Diaz-delCastillo Marta, Hansen Rie Bager, Appel Camilla Kristine, Nielsen Lykke, Nielsen Sascha Nolsøe, Karyniotakis Konstantinos, Dahl Louise M, Andreasen Rikke B, Heegaard Anne-Marie
Department of Drug Design and Pharmacology, University of Copenhagen, DK-2100 Copenhagen, Denmark.
Cancers (Basel). 2020 Sep 24;12(10):2740. doi: 10.3390/cancers12102740.
The dissemination of cancer to bone can cause significant cancer-induced bone pain (CIBP), severely impairing the patient's quality of life. Several rodent models have been developed to explore the nociceptive mechanisms of CIBP, including intratibial inoculation of breast carcinoma cells in syngeneic Sprague Dawley rats. Using this model, we investigated whether resident spinal microglial cells are involved in the transmission and modulation of CIBP, a long-debated disease feature. Immunohistochemical staining of ionizing calcium-binding adaptor molecule 1 (Iba-1) and phosphorylated p38-mitogen-activated protein kinase (P-p38 MAPK) showed no spinal microglial reaction in cancer-bearing rats, independently of disease stage, sex, or carcinoma cell line. As a positive control, significant upregulation of both Iba-1 and P-p38 was observed in a rat model of neuropathic pain. Additionally, intrathecal administration of the microglial inhibitor minocycline did not ameliorate pain-like behaviors in cancer-bearing rats, in contrast to spinal morphine administration. Our results indicate that microglial reaction is not a main player in CIBP, adding to the debate that even within the same models of CIBP, significant variations are seen in disease features considered potential drug targets. We suggest that this heterogeneity may reflect the clinical landscape, underscoring the need for understanding the translational value of CIBP models.
癌症转移至骨骼可引发严重的癌性骨痛（CIBP），严重损害患者的生活质量。人们已开发出多种啮齿动物模型来探究CIBP的伤害感受机制，包括在同基因的斯普拉格-道利大鼠胫骨内接种乳腺癌细胞。利用该模型，我们研究了脊髓内常驻小胶质细胞是否参与CIBP（一个长期存在争议的疾病特征）的传递和调节。对离子钙结合衔接分子1（Iba-1）和磷酸化p38丝裂原活化蛋白激酶（P-p38 MAPK）进行免疫组织化学染色显示，荷癌大鼠脊髓内无小胶质细胞反应，这与疾病阶段、性别或癌细胞系无关。作为阳性对照，在神经性疼痛大鼠模型中观察到Iba-1和P-p38均显著上调。此外，与鞘内注射吗啡不同，鞘内注射小胶质细胞抑制剂米诺环素并不能改善荷癌大鼠的疼痛样行为。我们的结果表明，小胶质细胞反应并非CIBP的主要因素，这也加入了关于以下问题的争论：即使在相同的CIBP模型中，被视为潜在药物靶点的疾病特征也存在显著差异。我们认为这种异质性可能反映了临床情况，强调了理解CIBP模型转化价值的必要性。
