title: PAR2-mediated upregulation of BDNF contributes to central sensitization in bone cancer pain.
abstract: BACKGROUND
  Bone cancer pain is currently a major clinical challenge for the management of cancer patients, and the cellular and molecular mechanisms underlying the spinal sensitization remain unclear. While several studies demonstrated the critical role of proteinase-activated receptor (PAR2) in the pathogenesis of several types of inflammatory or neuropathic pain, the involvement of spinal PAR2 and the pertinent signaling in the central sensitization is not determined yet in the rodent model of bone cancer pain.
  
  
  RESULTS
  Implantation of tumor cells into the tibias induced significant thermal hyperalgesia and mechanical allodynia, and enhanced glutamatergic strength in the ipsilateral dorsal horn. Significantly increased brain-derived neurotrophic factor (BDNF) expression was detected in the dorsal horn, and blockade of spinal BDNF signaling attenuated the enhancement of glutamatergic strength, thermal hyperalgesia and mechanical allodynia in the rats with bone cancer pain. Significantly increased spinal PAR2 expression was also observed, and inhibition of PAR2 signaling ameliorated BDNF upsurge, enhanced glutamatergic strength, and thermal hyperalgesia and mechanical allodynia. Inhibition of NF-κB pathway, the downstream of PAR2 signaling, also significantly decreased the spinal BDNF expression, glutamatergic strength of dorsal horn neurons, and thermal hyperalgesia and mechanical allodynia.
  
  
  CONCLUSIONS
  The present study demonstrated that activation of PAR2 triggered NF-κB signaling and significantly upregulated the BDNF function, which critically contributed to the enhancement of glutamatergic transmission in spinal dorsal horn and thermal and mechanical hypersensitivity in the rats with bone cancer. This indicated that PAR2 - NF-κB signaling might become a novel target for the treatment of pain in patients with bone cancer.
authors.forename: Yanju
authors.initials: Y
authors.lastname: Bao
authors.forename: Wei
authors.initials: W
authors.lastname: Hou
authors.forename: Rui
authors.initials: R
authors.lastname: Liu
authors.forename: Yebo
authors.initials: Y
authors.lastname: Gao
authors.forename: Xiangying
authors.initials: X
authors.lastname: Kong
authors.forename: Liping
authors.initials: L
authors.lastname: Yang
authors.forename: Zhan
authors.initials: Z
authors.lastname: Shi
authors.forename: Weidong
authors.initials: W
authors.lastname: Li
authors.forename: Honggang
authors.initials: H
authors.lastname: Zheng
authors.forename: Shulong
authors.initials: S
authors.lastname: Jiang
authors.forename: Conghuang
authors.initials: C
authors.lastname: Li
authors.forename: Yinggang
authors.initials: Y
authors.lastname: Qin
authors.affiliation: Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beixiange 5, Xicheng District, 100053 Beijing, China. huabaojin01@163.com.
authors.forename: Baojin
authors.initials: B
authors.lastname: Hua
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001859:Bone Neoplasms / Q000150:complications*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D002277:Carcinoma / Q000150:complications*; D004195:Disease Models, Animal; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D005260:Female; D006930:Hyperalgesia / Q000209:etiology; D066298:In Vitro Techniques; D016328:NF-kappa B / Q000737:chemistry / Q000378:metabolism; D009374:Neoplasms, Experimental; D009479:Neuropeptides / Q000494:pharmacology; D010146:Pain / Q000209:etiology*; D051381:Rats; D017208:Rats, Wistar; D044464:Receptor, PAR-2 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013116:Spinal Cord / Q000166:cytology; D013997:Time Factors; D015854:Up-Regulation / Q000502:physiology*
chemical_list: D000970:Antineoplastic Agents; D019208:Brain-Derived Neurotrophic Factor; D018683:Excitatory Amino Acid Agents; D016328:NF-kappa B; D009479:Neuropeptides; D044464:Receptor, PAR-2