Department of Anesthesiology and Perioperative Care, University of California, Irvine, CA, USA.
Department of Pain Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Neurol Res. 2021 Aug;43(8):683-692. doi: 10.1080/01616412.2021.1915079. Epub 2021 Apr 18.
Phospholipase A2 (PLA2) plays an important role in regulating the production of arachidonic acid and various eicosanoids. The aim of our study was to investigate the analgesic mechanisms of calcium-dependent cytosolic phospholipase A2 and calcium-independent PLA2 (iPLA2) inhibitors in the spinal cord in a rat model of neuropathic pain.
Lumbar 5 spinal nerve ligation was performed in male Sprague-Dawley rats to develop a peripheral neuropathic pain model. Paw withdrawal thresholds in response to von Frey filaments, brush, pressure, and pinch were measured. Lumbar wide dynamic range neuronal firing rates and iPLA2 subtype expression were measured by extracellular recording and double immunofluorescence staining, respectively.
In our rat models, oral administration of prednisolone, a non-selective PLA2 inhibitor, and intrathecal injection of bromoenolactone, a iPLA2 inhibitor, significantly increased the ipsilateral hindpaw withdrawal thresholds in response to von Frey filament stimulation, but intrathecal injection of arachidonyl trifluoromethyl ketone, a selective cytosolic PLA2 inhibitor, did not show significant changes. In spinal dorsal horn neurons, bromoenolactone reduced neuronal firing rates in response to withdrawal stimulation and spontaneous firing rates in the ipsilateral side of the spinal dorsal horn. In addition, the expression of iPLA2 was co-localized with astrocytes and neurons on the ipsilateral side of the dorsal horn in rats that underwent spinal nerve ligation.
These data suggest that selective iPLA2 inhibitor produce analgesia in neuropathic rats by reducing central sensitization in the dorsal horn.
磷脂酶 A2（PLA2）在调节花生四烯酸和各种前列腺素的产生中起着重要作用。我们的研究旨在探讨钙依赖性胞质 PLA2 和钙非依赖性 PLA2（iPLA2）抑制剂在脊髓中对神经病理性疼痛大鼠模型的镇痛机制。
对雄性 Sprague-Dawley 大鼠进行腰椎 5 脊神经结扎，以建立周围神经病理性疼痛模型。通过 von Frey 纤维、毛刷、压力和捏夹来测量足底退缩阈值。通过细胞外记录和双免疫荧光染色分别测量宽动态范围神经元的放电率和 iPLA2 亚型的表达。
在我们的大鼠模型中，口服非选择性 PLA2 抑制剂泼尼松龙和鞘内注射 iPLA2 抑制剂溴烯诺酮显著增加了对 von Frey 纤维刺激的同侧后爪退缩阈值，但鞘内注射选择性胞质 PLA2 抑制剂花生四烯酸三氟甲基酮则没有明显变化。在脊髓背角神经元中，溴烯诺酮降低了对撤去刺激和同侧背角自发性放电率的神经元放电率。此外，在接受脊神经结扎的大鼠中，iPLA2 的表达与背角同侧的星形胶质细胞和神经元共定位。
这些数据表明，选择性 iPLA2 抑制剂通过减少背角的中枢敏化，在神经病理性大鼠中产生镇痛作用。
