Role of extracellular calcitonin gene-related peptide in spinal cord mechanisms of cancer-induced bone pain
Role of extracellular calcitonin gene-related peptide in spinal cord mechanisms of cancer-induced bone pain
复制标题
DOI：
10.1097/j.pain.0000000000000416
复制
发表时间：
2016-03-01
期刊：
影响因子：
7.4
通讯作者：
Malcangio, Marzia
中科院分区：
文献类型：
--
作者：
Hansen, Rikke R.;Vacca, Valentina;Malcangio, Marzia
剧烈疼痛是转移性骨癌常见且使人衰弱的并发症。目前的镇痛剂提供的疼痛缓解不足，并且经常导致显著的不良反应。在癌症引起的骨痛模型中，肿瘤-骨界面处感觉纤维的病理性发芽伴随着脊髓背角中的反应性星形胶质细胞增多而发生。我们观察到，降钙素基因相关肽（CGRP）纤维在骨发芽与背根神经节（DRG）的感觉神经元细胞体中CGRP含量的增加和增加的基础和活动诱发的释放CGRP从他们的中央末梢在背角。鞘内给药肽拮抗剂（α-CGRP 8 -37）可减轻骨癌同侧后爪的牵涉性异常性疼痛。CGRP受体成分（RAMP 1和CGRP）在背角神经元中上调，并由反应性星形胶质细胞表达。在星形胶质细胞的原代培养物中，CGRP孵育导致毛喉素诱导的cAMP产生的浓度依赖性增加，其通过用CGRP 8 -37预处理而减弱。此外，CGRP诱导星形胶质细胞中ATP的释放，其被CGRP 8 -37抑制。我们认为，在癌症引起的骨痛中观察到的CGRP含量的外周增加反映了细胞外CGRP水平的中枢增加。这种CGRP的增加不仅可以促进谷氨酸驱动的神经元伤害性信号传导，而且还作用于星形胶质细胞CGRP受体并导致ATP的释放。
Severe pain is a common and debilitating complication of metastatic bone cancer. Current analgesics provide insufficient pain relief and often lead to significant adverse effects. In models of cancer-induced bone pain, pathological sprouting of sensory fibers at the tumor-bone interface occurs concomitantly with reactive astrocytosis in the dorsal horn of the spinal cord. We observed that calcitonin gene-related peptide (CGRP)-fiber sprouting in the bone was associated with an increase in CGRP content in sensory neuron cell bodies in the dorsal root ganglia (DRG) and increased basal and activity-evoked release of CGRP from their central terminals in the dorsal horn. Intrathecal administration of a peptide antagonist (alpha-CGRP8-37) attenuated referred allodynia in the hind paw ipsilateral to bone cancer. CGRP receptor components (CLR and RAMP1) were up-regulated in dorsal horn neurons and expressed by reactive astrocytes. In primary cultures of astrocytes, CGRP incubation led to a concentration-dependent increase of forskolin-induced cAMP production, which was attenuated by pretreatment with CGRP8-37. Furthermore, CGRP induced ATP release in astrocytes, which was inhibited by CGRP8-37. We suggest that the peripheral increase in CGRP content observed in cancer-induced bone pain is mirrored by a central increase in the extracellular levels of CGRP. This increase in CGRP not only may facilitate glutamate-driven neuronal nociceptive signaling but also act on astrocytic CGRP receptors and lead to release of ATP.