Behavioral, medical imaging and histopathological features of a new rat model of bone cancer pain.
Behavioral, medical imaging and histopathological features of a new rat model of bone cancer pain.
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DOI：
10.1371/journal.pone.0013774
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发表时间：
2010-10-29
期刊：
影响因子：
3.7
通讯作者：
Sarret P
中科院分区：
文献类型：
--
作者：
Doré-Savard L;Otis V;Belleville K;Lemire M;Archambault M;Tremblay L;Beaudoin JF;Beaudet N;Lecomte R;Lepage M;Gendron L;Sarret P
模拟人类状况的临床前骨癌疼痛模型需要符合临床实际。患有骨转移的乳腺癌或前列腺癌患者会经历顽固性疼痛，这影响了他们的生活质量。因此需要先进的监测来阐明骨癌疼痛机制并改进治疗方法。在我们的大鼠股骨乳腺癌MRMT - 1细胞植入模型中，对疼痛发作和肿瘤生长进行了21天的监测。在不进行关节切开术的情况下进行的手术操作使得能够记录自由活动大鼠的偶发性疼痛。随着机械性异常性疼痛和痛觉过敏逐渐发展，在第14天通过使用动态负重设备检测到了行走疼痛的行为迹象。从第14天开始发现骨质减少，同时伴有骨小梁结构紊乱（微计算机断层扫描）。在检测到疼痛之前，早在第8天通过磁共振成像（T1 - 钆 - 二乙三胺五乙酸）就可观察到骨转移。正电子发射断层扫描（氟化钠 - 18）共同配准显示出骨内活动，这是通过根据破骨细胞活性亢进（抗酒石酸酸性磷酸酶染色）在磁共振成像上进行解剖学叠加确定的。疼痛和骨破坏随着时间的推移而加重。骨重塑伴随着c - Fos（脊髓）和ATF3（背根神经节）神经元激活，并由腰椎脊髓中的星形胶质细胞（胶质纤维酸性蛋白）和小胶质细胞（离子钙结合衔接分子1）的反应性所维持。我们的动物模型证明了同时记录疼痛和肿瘤进展的重要性，并将使我们在未来能够更好地描述治疗策略的特征。
Pre-clinical bone cancer pain models mimicking the human condition are required to respond to clinical realities. Breast or prostate cancer patients coping with bone metastases experience intractable pain, which affects their quality of life. Advanced monitoring is thus required to clarify bone cancer pain mechanisms and refine treatments. In our model of rat femoral mammary carcinoma MRMT-1 cell implantation, pain onset and tumor growth were monitored for 21 days. The surgical procedure performed without arthrotomy allowed recording of incidental pain in free-moving rats. Along with the gradual development of mechanical allodynia and hyperalgesia, behavioral signs of ambulatory pain were detected at day 14 by using a dynamic weight-bearing apparatus. Osteopenia was revealed from day 14 concomitantly with disorganization of the trabecular architecture (µCT). Bone metastases were visualized as early as day 8 by MRI (T1-Gd-DTPA) before pain detection. PET (Na18F) co-registration revealed intra-osseous activity, as determined by anatomical superimposition over MRI in accordance with osteoclastic hyperactivity (TRAP staining). Pain and bone destruction were aggravated with time. Bone remodeling was accompanied by c-Fos (spinal) and ATF3 (DRG) neuronal activation, sustained by astrocyte (GFAP) and microglia (Iba1) reactivity in lumbar spinal cord. Our animal model demonstrates the importance of simultaneously recording pain and tumor progression and will allow us to better characterize therapeutic strategies in the future.
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