title: cGMP and cGMP-dependent protein kinase I pathway in dorsal root ganglia contributes to bone cancer pain in rats.
abstract: METHODS
  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.
  
  
  BACKGROUND
  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.
  
  
  CONCLUSIONS
  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.
  
  
  METHODS
  N/A.
authors.affiliation: 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.
authors.forename: Su
authors.initials: S
authors.lastname: Liu
authors.forename: Mao-yin
authors.initials: MY
authors.lastname: Zhang
authors.forename: Li-ping
authors.initials: LP
authors.lastname: Chen
authors.forename: Yue-peng
authors.initials: YP
authors.lastname: Liu
authors.forename: Gong-jian
authors.initials: GJ
authors.lastname: Liu
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000503:physiopathology / Q000556:secondary*; D002279:Carcinoma 256, Walker / Q000503:physiopathology / Q000556:secondary*; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000494:pharmacology / Q000502:physiology*; D062965:Cyclic GMP-Dependent Protein Kinase Type I / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D004790:Enzyme Induction; D005260:Female; D005727:Ganglia, Spinal / Q000503:physiopathology*; D006358:Hot Temperature; D006930:Hyperalgesia / Q000209:etiology / Q000503:physiopathology*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D017288:Pain Threshold; D018408:Patch-Clamp Techniques; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D011984:Sensory Receptor Cells / Q000502:physiology*; D013873:Thionucleotides / Q000494:pharmacology; D013977:Tibia / Q000294:innervation; D014110:Touch
chemical_list: C090860:8-(4-chlorophenylthio)guanosine 3',5'-cyclic monophosphorothioate; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D013873:Thionucleotides; D062965:Cyclic GMP-Dependent Protein Kinase Type I; D006152:Cyclic GMP