Department of Physiology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil.
Department of Physiology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil.
Eur J Pharmacol. 2022 Jul 5;926:175026. doi: 10.1016/j.ejphar.2022.175026. Epub 2022 May 13.
High doses of salicylate induce tinnitus in humans and experimental animals. The Dorsal Cochlear Nucleus is implicated with the genesis of tinnitus, and increased activity in this nucleus is seen in animal models of tinnitus. Incubation of brainstem slices containing the DCN with millimolar salicylate reduces the spontaneous firing of glycinergic cartwheel neurons and glycinergic neurotransmission on fusiform neurons, the principal neuron of this nucleus. However, the mechanism of salicylate mediating this effect is not known. Recently, we have shown that K channels strongly modulate the spontaneous firing of cartwheel neurons. We tested if K channels could mediate the effects of salicylate on cartwheel neurons. Perfusion of 1.4 mM salicylate hyperpolarizes the membrane of cartwheel neurons and stops firing. Salicylate produces an outward current similar to the K current seen in quiet cartwheel neurons. Activation of this current is occluded by the K agonist diazoxide, which is produced by the opening of K channels. The antagonist of AMP-kinase (AMPK), dorsomorphim, inhibited salicylate effects, suggesting that they could be mediated by activation of this kinase. Still, the AMPK agonist, AICAR, did not reproduce salicylate effects but occluded them. Additionally, inhibiting mitochondrial ATP synthesis with the protonophore CCCP reproduced, albeit with less efficacy, and inhibited the effects of salicylate. We concluded that salicylate in millimolar concentrations opens K channels in DCN cartwheel neurons, inhibiting spontaneous firing of these neurons, probably by activating AMPK and reducing mitochondrial ATP synthesis.
高剂量的水杨酸盐会在人类和实验动物中引起耳鸣。背侧耳蜗核与耳鸣的产生有关，在耳鸣的动物模型中，该核内的活动增加。用包含 DCN 的脑桥切片孵育毫摩尔水杨酸盐会降低甘氨酸轮状神经元的自发放电和梭形神经元（该核的主要神经元）上的甘氨酸能神经传递。然而，水杨酸盐介导这种作用的机制尚不清楚。最近，我们已经表明，K 通道强烈调节轮状神经元的自发放电。我们测试了 K 通道是否可以介导水杨酸盐对轮状神经元的影响。用 1.4mM 水杨酸盐灌流会使轮状神经元的膜超极化并停止放电。水杨酸盐产生的外向电流类似于安静轮状神经元中观察到的 K 电流。这种电流的激活被 K 激动剂二氮嗪阻断，二氮嗪是由 K 通道的开放产生的。AMP 激酶（AMPK）的拮抗剂（dorsomorphim）抑制了水杨酸盐的作用，表明它们可能通过激活这种激酶来介导。尽管如此，AMPK 激动剂 AICAR 并没有复制水杨酸盐的作用，但却阻断了它们的作用。此外，用质子载体 CCCP 抑制线粒体 ATP 合成，尽管效果稍差，但也能重现水杨酸盐的作用，并抑制其作用。我们得出结论，毫摩尔浓度的水杨酸盐会打开 DCN 轮状神经元中的 K 通道，抑制这些神经元的自发放电，可能是通过激活 AMPK 和减少线粒体 ATP 合成。
