Antinociceptive effect of prostatic acid phosphatase in a rat model of cancer-induced bone pain.
Antinociceptive effect of prostatic acid phosphatase in a rat model of cancer-induced bone pain.
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DOI：
10.36076/ppj.2013/16/e533
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发表时间：
2013-11
期刊：
影响因子：
3.7
通讯作者：
Lei Chen;Ling-qun Zhu;Kun Wang;W. Wang;X. Mei;Tao Liu;Fu-xing Zhang;Wen Wang;Tao Chen
中科院分区：
文献类型：
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作者：
Lei Chen;Ling-qun Zhu;Kun Wang;W. Wang;X. Mei;Tao Liu;Fu-xing Zhang;Wen Wang;Tao Chen
癌症诱发的骨痛（CIBP）是一种严重的慢性疼痛，常规镇痛药无法充分控制。前列腺酸性磷酸酶（PAP）已被认为是前列腺癌的诊断标志物，其跨膜异构体已被报道在神经性疼痛和炎性疼痛中发挥抗伤害性作用。然而，它是否对CIBP具有镇痛作用以及其潜在机制仍不清楚。目的在本研究中，我们测试了PAP是否可以减轻骨癌模型大鼠的疼痛症状。研究设计：随机、双盲、对照大鼠动物试验。方法建立大鼠CIBP模型，采用免疫荧光组织化学和Western blot方法观察PAP在脊髓中的表达。然后，在接种肿瘤细胞后15至18天（每天一次），以重复的方式向CIBP大鼠鞘内给予PAP（0.1、0.3或1 μg）。术后第18天测定机械缩足阈，计算PAP镇痛作用的量效曲线和ED 50。在另一项试验中，在POD 15鞘内注射单剂量的PAP的ED 50，以观察其作用的时间过程。此外，分别给予腺苷A1受体拮抗剂8-环戊基-1，3-二丙基黄嘌呤（DPCPX）（3 mg/kg）和核苷转运体抑制剂双嘧达莫（DIP）（10 μg），以探讨PAP的镇痛机制。CIBP大鼠鞘内注射PAP（0.57 μg）和DIP（10 μg）后，用微透析法测定细胞外腺苷的浓度。最后，采用在体电生理方法观察PAP（0.57 μg）、DIP（10 μg）和DPCPX（10 μ g）对CIBP大鼠脊髓宽动态范围（WDR）神经元电诱发反应的影响。结果CIBP大鼠脊髓背角PAP表达明显减少，鞘内注射PAP可通过腺苷A1受体剂量依赖性地减轻CIBP诱导的机械性痛觉超敏。同时，鞘内注射PAP可增加CIBP大鼠脊髓细胞外腺苷浓度，并通过腺苷A1受体抑制脊髓背角深层WDR神经元的神经反应。最后，PAP的镇痛作用被核苷转运体抑制剂DIP加强。目前尚不清楚PAP的抗伤害效应是否由腺苷A1受体以外的其他信号分子介导。此外，鞘内注射PAP的长期抗伤害作用尚不清楚。结论PAP参与了CIBP的维持过程，并通过增加脊髓细胞外腺苷浓度，通过腺苷A1受体发挥抗伤害作用，从而有效抑制CIBP大鼠的中枢敏感化。因此，我们的实验表明，内源性酶PAP可能是一个有前途的候选CIBP治疗。
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.