Facilitated spinal neuropeptide signaling and upregulated inflammatory mediator expression contribute to postfracture nociceptive sensitization.
Facilitated spinal neuropeptide signaling and upregulated inflammatory mediator expression contribute to postfracture nociceptive sensitization.
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DOI：
10.1097/j.pain.0000000000000204
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发表时间：
2015-10
期刊：
影响因子：
7.4
通讯作者：
Kingery WS
中科院分区：
文献类型：
--
作者：
Shi X;Guo TZ;Wei T;Li WW;Clark DJ;Kingery WS
脊髓神经肽信号传导和炎症介质表达支持复杂性局部疼痛综合征骨折模型中的伤害性敏化。胫骨骨折诱导夸张的P物质（SP）和降钙素基因相关肽（CGRP）信号和神经肽依赖性伤害性和炎症性变化在大鼠的后肢类似于那些在复杂的区域疼痛综合征。在多种动物疼痛模型中，脊髓中的炎性变化有助于伤害性敏化。本研究验证了这一假设，即骨折诱导的过度神经肽信号上调脊髓炎症介质的表达，导致骨折后后肢伤害性敏化。在大鼠胫骨骨折和铸型后4周，我们测量了后肢异常性疼痛、失重、温暖、水肿和脊髓神经肽和炎性介质含量。鞘内注射神经肽和炎性介质受体拮抗剂的抗伤害性作用在骨折大鼠进行了评价。使用缺乏SP或CGRP RAMP 1受体的转基因骨折小鼠来确定神经肽信号传导对骨折后疼痛行为和脊髓炎性介质表达的影响。大鼠骨折后4周观察到后肢异常性疼痛、失重、发热、水肿、脊髓SP和CGRP增加以及脊髓炎性介质（TNF、IL-1、IL-6、CCL 2和神经生长因子）表达增加。在缺乏SP或CGRP受体的骨折小鼠中未观察到骨折诱导的脊髓炎症介质增加，这些小鼠具有减弱的骨折后伤害性敏化。鞘内注射SP、CGRP、TNF、IL-1、IL-6、CCL 2或神经生长因子的选择性受体拮抗剂可降低骨折大鼠的疼痛行为。总的来说，这些数据支持这一假设，促进脊髓神经肽信号上调脊髓炎症介质的表达，有助于在啮齿动物骨折模型的复杂区域疼痛综合征的伤害性敏化。
Spinal neuropeptide signaling and inflammatory mediator expression supports nociceptive sensitization in a fracture model of complex regional pain syndrome. Tibia fracture induces exaggerated substance P (SP) and calcitonin gene–related peptide (CGRP) signaling and neuropeptide-dependent nociceptive and inflammatory changes in the hind limbs of rats similar to those seen in complex regional pain syndrome. Inflammatory changes in the spinal cord contribute to nociceptive sensitization in a variety of animal pain models. This study tested the hypothesis that fracture-induced exaggerated neuropeptide signaling upregulates spinal inflammatory mediator expression, leading to postfracture hind limb nociceptive sensitization. At 4 weeks after performing tibia fracture and casting in rats, we measured hind limb allodynia, unweighting, warmth, edema, and spinal cord neuropeptide and inflammatory mediator content. The antinociceptive effects of intrathecally injected neuropeptide and inflammatory mediator receptor antagonists were evaluated in fracture rats. Transgenic fracture mice lacking SP or the CGRP RAMP1 receptor were used to determine the effects of neuropeptide signaling on postfracture pain behavior and spinal inflammatory mediator expression. Hind limb allodynia, unweighting, warmth, edema, increased spinal SP and CGRP, and increased spinal inflammatory mediator expression (TNF, IL-1, IL-6, CCL2, and nerve growth factor) were observed at 4 weeks after fracture in rats. Fracture-induced increases in spinal inflammatory mediators were not observed in fracture mice lacking SP or the CGRP receptor, and these mice had attenuated postfracture nociceptive sensitization. Intrathecal injection of selective receptor antagonists for SP, CGRP, TNF, IL-1, IL-6, CCL2, or nerve growth factor each reduced pain behaviors in the fracture rats. Collectively, these data support the hypothesis that facilitated spinal neuropeptide signaling upregulates the expression of spinal inflammatory mediators contributing to nociceptive sensitization in a rodent fracture model of complex regional pain syndrome.