Olthof Bas Mj, Lyzwa Dominika, Gartside Sarah E, Rees Adrian
Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
Hear Res. 2022 Oct;424:108585. doi: 10.1016/j.heares.2022.108585. Epub 2022 Jul 22.
The anti-inflammatory drug salicylate induces tinnitus in animals and man. Salicylate reduces cochlear output but causes hyperactivity in higher auditory centres, including the inferior colliculus (the auditory midbrain). Using multi-electrode recording in anaesthetised guinea pigs (Cavia porcellus), we addressed the hypothesis that salicylate-induced hyperactivity in the inferior colliculus involves nitric oxide signalling secondary to increased ascending excitatory input. Systemic salicylate (200 mg/kg i.p., 0 h) markedly increased spontaneous and sound-driven neuronal firing in the inferior colliculus (3-6 h post drug), with both onset and sustained responses to pure tones being massively increased. Reverse microdialysis of increasing concentrations of salicylate directly into the inferior colliculus (100 µM-10 mM, from 0 h) failed to mimic systemic salicylate. In contrast, it caused a small, transient, increase in sound-driven firing (1 h), followed by a larger sustained decrease in both spontaneous and sound-driven firing (2-5 h). When salicylate was given systemically, reverse microdialysis of the neuronal nitric oxide synthase inhibitor L-methyl arginine into the inferior colliculus (500 mM, 2-6 h) completely blocked the salicylate-induced increase in spontaneous and sound-driven neuronal firing. Our data indicate that systemic salicylate induces neuronal hyperactivity in the auditory midbrain via a mechanism outside the inferior colliculus, presumably upstream in the auditory pathway; and that the mechanism is ultimately dependent on nitric oxide signalling within the inferior colliculus. Given that nitric oxide is known to mediate NMDA receptor signalling in the inferior colliculus, we propose that salicylate activates an ascending glutamatergic input to the inferior colliculus and that this is an important mechanism underlying salicylate-induced tinnitus.
抗炎药物水杨酸盐可在动物和人类中诱发耳鸣。水杨酸盐会降低耳蜗输出，但会导致包括下丘（听觉中脑）在内的高级听觉中枢的活动亢进。我们在麻醉的豚鼠（豚鼠）中使用多电极记录，探讨了水杨酸盐在下丘诱发的活动亢进涉及一氧化氮信号传导的假说，该信号传导继发于上升的兴奋性输入增加。全身给予水杨酸盐（腹腔注射200 mg/kg，0小时）显著增加了下丘的自发和声音驱动的神经元放电（给药后3 - 6小时），对纯音的起始和持续反应均大幅增加。将浓度不断增加的水杨酸盐直接逆向微透析到下丘（100 μM - 10 mM，从0小时开始）未能模拟全身给予水杨酸盐的效果。相反，它导致声音驱动的放电出现小的、短暂的增加（1小时），随后自发和声音驱动的放电均出现更大的持续减少（2 - 5小时）。当全身给予水杨酸盐时，将神经元型一氧化氮合酶抑制剂L - 甲基精氨酸逆向微透析到下丘（500 mM，2 - 6小时）可完全阻断水杨酸盐诱导的自发和声音驱动的神经元放电增加。我们的数据表明，全身给予水杨酸盐通过下丘以外的机制诱发听觉中脑的神经元活动亢进，推测是在听觉通路中上游的机制；并且该机制最终依赖于下丘内的一氧化氮信号传导。鉴于已知一氧化氮在下丘中介导NMDA受体信号传导作用，我们提出水杨酸盐激活了下丘的上升性谷氨酸能输入，这是水杨酸盐诱发耳鸣的重要机制。
