Antinociceptive Effect of Prostatic Acid
Phosphatase in a Rat Model of Cancer-induced
Bone Pain
Authors: Li Yun-Qing 
Published: March 2021

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.
Study Design: 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.
Limitations: 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.
Key words: Cancer-induced bone pain, prostatic acid phosphatase, adenosine, allodynia, spinal
dorsal horn, rat