Vit Jean-Philippe, Ohara Peter T, Tien Duc A, Fike John R, Eikmeier Laura, Beitz Alvin, Wilcox George L, Jasmin Luc
Department of Anatomy, University of California San Francisco, San Francisco, CA 94143-0452, USA Department of Neurological Surgery, University of California San Francisco, San Francisco, CA 94143, USA Departments of Veterinary and Biomedical Sciences, University of Minnesota, St. Paul, MN 55108, USA Departments of Neuroscience, Pharmacology and Dermatology, University of Minnesota, St. Paul, MN 55108, USA.
Pain. 2006 Jan;120(1-2):188-201. doi: 10.1016/j.pain.2005.10.033. Epub 2005 Dec 19.
Despite the widespread use of radiotherapy to treat painful bone metastases, the mechanism underlying the analgesic effect of low dose ionizing radiation is unknown. Bone cancer pain is mostly associated with an inflammatory response dominated by local activation of osteoclasts and by astrogliosis in the spinal cord. We determined the effects of a 6 Gy irradiation given focally on osteolytic sarcoma cells inoculated in humeri of mice. Pain behavior was assessed using the rota-rod and the grip force test. Seven days post-irradiation (day 17 post-tumor implantation) the performance of mice markedly improved on the rotarod (non-irradiated, 67+/-16s vs irradiated, 223 +/- 22 s; P = 0.0005), and the grip force test (non-irradiated, 34 +/- 4 g vs irradiated, 55 +/- 2 g; P = 0.001). This improvement was similar to the analgesia achieved with 30 mg/kg of the cyclooxygenase (COX) inhibitor ketorolac (Rota-rod, 67 +/- 16 s vs 178 +/- 35 s; P = 0.01: grip force test, 34 +/- 4 g, vs 60 +/- 5 g; P = 0.003). Following irradiation, the tumor mass and the number of osteoclasts did not decrease while the expression of two pro-inflammatory cytokines (monocyte chemoattractant protein (MCP)-1 and tumor necrosis factor (TNF)-alpha) increased. Tumor irradiation led to clear differences in the spinal cord. These include a decrease in glial activity (astrocytes and microglial cells) as well as pain mediators such as dynorphin, COX-2 and chemotactic cytokine receptor (CCR2). We conclude that the analgesic effect of low dose irradiation of bone cancer is associated with the alteration of nociceptive transmission in the central nervous system.
尽管放射疗法被广泛用于治疗疼痛性骨转移瘤，但低剂量电离辐射镇痛作用的潜在机制尚不清楚。骨癌疼痛主要与一种炎症反应相关，该炎症反应以破骨细胞的局部激活和脊髓中的星形胶质细胞增生为主导。我们确定了对接种于小鼠肱骨的溶骨性肉瘤细胞进行局部6 Gy照射的效果。使用转棒试验和握力试验评估疼痛行为。照射后7天（肿瘤植入后第17天），小鼠在转棒试验中的表现显著改善（未照射组，67±16秒 vs 照射组，223±22秒；P = 0.0005），在握力试验中也是如此（未照射组，34±4克 vs 照射组，55±2克；P = 0.001）。这种改善与30 mg/kg的环氧化酶（COX）抑制剂酮咯酸所达到的镇痛效果相似（转棒试验，67±16秒 vs 178±35秒；P = 0.01；握力试验，34±4克 vs 60±5克；P = 0.003）。照射后，肿瘤体积和破骨细胞数量并未减少，而两种促炎细胞因子（单核细胞趋化蛋白（MCP）-1和肿瘤坏死因子（TNF）-α）的表达增加。肿瘤照射导致脊髓出现明显差异。这些差异包括神经胶质细胞活性（星形胶质细胞和小胶质细胞）以及诸如强啡肽、COX-2和趋化细胞因子受体（CCR2）等疼痛介质的减少。我们得出结论，骨癌低剂量照射的镇痛作用与中枢神经系统中伤害性感受传递的改变有关。
