Palliation of bone cancer pain by antagonists of platelet-activating factor receptors.
Palliation of bone cancer pain by antagonists of platelet-activating factor receptors.
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DOI：
10.1371/journal.pone.0091746
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Dohi T
中科院分区：
文献类型：
--
作者：
Morita K;Shiraishi S;Motoyama N;Kitayama T;Kanematsu T;Uezono Y;Dohi T
骨癌疼痛是癌症疼痛中最严重的，并且通常对当前的止痛药具有抵抗力。因此，需要开发有效治疗骨癌疼痛的新型镇痛剂。血小板活化因子（PAF）受体拮抗剂最近在几种动物模型中被证明对神经病理性疼痛具有有效的镇痛作用。本研究采用小鼠股骨骨癌（FBC）模型，观察PAF受体拮抗剂对骨癌疼痛的缓解作用。将溶骨的NCTC 2472细胞注射到动物胫骨中，随后评价PAF受体拮抗剂对疼痛行为的影响。化学结构不同类型的拮抗剂TCV-309、BN 50739和WEB 2086改善了FBC模型小鼠的异常性疼痛，并改善了疼痛行为，如守卫行为和肢体使用异常。这些拮抗剂的疼痛缓解作用是在低剂量下实现的，并且是持久的。通过鞘内注射TCV-309和WEB 2086阻断脊髓PAF受体或通过鞘内转移PAF受体siRNA敲低脊髓PAF受体蛋白的表达也产生疼痛缓解作用。NCTC 2472肿瘤细胞移植到小鼠胫骨后，脊髓中可诱导的PAF合成酶溶血磷脂酰胆碱酰基转移酶2（LPCAT 2）蛋白的量显著增加。吗啡与PAF受体拮抗剂联合应用可显著增强对骨癌疼痛的镇痛作用，而不影响吗啡诱导的便秘。TCV-309的重复给药抑制了FBC小鼠疼痛行为的出现并延长了存活时间。目前的研究结果表明，PAF受体拮抗剂联合或不联合阿片类药物可能是治疗持续性骨癌疼痛和改善患者生活质量的新策略。
Bone cancer pain is the most severe among cancer pain and is often resistant to current analgesics. Thus, the development of novel analgesics effective at treating bone cancer pain are desired. Platelet-activating factor (PAF) receptor antagonists were recently demonstrated to have effective pain relieving effects on neuropathic pain in several animal models. The present study examined the pain relieving effect of PAF receptor antagonists on bone cancer pain using the femur bone cancer (FBC) model in mice. Animals were injected with osteolytic NCTC2472 cells into the tibia, and subsequently the effects of PAF receptor antagonists on pain behaviors were evaluated. Chemical structurally different type of antagonists, TCV-309, BN 50739 and WEB 2086 ameliorated the allodynia and improved pain behaviors such as guarding behavior and limb-use abnormalities in FBC model mice. The pain relieving effects of these antagonists were achieved with low doses and were long lasting. Blockade of spinal PAF receptors by intrathecal injection of TCV-309 and WEB 2086 or knockdown of the expression of spinal PAF receptor protein by intrathecal transfer of PAF receptor siRNA also produced a pain relieving effect. The amount of an inducible PAF synthesis enzyme, lysophosphatidylcholine acyltransferase 2 (LPCAT2) protein significantly increased in the spinal cord after transplantation of NCTC 2472 tumor cells into mouse tibia. The combination of morphine with PAF receptor antagonists develops marked enhancement of the analgesic effect against bone cancer pain without affecting morphine-induced constipation. Repeated administration of TCV-309 suppressed the appearance of pain behaviors and prolonged survival of FBC mice. The present results suggest that PAF receptor antagonists in combination with, or without, opioids may represent a new strategy for the treatment of persistent bone cancer pain and improve the quality of life of patients.
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影响因子：
3.8
作者：
de Oliveira, Soraya I.;Andrade, Luciana N. S.;Jancar, Sonia
通讯作者：
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影响因子：
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作者：
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影响因子：
7.3
作者：
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通讯作者：
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影响因子：
7.4
作者：
MINAMI, T;NISHIHARA, I;HAYAISHI, O
通讯作者：
HAYAISHI, O
影响因子：
9
作者：
LILLEMOE, KD;CAMERON, JL;ALDRETE, JS
通讯作者：
ALDRETE, JS