Department of Anesthesiology, Taipei Veterans General Hospital, Taipei, Taiwan.
School of Medicine, National Yang-Ming University, Taipei, Taiwan.
CNS Neurosci Ther. 2017 Jul;23(7):580-589. doi: 10.1111/cns.12705. Epub 2017 May 19.
We previously demonstrated that intrathecal IL-1β upregulated phosphorylation of p38 mitogen-activated protein kinase (P-p38 MAPK) and inducible nitric oxide synthase (iNOS) in microglia and astrocytes in spinal cord, increased nitric oxide (NO) release into cerebrospinal fluid, and induced thermal hyperalgesia in rats. This study investigated the role of spinal glutamatergic response in intrathecal IL-1β-induced nociception in rats.
The pretreatment effects of MK-801 (5 μg), minocycline (20 μg), and SB203580 (5 μg) on intrathecal IL-1β (100 ng) in rats were measured by behavior, Western blotting, CSF analysis, and immunofluorescence studies.
IL-1β increased phosphorylation of NR-1 (p-NR1) subunit of N-methyl-D-aspartate receptors in neurons and microglia, reduced glutamate transporters (GTs; glutamate/aspartate transporter by 60.9%, glutamate transporter-1 by 55.0%, excitatory amino acid carrier-1 by 39.8%; P<.05 for all), and increased glutamate (29%-133% increase from 1.5 to 12 hours; P<.05) and NO (44%-101% increase from 4 to 12 hours; P<.05) levels in cerebrospinal fluid. MK-801 significantly inhibited all the IL-1β-induced responses; however, minocycline and SB203580 blocked the IL-1β-downregulated GTs and elevated glutamate but not the upregulated p-NR1.
The enhanced glutamatergic response and neuron-glia interaction potentiate the intrathecal IL-1β-activated P-p38/iNOS/NO signaling and thermal hyperalgesia.
我们之前的研究表明，鞘内注射白介素-1β（IL-1β）可使脊髓内小胶质细胞和星形胶质细胞中丝裂原活化蛋白激酶（MAPK）p38 磷酸化（P-p38 MAPK）和诱导型一氧化氮合酶（iNOS）上调，增加一氧化氮（NO）释放到脑脊液中，并在大鼠中引起热痛觉过敏。本研究旨在探讨脊髓内谷氨酸反应在 IL-1β诱导的大鼠疼痛中的作用。
通过行为学、Western blot、CSF 分析和免疫荧光研究，检测 MK-801（5μg）、米诺环素（20μg）和 SB203580（5μg）预处理对鞘内注射 IL-1β（100ng）的影响。
IL-1β增加神经元和小胶质细胞中 N-甲基-D-天冬氨酸受体 NR-1（p-NR1）亚基的磷酸化，减少谷氨酸转运体（GT；谷氨酸/天冬氨酸转运体减少 60.9%，谷氨酸转运体-1 减少 55.0%，兴奋性氨基酸载体-1 减少 39.8%；所有均 P<0.05），并增加谷氨酸（1.5 至 12 小时增加 29%至 133%；所有均 P<0.05）和 NO（4 至 12 小时增加 44%至 101%；所有均 P<0.05）在脑脊液中的水平。MK-801 显著抑制了所有 IL-1β 诱导的反应；然而，米诺环素和 SB203580 阻断了 IL-1β 下调的 GTs，并增加了谷氨酸，但没有上调的 p-NR1。
增强的谷氨酸能反应和神经元-胶质细胞相互作用增强了鞘内 IL-1β 激活的 P-p38/iNOS/NO 信号转导和热痛觉过敏。
