title: Antinociceptive effect of prostatic acid phosphatase in a rat model of cancer-induced bone pain.
abstract: BACKGROUND
  Cancer-induced bone pain (CIBP) is a severe chronic pain that is less than adequately controlled by conventional analgesics. Prostatic acid phosphatase (PAP) has been considered as a diagnostic marker for prostate cancer and its transmembrane isoform has been reported to play an antinociceptive effect in neuropathic and inflammatory pain. However, it remains unknown whether it has an analgesic effect on CIBP and what are the underlying mechanisms.
  
  
  OBJECTIVE
  In the present study, we tested whether PAP could alleviate the pain symptoms induced by bone cancer in a rat model.
  
  
  METHODS
  A randomized, double blind, and controlled rat animal trial.
  
  
  METHODS
  We first established a rat CIBP model and observed the spinal expression of PAP by immunofluorescence histochemistry and Western blot. Then, PAP (0.1, 0.3, or 1 μg) was intrathecally administered in the CIBP rats in a repeated manner from 15 to 18 days (once per day) after inoculation of tumor cells. On postoperative day (POD) 18, the mechanical paw withdrawal threshold was tested for checking the dose-effect curve and ED50 of the antinociceptive effect of PAP. In an another test, a single dose of ED50 of PAP was intrathecally injected on POD 15 to observe the time course of its effect. Furthermore, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) (3 mg/kg), an adenosine A1 receptor antagonist, or dipyridamole (DIP) (10 μg), a nucleoside transporter inhibitor, was administered to the CIBP rats for exploring the analgesic mechanisms of PAP. The concentration of extracellular adenosine was also detected by microdialysis method after intrathecal injection of PAP (0.57 μg) and DIP (10 μg) in the CIBP rats. Finally, an in vivo electrophysiological study of the CIBP rats was performed to observe whether the electrically evoked response of spinal wide-dynamic-range (WDR) neurons could be affected by PAP (0.57 μg), DIP (10 μg), or DPCPX (10 μg).
  
  
  RESULTS
  The expression of PAP in the spinal dorsal horn was significantly reduced in the CIBP rats, and intrathecal injection of PAP dose-dependently attenuated CIBP-induced mechanical allodynia via the adenosine A1 receptor. Simultaneously, intrathecal injection of PAP increased the extracellular concentration of spinal adenosine in the CIBP rats, as well as inhibited the neuronal responses of WDR neurons in deep layers within the spinal dorsal horn through the adenosine A1 receptor. Finally, the analgesic effect of PAP was potentiated by DIP, the nucleoside transporter inhibitor.
  
  
  CONCLUSIONS
  It's not clear whether PAP's antinociceptive effect is mediated by other signaling molecules besides the adenosine A1 receptor. In addition, the long-term antinociceptive effect of intrathecal PAP is still not clear.
  
  
  CONCLUSIONS
  Our study demonstrated that PAP was involved in the maintenance of CIBP and could effectively suppress central sensitization by increasing spinal extracellular adenosine concentrations to exert a significant antinociceptive effect via the adenosine A1 receptor in CIBP rats. Therefore, our experiments suggest that the endogenous enzyme PAP may be a promising candidate for CIBP treatment.
authors.affiliation: Department of Anatomy, Histology, and Embryology, K. K. Leung Brain Research Centre, Fourth Military Medical University, Xi'an, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Chen
authors.forename: Ling
authors.initials: L
authors.lastname: Zhu
authors.forename: Kun
authors.initials: K
authors.lastname: Wang
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Xiao-Peng
authors.initials: XP
authors.lastname: Mei
authors.forename: Tao
authors.initials: T
authors.lastname: Liu
authors.forename: Fu-Xing
authors.initials: FX
authors.lastname: Zhang
authors.forename: Wen
authors.initials: W
authors.lastname: Wang
authors.forename: Tao
authors.initials: T
authors.lastname: Chen
authors.forename: Yun-Qing
authors.initials: YQ
authors.lastname: Li
mesh_terms: D000135:Acid Phosphatase; D000241:Adenosine / Q000096:biosynthesis; D000818:Animals; D015153:Blotting, Western; D001859:Bone Neoplasms / Q000378:metabolism* / Q000473:pathology; D001842:Bone and Bones / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D005455:Fluorescent Antibody Technique; D007278:Injections, Spinal; D010146:Pain / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D017027:Protein Tyrosine Phosphatases / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism
chemical_list: D000135:Acid Phosphatase; C428439:prostatic acid phosphatase; D017027:Protein Tyrosine Phosphatases; D000241:Adenosine