Distinct time courses of microglial and astrocytic hyperactivation and the glial contribution to pain hypersensitivity in a facial cancer model
Distinct time courses of microglial and astrocytic hyperactivation and the glial contribution to pain hypersensitivity in a facial cancer model
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DOI：
10.1016/j.brainres.2012.03.039
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发表时间：
2012-05
期刊：
影响因子：
2.9
通讯作者：
T. Sago;K. Ono;N. Harano;Kazumi Furuta-Hidaka;S. Hitomi;M. Nunomaki;Mitsuhiro Yoshida;S. Shiiba;O. Nakanishi;K. Matsuo;K. Inenaga
中科院分区：
文献类型：
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作者：
T. Sago;K. Ono;N. Harano;Kazumi Furuta-Hidaka;S. Hitomi;M. Nunomaki;Mitsuhiro Yoshida;S. Shiiba;O. Nakanishi;K. Matsuo;K. Inenaga
虽然最近的证据表明中枢神经胶质细胞的过度激活参与了癌症引起的持续性疼痛，但这种过度激活的时间进程和神经胶质细胞对疼痛过敏的贡献仍不清楚。本研究以Walker 256B细胞接种于振动垫内建立大鼠面部肿瘤模型，研究了三叉神经颈复合体(包括延髓(MDH)和上颈背角(UCDH))小胶质细胞和星形胶质细胞过度激活的时间依赖性空间变化以及疼痛相关行为。在这个模型中，肿瘤生长在触垫内，感觉神经纤维从触垫投射到MDH，但没有扩展到眶下区域，从那里投射到UCDH。然而，不仅在震动垫，而且在眶下区域也观察到机械性超敏和热痛敏。Western blotting和免疫荧光研究表明，小胶质细胞在第4天在三叉神经颈复合体中被广泛激活，到第11天逐渐失活。相反，星形胶质细胞仅在第4天在MDH被激活，这种过度激活后来扩展到UCDH。从第4天开始，每天给予神经胶质细胞过度激活抑制剂丙戊茶碱，可抑制随后几天的神经胶质细胞过度激活。从第5天开始，丙戊茶碱治疗很大程度上预防了眶下区域的超敏/痛觉过敏，尽管震动垫上已确定的超敏/痛觉过敏对该治疗不那么敏感。这些结果表明，在该模型中，中枢神经胶质细胞的过度激活、短暂的小胶质细胞过度激活和持续性的星形胶质细胞过度激活有助于疼痛超敏反应的发展，而不是疼痛的维持。
Although recent evidence suggests that central glial hyperactivation is involved in cancer-induced persistent pain, the time course of this hyperactivation and the glial contribution to pain hypersensitivity remain unclear. The present study investigated the time-dependent spatial changes of microglial and astrocytic hyperactivation in the trigeminocervical complex, which consists of the medullary (MDH) and upper cervical (UCDH) dorsal horns, and pain-related behaviors in a rat facial cancer model in which Walker 256B-cells are inoculated into the vibrissal pad. In this model, the tumors grew within the vibrissal pad, from which sensory nerve fibers project into the MDH, but did not expand into the infraorbital region, from which fibers project into the UCDH. Nevertheless, mechanical allodynia and thermal hyperalgesia were observed not only in the vibrissal pad but also in the infraorbital region. Western blotting and immunofluorescence studies indicated that microglia were widely activated in the trigeminocervical complex on day 4 and gradually inactivated by day 11. In contrast, astrocytes were only activated in the MDH on day 4; the hyperactivation later expanded into the UCDH. Daily administration of the glial hyperactivation inhibitor propentofylline beginning on day 4 suppressed the glial hyperactivation on later days. Propentofylline treatment largely prevented allodynia/hyperalgesia in the infraorbital region beginning on day 5, although established allodynia/hyperalgesia in the vibrissal pad was less sensitive to the treatment. These results suggest that central glial hyperactivation, transient microglial hyperactivation and persistent astrocytic hyperactivation, contributes to the development of pain hypersensitivity but not to the maintenance of pain in this model.