氯沙坦缓解术前焦虑应激诱发的术后痛觉过敏并抑制脊髓小胶质细胞活化

Losartan attenuates preoperative anxiety-induced postoperative hyperalgesia and suppresses microglial activation in the spinal cord

摘要:

目的 探讨鞘内注射血管紧张素II 1型受体（angiotensin II type 1 receptor，AT1R）拮抗剂氯沙坦对术前焦虑应激诱发的术后痛觉过敏以及脊髓小胶质细胞活化的影响。方法 将成年雄性SD大鼠分为对照组（Control），切口组（Incision）和单次延长应激（single prolonged stress，SPS）复合切口组（SPS+incision）；根据鞘内给药情况将成年雄性SD大鼠分为对照+溶剂组（Control+vehicle），模型+溶剂组（SPS+incision+vehicle）和模型+氯沙坦组（SPS+incision+LOR）。检测大鼠焦虑样行为；测定大鼠机械缩足反应阈值（mechanical withdrawal threshold，MWT）的变化；免疫荧光法检测大鼠脊髓背角小胶质细胞标记物Iba-1的表达情况；RT-PCR检测促炎性因子如白细胞介素-1β（interleukin-1β，IL-1β）和肿瘤坏死因子-α（tumor necrosis factor-α，TNF-α）mRNA的表达。结果 SPS可以诱发大鼠产生焦虑样行为，降低大鼠切口术后6h-48h的MWT，增加脊髓背角Iba-1及IL-1β和TNF-α的表达。与溶剂相比，鞘内注射氯沙坦可以升高SPS复合切口大鼠术后2h-48h的MWT，抑制脊髓背角Iba-1及IL-1β和TNF-α的表达。结论 鞘内注射氯沙坦可以缓解焦虑应激诱发的切口术后痛觉过敏并抑制脊髓小胶质细胞活化和促炎性因子上调。

Abstract:

Objective To investigate the effects of intrathecal injection of angiotensin II type 1 receptor (AT1R) antagonist losartan on microglial activation and preoperative anxiety-induced postoperative hyperalgesia. Methods Adult male SD rats were randomly divided into group Control, group Incision, and group SPS (single prolonged stress)+incision. In another experiment, adult male SD rats were randomly divided into group Control+vehicle, group SPS+incision+vehicle and group SPS+incision+LOR (losartan). The anxiety-like behaviors were determined by elevated plus maze. The pain behaviors were determined by measuring mechanical withdrawal threshold (MWT). We also evaluated the expression of Iba-1 (a marker for microglial activation) in spinal cord dorsal horn by immunofluorescence, and determined the spinal levels of IL-1β and TNF-α mRNA by RT-PCR. Results Preoperative SPS enhanced the mechanical allodynia induced by plantar incision (2h-48h after surgery), increased the expression of Iba-1 as well as IL-1β and TNF-α. Compared with vehicle, intrathecal injection of losartan increased the MWT in rats exposed both SPS and incisional surgery. Intrathecal injection of losartan also resulted in decreased expression of Iba-1 and lower expression of IL-1β and TNF-α. Conclusions Intrathecal injection of losartan attenuated the SPS-enhanced mechanical allodynia, and suppresses microglial activation and pro-inflammatory cytokines expression.