A rat model of bone cancer pain
A rat model of bone cancer pain
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DOI：
10.1016/s0304-3959(01)00437-7
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发表时间：
2002-03-01
期刊：
影响因子：
7.4
通讯作者：
Urban, L
中科院分区：
文献类型：
--
作者：
Medhurst, SJ;Walker, K;Urban, L
本研究描述了首个已知的大鼠骨癌疼痛模型。向Sprague - Dawley大鼠胫骨内注射同基因的MRMT - 1大鼠乳腺癌细胞后，大鼠出现了疼痛的行为迹象，包括：机械性异常性疼痛、后爪负重差异以及机械性痛觉过敏。通过放射学分析、矿物质含量定量测量和组织学方法监测骨肿瘤的发展以及骨结构损伤。
向胫骨内注射3×10³或3×10⁴个同基因的MRMT - 1细胞会在胫骨范围内产生快速增长的肿瘤，导致骨骼严重重塑。在接种3×10³个MRMT - 1细胞后的第10 - 14天，X射线照片显示皮质骨和骨小梁广泛受损，到第20天，损伤已危及胫骨的完整性。虽然患癌骨的矿物质含量和矿物质密度均显著降低，但肿瘤周围密质骨中的破骨细胞数量保持不变。然而，抗酒石酸酸性磷酸酶染色显示肿瘤内有大量多核细胞，类似于破骨细胞。注射热灭活的MRMT - 1细胞后未观察到肿瘤生长。
在19 - 20天内，向胫骨内注射3×10³或3×10⁴个MRMT - 1细胞、热灭活细胞或赋形剂，大鼠体重和核心温度均未出现变化。注射活的或热灭活的MRMT - 1细胞后，动物的总体活动量高于对照组，然而，MRMT - 1处理组的活动量在疾病进展过程中下降。
向大鼠胫骨内注射MRMT - 1细胞后，分别在注射3×10³或3×10⁴个细胞后的第12 - 14天或第10 - 12天开始，出现机械性异常性疼痛以及机械性痛觉过敏/患侧肢体负重减轻的逐渐发展。在注射热灭活细胞或赋形剂的大鼠中未观察到这些症状。
行为数据表明，在该模型中，癌细胞接种后的第14 - 20天是评估抗伤害感受药物的合理时间窗口。
在向胫骨内注射3×10³个MRMT - 1细胞后的第17或19天，皮下注射吗啡（1 - 3mg/kg）可使后爪对von Frey纤维刺激的回缩反应频率呈剂量依赖性降低，同时也观察到后肢负重差异显著减小。在向胫骨内注射3×10³个MRMT - 1细胞20天后，皮下注射塞来昔布（10 - 30mg/kg）对机械性异常性疼痛或负重差异没有影响。
尽管癌症疼痛的病理生理学在很大程度上尚不清楚，但同侧脊髓相应节段的胶质纤维酸性蛋白（GFAP）染色显著增强，凸显了星形胶质细胞可能参与其中。
总之，通过同基因的MRMT - 1乳腺肿瘤细胞系在大鼠中诱导骨癌，为与骨转移相关的疼痛提供了一个有效的临床前模型。随着骨髓腔内肿瘤的进展，出现了显著的机械性痛觉过敏和异常性疼痛，而动物的总体状况仍然良好。虽然吗啡急性治疗对后肢有一定的镇痛作用，但选择性COX - 2抑制剂塞来昔布对该模型中与疼痛相关的行为变化没有影响。（C）2002国际疼痛研究协会。由爱思唯尔科学出版社出版。保留所有权利。
This study describes the first known model of bone cancer pain in the rat. Sprague-Dawley rats receiving intra-tibial injections of syngeneic MRMT-1 rat mammary gland carcinoma cells developed behavioural signs indicative of pain, including: mechanical allodynia, difference of weight bearing between hind paws and mechanical hyperalgesia. The development of the bone tumour and structural damage to the bone was monitored by radiological analysis, quantitative measurement of mineral content and histology.Intra-tibial injections of 3 x 10(3) or 3 x 10(4) syngeneic MRMT-1 cells produced a rapidly expanding tumour within the boundaries of the tibia, causing severe remodelling of the bone. Radiographs showed extensive damage to the cortical bone and the trabeculae by day 10-14 after inoculation of 3 x 10(3) MRMT-1 cells, and by day 20, the damage was threatening the integrity of the tibial bone. While both mineral content and mineral density decreased significantly in the cancerous bone, osteoclast numbers in the peritumoural compact bone remained unchanged. However. tartarate-resistant acid phosphatase staining revealed a large number of polykariotic cells. resembling those of osteoclasts within the tumour. No tumour growth was observed after the injection of heat-killed MRMT-1 cells.Intra-tibial injections of 3 x 103 or 3 x 104 MRMT-1 cells, heat-killed cells or vehicle did not show changes in body weight and core temperature over 19-20 days. The general activity of animals after injection with live or heat-killed MRMT-1 cells was higher than that of the control group, however, the activity of the MRMT-1 treated group declined during the progress of the disease.Rats receiving intra-tibial injections of MRMT-1 cells displayed the gradual development of mechanical allodynia and mechanical hyperalgesia/reduced weight bearing on the affected limb, beginning on day 12-14 or 10-12 following injection of 3 x 10(3) or 3 x 10(4) cells, respectively. These symptoms were not observed in rats receiving heat-killed cells or vehicle.Behavioural data suggest a reasonable time window for evaluation of anti-nociceptive agents between day 14 and 20 after cancer cell inoculation in this model.Acute treatment with morphine (1-3 mg/kg, subcutanously (s.c.)) produced a dose-dependent reduction in the response frequency of hind paw withdrawal to von Frey filament stimulation 17 or 19 days following intra-tibial injections of 3 x 103 MRMT-1 cells. A significant reduction in the difference in hind limb weight bearing was also observed. Acute treatment with celebrex (10-30 mg/kg, s.c.) did not affect mechanical allodynia or difference in weight bearing in rats 20 days following treatment with 3 x 10(3) MRMT-1 cells.Although the pathophysiology of cancer pain is largely unknown, significant enhancement of glial fibrillary acidic protein (GFAP) staining in the corresponding segments of the ipsilateral spinal cord highlights the possible involvement of astrocytes.In summary, the induction of bone cancer in the rat by the syngencic MRMT-1 mammary tumour cell line provides a valid pre-clinical model for pain associated With bone metastases. Significant mechanical hyperalgesia and allodynia develops in association with the progression of the tumour in the bone marrow cavity, while the general condition of the animal remains satisfactory. While acute treatment with morphine has sonic analgesic effect on hind limb sparing the selective COX-2 inhibitor, celebrex, has no influence on the pain-related behavioural changes in this model. (C) 2002 International Association for the Study of Pain. Published by Elsevier Science B.V. All rights reserved.