Substance P spinal signaling induces glial activation and nociceptive sensitization after fracture.
Substance P spinal signaling induces glial activation and nociceptive sensitization after fracture.
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DOI：
10.1016/j.neuroscience.2015.09.036
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发表时间：
2015-12-03
期刊：
影响因子：
3.3
通讯作者：
Kingery WS
中科院分区：
文献类型：
--
作者：
Li WW;Guo TZ;Shi X;Sun Y;Wei T;Clark DJ;Kingery WS
啮齿类动物胫骨骨折诱导P物质（SP）依赖性角化细胞活化和后肢炎症变化，类似于复杂区域疼痛综合征（CRPS）。在动物疼痛模型中，脊髓胶质细胞激活导致伤害性致敏。本研究验证了肢体骨折触发背角传入c纤维SP释放，导致慢性胶质细胞激活和中枢致敏的假设。大鼠胫骨骨折后4周取下石膏，观察后爪异常性痛、失重、体温和水肿，然后检测小胶质细胞（米诺环素）或星形胶质细胞（LAA）抑制剂或SP受体拮抗剂（LY303870）的抗伤感受作用。采用免疫组织化学和PCR技术检测大鼠背角小胶质细胞和星形胶质细胞的活化情况。在完整大鼠坐骨神经短暂电刺激c纤维强度后进行类似实验。小胶质细胞和星形胶质细胞在骨折后4周被慢性激活，并有助于维持后肢异常性疼痛和减轻体重。此外，LY303870治疗在骨折后4周开始部分逆转脊髓胶质激活和伤害性致敏。同样，在坐骨神经c纤维刺激48小时后，观察到持续的脊髓小胶质细胞激活和后爪伤害性致敏，这种作用被二甲胺四环素、LAA或LY303870治疗抑制。这些数据支持了c纤维传入SP信号在肢体骨折后长期支持脊髓神经胶质细胞激活的假设，并且神经胶质细胞激活有助于维持CRPS中枢性伤害知觉敏化。抑制神经胶质活化和脊髓炎症的治疗可能是治疗CRPS的有效方法。
Tibia fracture in rodents induces substance P (SP)-dependent keratinocyte activation and inflammatory changes in the hindlimb, similar to those seen in complex regional pain syndrome (CRPS). In animal pain models spinal glial cell activation results in nociceptive sensitization. This study tested the hypothesis that limb fracture triggers afferent C-fiber SP release in the dorsal horn, resulting in chronic glia activation and central sensitization. At 4 weeks after tibia fracture and casting in rats, the cast was removed and hind paw allodynia, unweighting, warmth, and edema were measured, then the antinociceptive effects of microglia (minocycline) or astrocyte (LAA) inhibitors or an SP receptor antagonist (LY303870) were tested. Immunohistochemistry and PCR were used to evaluate microglia and astrocyte activation in the dorsal horn. Similar experiments were performed in intact rats after brief sciatic nerve electric stimulation at C-fiber intensity. Microglia and astrocytes were chronically activated at 4 weeks after fracture and contributed to the maintenance of hind paw allodynia and unweighting. Furthermore, LY303870 treatment initiated at 4 weeks after fracture partially reversed both spinal glial activation and nociceptive sensitization. Similarly, persistent spinal microglial activation and hind paw nociceptive sensitization were observed at 48 hours after sciatic nerve C-fiber stimulation and this effect was inhibited by treatment with minocycline, LAA, or LY303870. These data support the hypothesis that C-fiber afferent SP signaling chronically supports spinal neuroglia activation after limb fracture and that glial activation contributes to the maintenance of central nociceptive sensitization in CRPS. Treatments inhibiting glial activation and spinal inflammation may be therapeutic for CRPS.