Intrathecal administration of adrenomedullin induces mechanical allodynia and neurochemical changes in spinal cord and DRG
Intrathecal administration of adrenomedullin induces mechanical allodynia and neurochemical changes in spinal cord and DRG
复制标题
鞘内注射肾上腺髓质素可引起脊髓和背根神经节的机械性异常性疼痛和神经化学变化
DOI：
10.1016/j.neulet.2018.10.037
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发表时间：
2019-01-18
影响因子：
2.5
通讯作者：
Hong, Yanguo
中科院分区：
文献类型：
--
作者：
Huang, Hao;Wang, Mei;Hong, Yanguo
本研究探讨肾上腺髓质素(AM)对机械痛敏感性的影响及其可能机制。鞘内注射AM受体激动剂AM(1-50)(20 mg/d)后，第1天和第2天的机械痛阈值短暂降低，但在第3天出现较长时间的机械痛觉超敏。鞘内注射AM受体拮抗剂AM(22-52)(20 Mg)后，AM(1-50)对机械痛觉无明显影响。AM(1-50)(20 MU G)每日给药3d可增加脊髓背角磷酸化细胞外信号调节蛋白激酶(PERK)和神经元型一氧化氮合酶(NNOS)的表达。AM(22-52)可抑制AM诱导的PERK和nNOS的升高。长期给予AM(1-50)还以AM(22-52)敏感的方式增加小胶质细胞标志物IBA1和星形胶质细胞标志物GFAP(胶质纤维酸性蛋白)在脊髓背角的表达。此外，AM(1.50)(10 nM，3h)作用于背根神经节(DRG)外植体培养可诱导瞬时受体电位香草素1(TRPV1)表达增加。当AM(22.52)(2mU M)存在时，AM(1-50)处理不改变DRG中TRPV1的表达。这些结果提示AM生物活性的增强导致了机械性痛觉异常，并可能参与了病理条件下的机械性疼痛超敏反应。其机制可能涉及ERK信号通路和脊髓胶质细胞的激活以及nNOS和TRPV1在脊髓背角或背根节的募集。目前的研究表明，抑制AM受体的激活可能为缓解慢性疼痛提供了一种有效的策略。
This study investigated the effect of adrenomedullin (AM) on mechanical pain sensitivity and its possible mechanisms. Intrathecal injection of AM receptor agonist AM(1-50) (20 mu g) once per day briefly reduced mechanical pain threshold on days 1 and 2 but induced prolonged mechanical allodynia on day 3. However, AM(1-50) did not change mechanical pain sensation when the AM receptor antagonist AM(22-52) (20 mu g) was intrathecally co-administered. Daily administration of AM(1-50) (20 mu g) for 3 days increased expression of phosphorylated extra cellular signal-regulated protein kinase (pERK) and neuronal nitric oxide synthase (nNOS) in the spinal dorsal horn. The AM-induced increase in pERK and nNOS was inhibited by the co-administration of AM(22-52). The chronic administration of AM(1-50) also increased expression of microglial maker Iba1 and astrocytic marker GFAP (glial fibrillary acidic protein) in the spinal dorsal hom in an AM(22-52)-sensitive manner. Furthermore, the application of AM(1.50) (10 nM, 3 h) to dorsal root ganglion (DRG) explant cultures induced an increase in the expression of transient receptor potential vanilloid 1 (TRPV1). The treatment with AM(1-50) did not change TRPV1 expression in DRG in the presence of AM(22.52) (2 mu M). These results suggest that the increased AM bioactivity induced mechanical allodynia and may contribute to the mechanical pain hypersensitivity under pathological conditions. The mechanisms may involve the activation of ERK signaling pathway and spinal glia as well as the recruitment of nNOS and TRPV1 in the spinal dorsal horn or DRG. The present study indicates that inhibition of the activation AM receptor might provide a fruitful strategy to relieving chronic pain.