Tseng Kuang-Yi, Wang Hung-Chen, Cheng Kai-Feng, Wang Yi-Hsuan, Chang Lin-Li, Cheng Kuang-I
Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
Department of Anesthesiology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
Front Pharmacol. 2022 May 20;13:859982. doi: 10.3389/fphar.2022.859982. eCollection 2022.
Peripheral nerve block (PNB) under echo guidance may not prevent intrafascicular anesthetic injection-induced nerve injury. This study investigated whether unintended needle piercing alone, or the intrafascicular nerve injectant could induce neuropathy. 120 adult male Sprague-Dawley rats were divided into four groups: 1) group S, only the left sciatic nerve was exposed; 2) group InF-P, the left sciatic nerve was exposed and pierced with a 30 G needle; 3) group InF-S, left sciatic nerve was exposed and injected with saline (0.9% NaCl 30 µL); 4) group InF-R, left sciatic nerve was exposed and injected with 0.5% (5 mg/mL, 30 µL) ropivacaine. Behaviors of thermal and mechanical stimuli responses from hindpaws, sciatic nerve vascular permeability and tight junction protein expression, and macrophage infiltration were assessed. Pro-inflammatory cytokine expression and TIMP-1 and MMP-9 activation at the injection site and the swollen, and distal sites of the sciatic nerve were measured by cytokine array, western blotting, and immunofluorescence of POh14 and POD3. Intrafascicular saline and ropivacaine into the sciatic nerve, but not needle piercing alone, significantly induced mechanical allodynia that lasted for seven days. In addition, the prior groups increased vascular permeability and macrophage infiltration, especially in the swollen site of the sciatic nerve. Thermal hypersensitivity was induced and lasted for only 3 days after intrafascicular saline injection. Obvious upregulation of TIMP-1 and MMP-9 on POh6 and POh14 occurred regardless of intrafascicular injection or needle piercing. Compared to the needle piercing group, the ratio of MMP-9/TIMP-1 was significantly higher in the intrafascicular injectant groups at the injected and swollen sites of the sciatic nerve. Although no gross changes in the expressions of tight junction proteins (TJPs) claudin-5 and ZO-1, the TJPs turned to apparent fragmentation and fenestration-like degenerative change in swollen endothelial cells and thickened microvessels. Intrafascicular nerve injection is a distinct mechanism that induces neuropathy. It is likely that the InF nerve injection-induced neuropathy was largely due to dramatic, but transient, increases in enzymatic activities of MMP-9 and activating TIMP-1 in the operated nerves. The changes in enzymatic activities then contributed to certain levels of extracellular matrix degradation, which leads to increases in endoneurial vascular permeability.
超声引导下的周围神经阻滞（PNB）可能无法预防束内注射麻醉剂引起的神经损伤。本研究调查了单纯意外针刺或束内神经注射剂是否会诱发神经病变。120只成年雄性Sprague-Dawley大鼠被分为四组：1）S组，仅暴露左侧坐骨神经；2）InF-P组，暴露左侧坐骨神经并用30G针头穿刺；3）InF-S组，暴露左侧坐骨神经并注射生理盐水（0.9% NaCl 30 μL）；4）InF-R组，暴露左侧坐骨神经并注射0.5%（5 mg/mL，30 μL）罗哌卡因。评估后爪对热和机械刺激反应的行为、坐骨神经血管通透性和紧密连接蛋白表达以及巨噬细胞浸润情况。通过细胞因子阵列、蛋白质印迹法以及对POh14和POD3进行免疫荧光检测，测量注射部位以及坐骨神经肿胀部位和远端部位的促炎细胞因子表达以及TIMP-1和MMP-9的激活情况。向坐骨神经内注射束内生理盐水和罗哌卡因，而非单纯针刺，会显著诱发持续7天的机械性异常性疼痛。此外，上述各组均增加了血管通透性和巨噬细胞浸润，尤其是在坐骨神经的肿胀部位。束内注射生理盐水后会诱发热超敏反应，且仅持续3天。无论束内注射还是针刺，POh6和POh14上的TIMP-1和MMP-9均明显上调。与针刺组相比，在坐骨神经的注射部位和肿胀部位，束内注射剂组的MMP-9/TIMP-1比值显著更高。尽管紧密连接蛋白（TJPs）claudin-5和ZO-1的表达无明显变化，但在肿胀的内皮细胞和增厚的微血管中，TJPs出现明显的碎片化和类似窗孔的退行性改变。束内神经注射是诱发神经病变的一种独特机制。InF神经注射诱发的神经病变很可能主要是由于手术神经中MMP-9的酶活性急剧但短暂增加以及TIMP-1被激活。酶活性的变化进而导致一定程度的细胞外基质降解，从而使神经内膜血管通透性增加。
