Morita Katsuya, Shiraishi Seiji, Motoyama Naoyo, Kitayama Tomoya, Kanematsu Takashi, Uezono Yasuhito, Dohi Toshihiro
Department of Pharmacology, Faculty of Nursing, Hiroshima Bunka Gakuen University, Hiroshima, Japan; Cancer Pathophysiology, Division National Cancer Center Research Institute, Tokyo, Japan; Department of Cell and Molecular Pharmacology, Division of Basic Life Science, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
Cancer Pathophysiology, Division National Cancer Center Research Institute, Tokyo, Japan.
PLoS One. 2014 Mar 17;9(3):e91746. doi: 10.1371/journal.pone.0091746. eCollection 2014.
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.
骨癌疼痛是癌症疼痛中最严重的，并且常常对目前的镇痛药有抗性。因此，人们期望开发出对治疗骨癌疼痛有效的新型镇痛药。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性疼痛有有效的止痛作用。本研究使用小鼠股骨骨癌（FBC）模型研究了PAF受体拮抗剂对骨癌疼痛的止痛作用。将溶骨性NCTC2472细胞注射到动物的胫骨中，随后评估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，并改善了诸如保护性动作和肢体使用异常等疼痛行为。这些拮抗剂的止痛作用在低剂量时即可实现，并且持续时间长。鞘内注射TCV-309和WEB 2086阻断脊髓PAF受体，或鞘内注射PAF受体siRNA敲低脊髓PAF受体蛋白的表达也产生了止痛作用。将NCTC 2472肿瘤细胞移植到小鼠胫骨后，脊髓中一种可诱导的PAF合成酶，溶血磷脂酰胆碱酰基转移酶2（LPCAT2）蛋白的量显著增加。吗啡与PAF受体拮抗剂联合使用可显著增强对骨癌疼痛的镇痛效果，而不影响吗啡引起的便秘。重复给予TCV-309可抑制FBC小鼠疼痛行为的出现并延长其生存期。目前的结果表明，PAF受体拮抗剂与阿片类药物联合或不联合使用，可能代表了一种治疗持续性骨癌疼痛的新策略，并可改善患者的生活质量。
