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

Abstract

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.

• Authors: Li-Hua Hang, Jian-Ping Yang, Wei Yin, Li-Na Wang, Feng Guo, Fu-Hai Ji, Dong-Hua Shao, Qi-Nian Xu, Xiu-Yun Wang, Jian-Ling Zuo
• Journal: The European journal of neuroscience (Eur J Neurosci) Vol. 36 Issue 1 Pg. 2107-17 (Jul 2012) ISSN: 1460-9568 [Electronic] France
• PMID: 22515300 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2012 The Authors. European Journal of Neuroscience © 2012 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

Chemical References

• Cyclic AMP Response Element-Binding Protein
• GPR65 protein, rat
• Isoquinolines
• Protein Kinase Inhibitors
• RNA, Small Interfering
• Receptors, G-Protein-Coupled
• Sulfonamides
• Cyclic AMP-Dependent Protein Kinases
• N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide

Topics

• Animals
• Bone Neoplasms (complications)
• Carcinoma 256, Walker
• Cyclic AMP Response Element-Binding Protein (metabolism)
• Cyclic AMP-Dependent Protein Kinases (antagonists & inhibitors, metabolism)
• Female
• Isoquinolines (pharmacology)
• Neoplasm Transplantation
• Pain (enzymology, etiology, metabolism)
• Posterior Horn Cells (metabolism)
• Protein Kinase Inhibitors (pharmacology)
• RNA, Small Interfering
• Rats
• Rats, Sprague-Dawley
• Receptors, G-Protein-Coupled (antagonists & inhibitors, metabolism)
• Sulfonamides (pharmacology)
• Up-Regulation