Centre for Integrated Preclinical Drug Development, The University of Queensland, Brisbane, Queensland, Australia; The School of Pharmacy, The University of Queensland, Brisbane, Queensland, Australia.
Pain Med. 2014 Jan;15(1):93-110. doi: 10.1111/pme.12258. Epub 2013 Oct 30.
The pathobiology of prostate cancer (PCa)-induced bone pain (PCIBP) has both inflammatory and neuropathic components. Previously, we showed that small molecule angiotensin II type 2 receptor (AT2 R) antagonists with >1,000-fold selectivity over the angiotensin II type 1 receptor produced dose-dependent analgesia in a rat model of neuropathic pain. Here, we assessed the analgesic efficacy and mode of action of the AT2 R antagonist, EMA200, in a rat model of PCIBP.
At 14-21 days after unilateral intratibial injection of AT3B PCa cells, rats exhibiting hindpaw hypersensitivity received single intravenous bolus doses of EMA200 (0.3-10 mg/kg) or vehicle, and analgesic efficacy was assessed. The mode of action was investigated using immunohistochemical, Western blot, and/or molecular biological methods in lumbar dorsal root ganglia (DRGs) removed from drug-naïve and EMA200-treated PCIBP rats relative to sham-control rats.
Intravenous bolus doses of EMA200 produced dose-dependent analgesia in PCIBP rats. Lumbar DRG levels of angiotensin II, nerve growth factor (NGF), tyrosine kinase A (TrkA), phospho-p38 mitogen-activated protein kinase (MAPK), and phospho-p44/p42 MAPK, but not the AT2 R, were increased significantly (P < 0.05) in PCIBP rats, c.f. the corresponding levels for sham controls. EMA200 produced analgesia in PCIBP rats by reducing elevated angiotensin II levels in the lumbar DRGs to attenuate augmented angiotensin II/AT2 R signaling. This in turn reduced augmented NGF/TrkA signaling in the lumbar DRGs. The net result was inhibition of p38 MAPK and p44/p42 MAPK activation.
Small molecule AT2 R antagonists are worthy of further investigation as novel analgesics for relief of intractable PCIBP and other pain types where hyperalgesia worsens symptoms.
前列腺癌（PCa）诱导的骨痛（PCIBP）的发病机制既有炎症成分也有神经病理性成分。之前，我们已经证明，血管紧张素 II 型 2 受体（AT2R）的小分子拮抗剂对血管紧张素 II 型 1 受体的选择性超过 1000 倍，在神经病理性疼痛的大鼠模型中产生了剂量依赖性的镇痛作用。在这里，我们评估了 AT2R 拮抗剂 EMA200 在 PCIBP 大鼠模型中的镇痛效果和作用机制。
在单侧胫骨内注射 AT3B PCa 细胞后 14-21 天，出现后爪过敏的大鼠接受单次静脉推注 EMA200（0.3-10mg/kg）或载体，并评估镇痛效果。通过免疫组织化学、Western blot 和/或分子生物学方法，从药物-naive 和 EMA200 治疗的 PCIBP 大鼠的腰椎背根神经节（DRG）中，以及假手术对照大鼠的腰椎 DRG 中，研究作用机制。
静脉推注 EMA200 剂量依赖性地减轻了 PCIBP 大鼠的疼痛。与假手术对照大鼠相比，PCIBP 大鼠的腰椎 DRG 中血管紧张素 II、神经生长因子（NGF）、酪氨酸激酶 A（TrkA）、磷酸化 p38 丝裂原激活蛋白激酶（p38 MAPK）和磷酸化 p44/p42 MAPK 的水平显著升高（P<0.05），但 AT2R 水平没有升高。EMA200 通过降低腰椎 DRG 中升高的血管紧张素 II 水平来减轻增强的血管紧张素 II/AT2R 信号，从而减轻了腰椎 DRG 中增强的 NGF/TrkA 信号，最终抑制了 p38 MAPK 和 p44/p42 MAPK 的激活。
小分子 AT2R 拮抗剂作为治疗难治性 PCIBP 和其他痛觉过敏加重症状的疼痛类型的新型镇痛药值得进一步研究。
