title: Midazolam and ropivacaine act synergistically to inhibit bone cancer pain with different mechanisms in rats.
abstract: Analgesic strategy of a single drug analgesia in bone cancer pain (BCP) has shifted to combined analgesia with different drugs which have different mechanism. After tumor cell inculation, the activation of signal transducer and activator of transcription (STAT3) and extracellular signal-regulated kinase (ERK) signaling pathway are involved in the development and maintenance of BCP, whereas a decrease in the expression of spinal STAT3 and ERK through using their specific blocker, lead to attenuation of BCP. Hence, in this study, we clarified that intrathecal (i.t.) injection of midazolam (MZL) and ropivacaine (Ropi) induces synergistic analgesia on BCP and is accompanied with different mechanisms of these analgesic effect. Hargreaves heat test was used to detect the analgesic effect of single dose of i.t. MZL, Ropi and their combination on the BCP rats. At consecutive daily administration experiment, thermal hyperalgesia was recorded, and immunohistochemical staining was used to detect the expression of c-Fos, spinal glial fibrillary acidic protein (GFAP) and ionized calcium binding adapter molecule-1 (IBA-1). Then, western blot analysis was used to examine spinal TSPO, GFAP, IBA-1, pERK/ERK and pSTAT3/STAT3 levels on day 14 after tumor cell inoculation. i.t. MZL or Ropi showed a short-term analgesia dose-dependently, and MZL displayed better effect on inhibition of pSTAT3 expression than pERK, but Ropi was just the reverse, then consecutive daily administrations of their combination acted synergistically to attenuate thermal hyperalgesia with downregulated spinal 'neuron-astrocytic activation' in the BCP rats. i.t. co-delivery of MZL and Ropi shows synergistic analgesia on the BCP with the inhibition of spinal 'neuron-astrocytic activation'. Spinal different signaling pathway inhibition for MZL and Ropi may be involved in this process.
authors.affiliation: Department of Orthopedics, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
authors.forename: Chi-Hua
authors.initials: CH
authors.lastname: Guo
authors.affiliation: Department of Medical Imaging, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
authors.forename: Lu
authors.initials: L
authors.lastname: Bai
authors.affiliation: Department of Anesthesiology, Fuzhou General Hospital of Nanjing Military Region, Fuzhou, Fujian 350025, P.R. China.
authors.forename: Huang-Hui
authors.initials: HH
authors.lastname: Wu
authors.affiliation: Institute of Neuroscience, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, P.R. China.
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Neurobiology and Collaborative Innovation Center for Brain Science, Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China.
authors.forename: Guo-Hong
authors.initials: GH
authors.lastname: Cai
authors.affiliation: Department of Orthopedics, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
authors.forename: Si-Xiang
authors.initials: SX
authors.lastname: Zeng
authors.affiliation: Department of Neurobiology and Collaborative Innovation Center for Brain Science, Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China.
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Neurobiology and Collaborative Innovation Center for Brain Science, Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China.
authors.forename: Sheng-Xi
authors.initials: SX
authors.lastname: Wu
authors.affiliation: Department of Orthopedics, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Ma
mesh_terms: D000577:Amides / Q000008:administration & dosage / Q000494:pharmacology*; D000779:Anesthetics, Local / Q000494:pharmacology; D000818:Animals; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000473:pathology; D000072716:Cancer Pain / Q000188:drug therapy*; D004357:Drug Synergism; D004359:Drug Therapy, Combination / Q000379:methods; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D007278:Injections, Spinal; D008874:Midazolam / Q000008:administration & dosage / Q000494:pharmacology*; D009457:Neuroglia / Q000187:drug effects; D017207:Rats, Sprague-Dawley; D018079:Receptors, GABA / Q000378:metabolism; D000077212:Ropivacaine; D050796:STAT3 Transcription Factor / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism
chemical_list: D000577:Amides; D000779:Anesthetics, Local; D006993:Hypnotics and Sedatives; D018079:Receptors, GABA; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C499229:TSPO protein, human; D000077212:Ropivacaine; D048049:Extracellular Signal-Regulated MAP Kinases; D008874:Midazolam