Nitric oxide signalling underlies salicylate-induced increases in neuronal firing in the inferior colliculus: a central mechanism of tinnitus?
The tinnitus-inducing agent 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. In the inferior colliculus, systemic salicylate (200 mg/kg i.p., 0 h) markedly increased spontaneous and sound-driven neuronal firing (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 {micro}M-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. Graphical abstractTinnitus is associated with increased activity in the central auditory pathway, an effect replicated by high dose sodium salicylate. Here we show that salicylate-induced increases in neuronal activity in the auditory midbrain are mediated by nitric oxide signalling within this region. Nitric oxide is a key mediator of neuronal responses to NMDA receptor stimulation in this region. Our data support the hypothesis that tinnitus is mediated by increased ascending glutamatergic input to the auditory midbrain. O_FIG O_LINKSMALLFIG WIDTH=160 HEIGHT=200 SRC="FIGDIR/small/444151v1_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@1d732dcorg.highwire.dtl.DTLVardef@14c2314org.highwire.dtl.DTLVardef@1930a33org.highwire.dtl.DTLVardef@82d799_HPS_FORMAT_FIGEXP M_FIG C_FIG