Salicylate activates K-ATP channels and reduces spontaneous firing in glycinergic cartwheel neurons in the dorsal cochlear nucleus of rats

Author(s)

de Siqueira, Daniela Vanessa F. ; Strazza Jr, Paulo S. ; Benites, Nikollas M. ; Leao, Ricardo M.

• Document type: Journal article
• Source: European Journal of Pharmacology; v. 926, p. 10-pg., 2022-07-05.

Abstract

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 KATP channels strongly modulate the spontaneous firing of cartwheel neurons. We tested if KATP 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 KATP current seen in quiet cartwheel neurons. Activation of this current is occluded by the KATP agonist diazoxide, which is produced by the opening of KATP 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 KATP channels in DCN cartwheel neurons, inhibiting spontaneous firing of these neurons, probably by activating AMPK and reducing mitochon-drial ATP synthesis. (AU)

• FAPESP's process: 19/13458-1 - Changes during the development of ionic currents and neurotransmission of auditory neurons: effects of the acoustic environment
• Grantee: Ricardo Mauricio Xavier Leão
• Support Opportunities: Regular Research Grants