Hospital of Nanjing Military Command, Second Military Medical University, Nanjing, China.
Wen-Bo
WB
Kang
Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, China.
Qi
Q
Yang
Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, China.
Yan-Yan
YY
Guo
Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, China.
Lu
L
Wang
Department of Orthopedics, Nanjing General Hospital of Nanjing Military Command, Second Military Medical University, Nanjing, China.
Dong-Sheng
DS
Wang
Department of Orthopedics, Nanjing General Hospital of Nanjing Military Command, Second Military Medical University, Nanjing, China.
Qiang
Q
Cheng
Department of Orthopedics, Nanjing General Hospital of Nanjing Military Command, Second Military Medical University, Nanjing, China.
Xiao-Ming
XM
Li
Department of Orthopedics, Nanjing General Hospital of Nanjing Military Command, Second Military Medical University, Nanjing, China.
Jun
J
Tang
Department of Orthopedics, Nanjing General Hospital of Nanjing Military Command, Second Military Medical University, Nanjing, China.
Jian-Ning
JN
Zhao
Department of Orthopedics, Nanjing General Hospital of Nanjing Military Command, Second Military Medical University, Nanjing, China.
Gang
G
Liu
Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada Center for Neuron and Disease, Frontier Institutes of Life Science and of Science and Technology, Xi'an Jiaotong University, Xi'an, China.
Min
M
Zhuo
Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, China Center for Neuron and Disease, Frontier Institutes of Life Science and of Science and Technology, Xi'an Jiaotong University, Xi'an, China minggao@fmmu.edu.cn.
Ming-Gao
MG
Zhao
D000255:Adenosine Triphosphate / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000700:Analgesics / Q000627:therapeutic use*; D000818:Animals; D001859:Bone Neoplasms / Q000150:complications / Q000000981:diagnostic imaging; D000072716:Cancer Pain / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D045744:Cell Line, Tumor; D000242:Cyclic AMP / Q000378:metabolism; D004195:Disease Models, Animal; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005500:Follow-Up Studies; D006179:Gyrus Cinguli / Q000473:pathology; D006930:Hyperalgesia / Q000188:drug therapy / Q000209:etiology; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D017288:Pain Threshold / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D012509:Sarcoma / Q000473:pathology; D012513:Sarcoma, Experimental / Q000150:complications / Q000000981:diagnostic imaging; D015398:Signal Transduction / Q000187:drug effects
C557530:5-((2-(6-Amino-9H-purin-9-yl) ethyl) amino)-1-pentanol; D000700:Analgesics; D016194:Receptors, N-Methyl-D-Aspartate; D000255:Adenosine Triphosphate; D000242:Cyclic AMP
NB001; adenylyl cyclase 1; anterior cingulate cortex; bone cancer pain