Spinal astrocytic activation contributes to mechanical allodynia in a rat model of cyclophosphamide-induced cystitis.
Spinal astrocytic activation contributes to mechanical allodynia in a rat model of cyclophosphamide-induced cystitis.
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脊髓星形细胞激活导致环磷酰胺诱导膀胱炎大鼠模型机械性异常性疼痛
DOI：
10.1177/1744806916674479
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发表时间：
2016
期刊：
影响因子：
3.3
通讯作者：
Xie J
中科院分区：
文献类型：
--
作者：
Liu B;Su M;Tang S;Zhou X;Zhan H;Yang F;Li W;Li T;Xie J
背景以往的研究表明，神经胶质细胞在神经病理性疼痛的产生和维持中起着重要作用。激活的神经胶质细胞产生许多介质，如促炎症细胞因子，促进神经元活动和突触可塑性。同样，膀胱痛综合征/间质性膀胱炎有许多神经病理性疼痛的特征。然而，有关脊髓胶质细胞参与膀胱痛综合征/间质性膀胱炎相关性病理性疼痛及其机制的相关报道尚不多见。本研究在大鼠膀胱痛综合征/间质性膀胱炎模型中研究了脊髓神经胶质细胞的激活及其潜在的分子机制。结果环磷酰胺全身注射建立了大鼠膀胱痛综合征/间质性膀胱炎模型。用von Frey单丝法和升降法检测机械性超敏反应。用免疫印迹和双重免疫荧光方法检测L6-S1脊髓中胶质纤维酸性蛋白、OX42/IBA1、P-P38、NeuN、IL-1β、N-甲基-D-天冬氨酸受体1(P-NR1)和IL-1受体I(IL-1RI)的表达和定位。我们发现，在环磷酰胺诱导的膀胱炎脊髓中，胶质纤维酸性蛋白明显增加，而不是OX42/IBA1或P-P38。L-α-氨基己二酸酯可明显减轻痛觉过敏，而米诺环素无此作用。此外，我们还发现，在环磷酰胺诱导的膀胱炎中，脊髓IL-1β显著增加，而激活的星形胶质细胞是IL-1β释放的唯一来源，这与膀胱炎大鼠的痛觉过敏有关。此外，在环磷酰胺诱导的膀胱炎模型中，脊髓P-NR1的表达显著增加，并且仅定位于脊髓背角的IL-1RI阳性神经元。此外，NR拮抗剂可显著减轻膀胱炎引起的疼痛。有趣的是，P-nr1表达的时程与IL-1β或胶质纤维酸性蛋白表达的时程平行。结论星形胶质细胞激活而不是小胶质细胞激活参与了环磷酰胺诱导的膀胱炎的痛觉过敏，星形胶质细胞释放的IL-1β可能与其神经元上的内源性受体结合，诱导NR1亚单位的磷酸化，导致感觉神经元兴奋性亢进和病理性疼痛。
Background Previous studies have demonstrated that glial cells play an important role in the generation and maintenance of neuropathic pain. Activated glial cells produce numerous mediators such as proinflammatory cytokines that facilitate neuronal activity and synaptic plasticity. Similarly, bladder pain syndrome/interstitial cystitis shares many characteristics of neuropathic pain. However, related report on the involvement of spinal glia in bladder pain syndrome/interstitial cystitis-associated pathological pain and the underlying mechanisms are still lacking. The present study investigated spinal glial activation and underlying molecular mechanisms in a rat model of bladder pain syndrome/interstitial cystitis. Results A rat model of bladder pain syndrome/interstitial cystitis was established via systemic injection with cyclophosphamide. Mechanical allodynia was tested with von Frey monofilaments and up-down method. Moreover, Western blots and double immunofluorescence were used to detect the expression and location of glial fibrillary acidic protein, OX42/Iba1, P-P38, NeuN, interleukin (IL)-1β, phosphorylation of N-methyl-D-aspartate receptor 1 (P-NR1), and IL-1 receptor I (IL-1RI) in the L6-S1 spinal cord. We found that glial fibrillary acidic protein rather than OX42/Iba1 or P-P38 was significantly increased in the spinal cord of cyclophosphamide-induced cystitis. L-alpha-aminoadipate but not minocycline markedly attenuated the allodynia. Furthermore, we found that spinal IL-1β was dramatically increased in cyclophosphamide-induced cystitis, and activated astrocytes were the only source of IL-1β release, which contributed to allodynia in cystitis rats. Besides, spinal P-NR1 was statistically increased in cyclophosphamide-induced cystitis and only localized in IL-1RI positive neurons in spinal dorsal horn. Additionally, NR antagonist significantly attenuated the cystitis-induced pain. Interestingly, the time course of the P-NR1 expression paralleled to that of IL-1β or glial fibrillary acidic protein. Conclusions Our results demonstrated that astrocytic activation but not microglial activation contributed to the allodynia in cyclophosphamide-induced cystitis and IL-1β released from astrocytes might bind to its endogenous receptor on the neurons inducing the phosphorylation of NR1 subunit, leading to sensory neuronal hyperexcitability and pathological pain.
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影响因子：
2
作者：
Birder, Lori A.;Wolf-Johnston, Amanda S.;Chib, Manjul K.;Buffington, Charles A.;Roppolo, James R.;Hanna-Mitchell, Ann T.
通讯作者：
Hanna-Mitchell, Ann T.
影响因子：
5.6
作者：
Freitas, Raquel D. S.;Costa, Kesiane M.;Campos, Maria M.
通讯作者：
Campos, Maria M.
影响因子：
9.3
作者：
Gardoni F;Boraso M;Zianni E;Corsini E;Galli CL;Cattabeni F;Marinovich M;Di Luca M;Viviani B
通讯作者：
Viviani B
影响因子：
7.4
作者：
Ledeboer, A;Sloane, EM;Watkins, LR
通讯作者：
Watkins, LR
影响因子：
2.9
作者：
Liao, Yong-Hui;Zhang, Gui-He;Dou, Ke-Feng
通讯作者：
Dou, Ke-Feng