【摘要】 目的：探讨选择性磷酸二酯酶-2A (phosphodiesterase-2A, PDE2A)抑制剂Bay 60-7550对脊髓损伤(spinal cord injury, SCI)后神经病理性疼痛(neuropathic pain, NP)模型大鼠机械痛阈的影响及其可能机制。方法：雄性SPF级SD大鼠随机分为4组：假手术组（Sham组）、模型组（SCI组）、给药组（Bay60-7550组）和溶媒组（vehicle组）。术前1天至术后21天采用von Frey纤维丝间断测试大鼠后爪机械痛阈值。免疫组化和Western blot检测大鼠脊髓组织中PDE2A表达。流式细胞术检测M1/M2型小胶质细胞/巨噬细胞极化比例；q RT-PCR检测小胶质细胞/巨噬细胞及其下游生物标志物(CD86、CD163、IL-6、IL-1β、IL-10、TGF-β)的表达。结果：鞘内注射Bay 60-7550可显著降低脊髓损伤大鼠的机械痛阈值。与Sham组相比，在SCI组观察到大鼠脊髓背角PDE2A表达增加，而Bay 60-7550组PDE2A的过表达被抑制。与vehicle组相比，Bay 60-7550组脊髓促炎因子(IL-6、IL-1β)表达降低、抗炎因子(IL-10、TGF-β)m RNA的表达增加。同时，还观察到鞘内注射Bay 60-7550可使SCI后小胶质细胞/巨噬细胞M2型比例增加，而M1型细胞比例降低。结论：抑制PDE2A的过表达能有效缓解大鼠脊髓损伤后神经病理性疼痛，其机制可能与其调节小胶质细胞/巨噬细胞的极化状态有关。更多还原

【Abstract】 Objective: To investigate the effects of Bay 60-7550, a selective phosphodiesterase-2A(PDE2A) inhibitor, on mechanical pain threshold and its potential mechanism in the neuropathic pain(NP) using spinal cord injury(SCI) rat model. Methods: Male SD rats were randomly divided into four groups: the Sham group, SCI group, SCI + Bay 60-7550 group, and SCI + Vehicle group. The mechanical pain thresholds were evaluated by the von Frey test from the day before surgery until the 21th postoperative day. The expression level of PDE2A in the spinal cord was measured by immunohistochemistry and Western blot. The proportion of M1/M2 microglia/macrophages polarization was assessed by flow cytometry. The expression of microglia/macrophages and their downstream biomarkers(CD86, CD163, IL-6, IL-1β, IL-10, TGF-β) were measured by qRT-PCR. Results: Intrathecal administration of Bay 60-7550, significantly attenuated mechanical allodynia in SCI rats. Compared with the Sham group, PDE2A expression was elevated in the spinal dorsal horn of SCI rats, while the overexpression of PDE2A was inhibited by the treatment of Bay 60-7550. Bay 60-7550 reduced pro-inflammatory factors(IL-6, IL-1β) expression, increased anti-inflammatory factors(IL-10, TGF-β) expression in the spinal cord compared with group vehicle. Consistently, Bay 60-7550 treatment promoted the proportion of M2-type microglia/macrophages, but decreased the proportion of M1-type microglia/macrophages in SCI rats. Conclusion: Inhibiting the overexpression of PDE2A might attenuate the development of NP in rats with neuropathic pain, and the mechanism might be related to the polarization of microglia/macrophages polarization.更多还原