Department of Urology, Second Affiliated Hospital, Army Medical University, Chongqing, 400037, People's Republic of China.
Drug Des Devel Ther. 2022 Jan 6;16:67-81. doi: 10.2147/DDDT.S336242. eCollection 2022.
Cross-sensitization of pelvic organs is one theory for why symptoms of gut sickness and interstitial cystitis/bladder pain syndrome overlap. Experimental colitis has been shown to trigger bladder hyperactivity and hyperalgesia in rats. The chemokine receptor CXCR4 plays a key role in bladder function and central sensitization. We aim to study the role of CXCR4 and its inhibitor AMD3100 in colon-bladder cross-organ sensitization.
The colitis model was established by rectal infusion of trinitrobenzene sulfonic acid. Western blot and immunofluorescence were used to assess the expression and distribution of CXCR4. Intrathecal injection of AMD3100 (a CXCR4 inhibitor) and PD98059 (an ERK inhibitor) were used to inhibit CXCR4 and downstream extracellular signal-regulated kinase (ERK) in the spinal cord and dorsal root ganglion (DRG). Intravesical perfusion of resiniferatoxin was performed to measure the pain behavior counts of rats, and continuous cystometry was performed to evaluate bladder voiding function.
Compared to the control group, CXCR4 was expressed more in bladder mucosa and colon mucosa, L6-S1 dorsal root ganglion (DRG), and the corresponding segment of the spinal dorsal horn (SDH) in rats with colitis. Moreover, intrathecal injection of the AMD3100 suppressed bladder overactivity, bladder hyperalgesia, and mastocytosis symptoms caused by colitis. Furthermore, AMD3100 effectively inhibited ERK activation in the spinal cord induced by experimental colitis. Finally, treatment with PD98059 alleviated bladder overactivity and hyperalgesia caused by colitis.
Increased CXCR4 in the DRG and SDH contributes to colon inflammation-induced bladder overactivity and hyperalgesia partly via the phosphorylation of spinal ERK. Treatment targeting the CXCR4/ERK pathway might provide a potential new approach for the comorbidity between the digestive system and the urinary system.
盆腔器官交叉敏感是肠道疾病和间质性膀胱炎/膀胱疼痛综合征症状重叠的一个理论。实验性结肠炎已被证明可在大鼠中引发膀胱过度活动和痛觉过敏。趋化因子受体 CXCR4 在膀胱功能和中枢敏化中发挥关键作用。我们旨在研究 CXCR4 及其抑制剂 AMD3100 在结肠-膀胱跨器官敏化中的作用。
通过直肠给予三硝基苯磺酸建立结肠炎模型。使用 Western blot 和免疫荧光评估 CXCR4 的表达和分布。鞘内注射 AMD3100（CXCR4 抑制剂）和 PD98059（ERK 抑制剂）用于抑制脊髓和背根神经节（DRG）中的 CXCR4 和下游细胞外信号调节激酶（ERK）。膀胱内灌注树脂毒素用于测量大鼠的疼痛行为计数，并进行连续膀胱测压以评估膀胱排空功能。
与对照组相比，结肠炎大鼠的膀胱黏膜和结肠黏膜、L6-S1 背根神经节（DRG）和脊髓背角（SDH）相应节段中 CXCR4 的表达增加。此外，鞘内注射 AMD3100 抑制了结肠炎引起的膀胱过度活动、膀胱痛觉过敏和肥大细胞症状。此外，AMD3100 有效抑制了实验性结肠炎引起的脊髓 ERK 激活。最后，PD98059 治疗减轻了结肠炎引起的膀胱过度活动和痛觉过敏。
DRG 和 SDH 中 CXCR4 的增加部分通过脊髓 ERK 的磷酸化有助于结肠炎症引起的膀胱过度活动和痛觉过敏。针对 CXCR4/ERK 通路的治疗可能为消化系统和泌尿系统的共病提供一种新的潜在方法。
