BACKGROUND Patients with interstitial cystitis/bladder pain syndrome (IC/BPS) often grieve over a low quality of life brought about by chronic pain. In our previous studies, we determined that neuroinflammation of the spinal dorsal horn (SDH) was associated with mechanisms of interstitial cystitis. Moreover, it has been shown that brain-derived neurotrophic factor (BDNF) participates in the regulation of neuroinflammation and pathological pain through BDNF-TrkB signaling; however, whether it plays a role in cyclophosphamide (CYP)-induced cystitis remains unclear. This study aimed to confirm whether BDNF-TrkB signaling modulates neuroinflammation and mechanical allodynia in CYP-induced cystitis and determine how it occurs. METHODS Systemic intraperitoneal injection of CYP was performed to establish a rat cystitis model. BDNF-TrkB signaling was modulated by intraperitoneal injection of the TrkB receptor antagonist, ANA-12, or intrathecal injection of exogenous BDNF. Mechanical allodynia in the suprapubic region was assessed using the von Frey filaments test. The expression of BDNF, TrkB, p-TrkB, Iba1, GFAP, p-p38, p-JNK, IL-1β, and TNF-α in the L6-S1 SDH was measured by Western blotting and immunofluorescence analysis. RESULTS BDNF-TrkB signaling was upregulated significantly in the SDH after CYP was injected. Similarly, the expressions of Iba1, GFAP, p-p38, p-JNK, IL-1β, and TNF-α in the SDH were all upregulated. Treatment with ANA-12 could attenuate mechanical allodynia, restrain activation of astrocytes and microglia and alleviate neuroinflammation. Besides, the intrathecal injection of exogenous BDNF further decreased the mechanical withdrawal threshold, promoted activation of astrocytes and microglia, and increased the release of TNF-α and IL-1β in the SDH of our CYP-induced cystitis model. CONCLUSIONS In our CYP-induced cystitis model, BDNF promoted the activation of astrocytes and microglia to release TNF-α and IL-1β, aggravating neuroinflammation and leading to mechanical allodynia through BDNF-TrkB-p38/JNK signaling.

中文翻译：

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BDNF促进星形胶质细胞和小胶质细胞的活化，从而促进环磷酰胺诱发的膀胱炎中的神经炎症和机械性异常性疼痛。

背景技术患有间质性膀胱炎/膀胱疼痛综合征（IC / BPS）的患者经常为慢性疼痛带来的低质量生活感到悲伤。在我们以前的研究中，我们确定脊髓背角（SDH）的神经炎症与间质性膀胱炎的机制有关。而且，已经表明脑源性神经营养因子（BDNF）通过BDNF-TrkB信号传导参与神经发炎和病理性疼痛的调节。然而，尚不清楚它是否在环磷酰胺（CYP）引起的膀胱炎中起作用。这项研究旨在确认BDNF-TrkB信号传导是否能调节CYP诱导的膀胱炎中的神经炎症和机械性异常性疼痛并确定其发生方式。方法采用全身腹膜内注射CYP建立大鼠膀胱炎模型。通过腹膜内注射TrkB受体拮抗剂，ANA-12或鞘内注射外源BDNF来调节BDNF-TrkB信号传导。使用冯·弗雷丝测试法评估耻骨上区域的机械性异常性疼痛。通过Western印迹和免疫荧光分析测量BD6-L1SSDH中BDNF，TrkB，p-TrkB，Iba1，GFAP，p-p38，p-JNK，IL-1β和TNF-α的表达。结果CYP注射后，SDH中的BDNF-TrkB信号明显上调。同样，SDH中Iba1，GFAP，p-p38，p-JNK，IL-1β和TNF-α的表达均被上调。ANA-12治疗可以减轻机械性异常性疼痛，抑制星形胶质细胞和小胶质细胞的活化并减轻神经炎症。此外，鞘内注射外源性BDNF可进一步降低机械退缩阈值，促进星形胶质细胞和小胶质细胞的活化，并增加CYP诱导的膀胱炎模型SDH中TNF-α和IL-1β的释放。结论在我们的CYP诱导的膀胱炎模型中，BDNF促进星形胶质细胞和小胶质细胞的活化以释放TNF-α和IL-1β，加剧神经炎症并通过BDNF-TrkB-p38 / JNK信号传导导致机械性异常性疼痛。