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Nitric oxide signalling underlies salicylate-induced increases in neuronal firing in the inferior colliculus: A central mechanism of tinnitus?

Lookup NU author(s): Dr Bas OlthofORCiD, Dr Dominika Lyzwa, Dr Sasha Gartside, Professor Adrian ReesORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2022. 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.

Publication metadata

Author(s): Olthof BM, Lyzwa D, Gartside SE, Rees A

Publication type: Article

Publication status: Published

Journal: Hearing Research

Year: 2022

Volume: 424

Print publication date: 01/10/2022

Online publication date: 22/07/2022

Acceptance date: 21/07/2022

Date deposited: 15/08/2022

ISSN (print): 0378-5955

ISSN (electronic): 1878-5891

Publisher: Elsevier BV


DOI: 10.1016/j.heares.2022.108585


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Funder referenceFunder name
BB/P003249/1Biotechnology and Biological Sciences Research Council (BBSRC)