Activation of spinal TDAG8 and its downstream PKA signaling pathway contribute to bone cancer pain in rats

Bone cancer pain is difficult to treat and has a strong impact on the quality of life of patients. Few therapies have emerged because the molecular mechanisms underlying bone cancer pain are poorly understood. Recently, T‐cell death‐associated gene 8 (TDAG8) has been shown to participate in complete...

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Published in:The European journal of neuroscience 2012-07, Vol.36 (1), p.2107-2117
Main Authors: Hang, Li-Hua, Yang, Jian-Ping, Yin, Wei, Wang, Li-Na, Guo, Feng, Ji, Fu-Hai, Shao, Dong-Hua, Xu, Qi-Nian, Wang, Xiu-Yun, Zuo, Jian-Ling
Format: Article
Language:English
Subjects:
Animal models
Animals
Bone cancer
bone cancer pain
Bone Neoplasms - complications
Carcinoma 256, Walker
Cyclic AMP
Cyclic AMP Response Element-Binding Protein - metabolism
Cyclic AMP-Dependent Protein Kinases - antagonists & inhibitors
Cyclic AMP-Dependent Protein Kinases - metabolism
Female
Inflammation
Inoculation
Isoquinolines - pharmacology
Lymphocytes T
Molecular modelling
mRNA
Neoplasm Transplantation
Nervous system
Pain
Pain - enzymology
Pain - etiology
Pain - metabolism
Posterior Horn Cells - metabolism
Protein kinase A
Protein Kinase Inhibitors - pharmacology
Quality of life
Rats
Rats, Sprague-Dawley
Receptors, G-Protein-Coupled - antagonists & inhibitors
Receptors, G-Protein-Coupled - metabolism
RNA, Small Interfering
Signal transduction
siRNA
Spinal cord
Sulfonamides - pharmacology
TDAG8
Tibia
Tumor cells
Up-Regulation
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Summary:Bone cancer pain is difficult to treat and has a strong impact on the quality of life of patients. Few therapies have emerged because the molecular mechanisms underlying bone cancer pain are poorly understood. Recently, T‐cell death‐associated gene 8 (TDAG8) has been shown to participate in complete Freund’s adjuvant‐induced chronic inflammatory pain. In this study, we aimed to examine whether TDAG8 and its downstream protein kinase A (PKA) pathway are involved in bone cancer pain. A bone cancer pain model was made by inoculation of Walker 256 cells into the intramedullary space of rat tibia. Spinal TDAG8 expression was increased after inoculation with tumor cells. Intrathecal TDAG8 siRNA attenuated bone cancer pain behaviors during the initiation and maintenance phases; there were also concomitant decreases in TDAG8 mRNA and protein levels in spinal cord. Moreover, we found spinal PKA and phosphorylated cAMP response element‐binding (pCREB) protein levels were up‐regulated in the rat model of bone cancer pain. Knockdown of TDAG8 resulted in reduced bone cancer pain‐induced spinal PKA and pCREB protein expression in two procedures. Furthermore, intrathecal H‐89 (a PKA inhibitor) significantly attenuated bone cancer pain behaviors in rats. Our results suggest a causal relationship between TDAG8 expression and the initiation and maintenance of bone cancer pain. Activation of spinal TDAG8 contributes to bone cancer pain through the PKA signaling pathway in rats. These findings may lead to novel strategies for the treatment of bone cancer pain. Bone cancer pain is difficult to treat and has a strong impact on the quality of life of patients. Few therapies have emerged because the molecular mechanisms underlying bone cancer pain are poorly understood.
ISSN:0953-816X
1460-9568
DOI:10.1111/j.1460-9568.2012.08087.x