Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China.
Department of Urology, The Second Affiliated Hospital of Nantong University (The First People's Hospital of Nantong), Nantong, China.
J Neuroinflammation. 2019 Oct 25;16(1):189. doi: 10.1186/s12974-019-1584-3.
Prostatodynia is the main symptom of chronic prostatitis and the main reason that patients go to the hospital for treatment. Although a variety of factors, including inflammatory immune response, nervous system sensitization, and psychological factors, have been shown to play important roles in the induction and development of chronic pain in prostatitis, the underlying cause of chronic prostatodynia maintenance in prostatitis patients remains unclear.
A mouse model of chronic prostatitis induced by carrageenan injection was used. The von Frey test was used to measure pain behavior. The microglial and astrocyte activations were immunohistochemically demonstrated with antibodies against Iba1 and GFAP. The expression of cytokine or signaling pathway was detected by enzyme-linked immunosorbent assay (ELISA) and Western blotting.
In this study, we provide several lines of evidence to demonstrate that activated spinal astrocytes contribute to the later phase (5 weeks after carrageenan injection) of carrageenan-induced prostatitis pain. First, activation of spinal astrocytes but not microglia was found in the spinal cord dorsal horn at 5 weeks. Second, intrathecal injection of the astroglial toxin L-2-Aminoadipate acid (L-AA) but not microglial inhibitor minocycline reduced mechanical allodynia at 5 weeks. Third, chronic prostatitis induced a profound and persistent upregulation of connexin-43 hemichannels in spinal astrocytes, and spinal injection of the connexin-43 inhibitor carbenoxolone (CBX) effectively reduced pain symptoms. Fourth, increased expression and release of chemokine C-X-C motif ligand 1 (CXCL1) in the spinal dorsal horn and intrathecal injection of a CXCL1 neutralizing antibody or the CXCR2 (a major receptor of CXCL1) antagonist SB225002 significantly reduced mechanical allodynia at 5 weeks.
In this study, we found that a novel mechanism of activated spinal astrocytes plays a crucial role in maintaining chronic prostatitis-induced persistent pain via connexin-43-regulated CXCL1 production and secretion.
前列腺痛是慢性前列腺炎的主要症状，也是患者就医治疗的主要原因。虽然已经证实多种因素，包括炎症免疫反应、神经系统致敏和心理因素，在前列腺炎慢性疼痛的诱导和发展中发挥重要作用，但前列腺炎患者慢性前列腺痛持续存在的根本原因仍不清楚。
使用角叉菜胶注射诱导的慢性前列腺炎小鼠模型。使用 von Frey 测试测量疼痛行为。用针对 Iba1 和 GFAP 的抗体通过免疫组织化学显示小胶质细胞和星形胶质细胞的激活。通过酶联免疫吸附试验 (ELISA) 和 Western blot 检测细胞因子或信号通路的表达。
在这项研究中，我们提供了几条证据来证明激活的脊髓星形胶质细胞有助于角叉菜胶诱导的前列腺炎疼痛的后期阶段（角叉菜胶注射后 5 周）。首先，在脊髓背角中发现激活的脊髓星形胶质细胞而不是小胶质细胞在 5 周时。其次，鞘内注射星形胶质细胞毒素 L-2-氨基己二酸 (L-AA) 而不是小胶质细胞抑制剂米诺环素可减轻 5 周时的机械性痛觉过敏。第三，慢性前列腺炎导致脊髓星形胶质细胞中缝隙连接蛋白 43 半通道的显著且持续上调，脊髓内注射缝隙连接蛋白 43 抑制剂 carbenoxolone (CBX) 可有效减轻疼痛症状。第四，脊髓背角中趋化因子 C-X-C 基序配体 1 (CXCL1) 的表达和释放增加，鞘内注射 CXCL1 中和抗体或 CXCR2（CXCL1 的主要受体）拮抗剂 SB225002 可显著减轻 5 周时的机械性痛觉过敏。
在这项研究中，我们发现激活的脊髓星形胶质细胞的新机制通过缝隙连接蛋白 43 调节的 CXCL1 产生和分泌在维持慢性前列腺炎诱导的持续性疼痛中发挥关键作用。
