Functional interactions between tumor and peripheral nerve: Changes in excitability and morphology of primary afferent fibers in a murine model of cancer pain
Functional interactions between tumor and peripheral nerve: Changes in excitability and morphology of primary afferent fibers in a murine model of cancer pain
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DOI：
10.1523/jneurosci.21-23-09367.2001
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发表时间：
2001-12-01
影响因子：
5.3
通讯作者：
Simone, DA
中科院分区：
文献类型：
--
作者：
Cain, DM;Wacnik, PW;Simone, DA
我们使用小鼠模型来研究肿瘤和周围神经之间的功能相互作用，这些相互作用可能导致与癌症相关的疼痛。植入纤维肉瘤细胞在跟骨和周围产生机械痛觉过敏的同侧爪。在对照组和患肿瘤的痛觉过敏小鼠的初级传入纤维的电生理记录显示，在肿瘤附近的34%的皮肤C纤维中（植入后9-17天）出现自发活动（0.2-3.4 Hz）。荷瘤小鼠的C纤维表现出平均3.5 +/- 0.10 ℃的热阈值下降。我们还检查了肿瘤上皮肤的神经支配。对表皮神经纤维（ENF）进行蛋白质基因产物9.5的免疫染色，使用共聚焦显微镜成像，并根据每毫米表皮长度的纤维数和分支（每根纤维的节点数）进行分析。不同的形态学变化与肿瘤进展有关。尽管ENFs的分支相对于对照值显著增加，但在肿瘤生长的后期阶段（植入后16-24天），观察到ENFs的数量急剧减少。这种肿瘤上方皮肤表皮神经支配的衰退与荷瘤小鼠电生理活性的逐渐丧失在时间上一致。在肿瘤生长的前2周内，C纤维中自发活动和对热的敏感性的发展以及皮肤结构的神经支配增加表明一定比例的C纤维的激活和敏感性。在肿瘤发展的后期观察到的ENF数量的减少暗示了在该癌症疼痛模型中的神经病理性参与。
We used a murine model to investigate functional interactions between tumors and peripheral nerves that may contribute to pain associated with cancer. Implantation of fibrosarcoma cells in and around the calcaneus bone produced mechanical hyperalgesia of the ipsilateral paw. Electrophysiological recordings from primary afferent fibers in control and hyperalgesic mice with tumor revealed the development of spontaneous activity (0.2-3.4 Hz) in 34% of cutaneous C-fibers adjacent to the tumor (9-17 d after implantation). C-fibers in tumor-bearing mice exhibited a mean decrease in heat threshold of 3.5 +/- 0.10 degreesC. We also examined innervation of the skin overlying the tumor. Epidermal nerve fibers (ENFs) were immunostained for protein gene product 9.5, imaged using confocal microscopy, and analyzed in terms of number of fibers per millimeter of epidermal length and branching (number of nodes per fiber). Divergent morphological changes were linked to tumor progression. Although branching of ENFs increased significantly relative to control values, in later stages (16-24 d after implantation) of tumor growth a sharp decrease in the number of ENFs was observed. This decay of epidermal innervation of skin over the tumor coincided temporally with gradual loss of electrophysiological activity in tumor-bearing mice. The development of spontaneous activity and sensitization to heat in C-fibers and increased innervation of cutaneous structures within the first 2 weeks of tumor growth suggest activation and sensitization of a proportion of C-fibers. The decrease in the number of ENFs observed in later stages of tumor development implicates neuropathic involvement in this model of cancer pain.