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cGMP and cGMP-Dependent Protein Kinase I Pathway in Dorsal Root Ganglia Contributes to Bone Cancer Pain in Rats

Liu, Su, MD, PhD*; Zhang, Mao-yin, MD*; Chen, Li-ping, MD; Liu, Yue-peng, MD, PhD; Liu, Gong-jian, MD, PhD*

doi: 10.1097/BRS.0000000000000456
Basic Science

Study Design. A prospective, randomized experimental research.

Objective. To demonstrate the role of cGMP (cyclic guanosine monophosphate)-cGKI (cGMP-dependent protein kinase I) pathway in dorsal root ganglia (DRG) in bone cancer pain.

Summary of Background Data. Treating bone cancer pain continues to possess a major clinical challenge because the specific cellular and molecular mechanisms underlying bone cancer pain remain elusive. cGMP and cGMP-dependent protein kinases pathway in DRG plays important role in nerve injury-induced hyperexcitability of DRG neurons, as well as neuropathic pain, however, whether this pathway participates in bone cancer pain is unknown.

Methods. The rat model of bone cancer pain was produced by intramedullary injection of rat breast cancer cells (Walker 256) into right tibia. Thermal hyperalgesia and mechanical allodynia were measured before and after administration of inhibitor of cGMP-cGKs pathway (Rp-8-pCPT-cGMPS). Immunofluorescence and reverse transcription-polymerase chain reaction were used to reflect expression of cGKI in DRG neurons, whereas the concentration of cGMP in DRG was tested using enzyme-linked immunosorbent assay method. Whole-cell patch clamp was used to record the hyperexcitability of small neurons in DRG with or without cGKs inhibitor after tumor cell implantation (TCI).

Results. TCI treatment significantly increased the concentration of cGMP in DRG and activity of cGKs in DRG and the spinal cord. TCI treatment also induced upregulation of cGKI messenger ribonucleic acid and protein in DRG, as well as enhanced hyperexcitability in DRG neurons. Spinal administration of Rp-8-pCPT-cGMPS, cGMP-cGKs inhibitor, significantly suppressed TCI-induced activation of cGMP-cGKI signaling, and hyperexcitability of DRG neurons. Meanwhile, in vivo intrathecal delivery of the Rp-8-pCPT-cGMPS significantly prevented and suppressed TCI-induced hyperalgesia and allodynia.

Conclusion. From these results, we confirm that TCI treatment activates cGMP-cGKI signaling pathway and continuing activation of this pathway in DRG is required for hyperalgesia and/or hyperalgesia and allodynia after TCI treatment.

Level of Evidence: N/A

Tumor cell implantation into tibia induced increase of cGMP concentration, cGKI messenger ribonucleic acid/protein expression, and cGKs activity in dorsal root ganglia (DRG). Blocking cGMP-cGKI signaling suppressed the bone cancer-induced hyperexcitability of DRG neurons and pain behaviors. These results indicate that cGMP-cGKI signaling in DRG may contribute to bone cancer pain.

Departments of *Anesthesiology and

Pain Medicine, Affiliated Hospital of Xuzhou Medical College, Xuzhou, Jiangsu, China; and

Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical College, Xuzhou, Jiangsu, China.

Address correspondence and reprint requests to Yue-peng Liu, MD, PhD, Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical College, Xuzhou, Jiangsu, 221004, China; E-mail:

Acknowledgment date: July 17, 2013. Revision date: March 27, 2014. Acceptance date: May 27, 2014.

The manuscript submitted does not contain information about medical device(s)/drug(s).

National Science Foundation of China (NSFC- 81000475, 81371242) grant funds were received to support this work.

No relevant financial activities outside the submitted work.

© 2014 by Lippincott Williams & Wilkins