Effects Of Sodium Salicylate On Neural Excitability Of The Auditory Cortex And The Medial Geniculate Body

BACKGROUND:Sodium salicylate (NaSal), the active metabolite of aspirin, is one of the most widely used analgesic, anti-inflammatory and antipyretic drugs. High doses of NaSal has long been known to cause reversible tinnitus in humans as well as in animals. Because the clinical presentation of tinnitus is subjective and variable, directly observing and exploring tinnitus in humans are difficult. To explore the biological bases of tinnitus, NaSal is frequently used to induce transient tinnitus in animal models. Previous data have provided evidence that NaSal could lead to hyperexcitability in some regions along the auditory pathway through shifting the balance between excitation and inhibition, which is proposed to be one of the underlying mechanisms of NaSal-induced tinnitus.Since NaSal can penetrate the blood—brain barrier to target neurons in the central auditory system. Therefore I wondered whether NaSal could directly alter the neural excitability in central auditory structures. And whether NaSal exert similar effects in different central auditory regions.METHODS:In the present studies, I applied whole-cell patch-clamp recordings in the rat brain slices of the auditory cortex and the medial geniculate body (MGB) to examine whether perfusing the slices with sodium salicylate (1.4mmol/L) would change the intrinsic membrane properties of neurons and/or the synaptic transmission and thus influences the neural excitability in these structures.RESULTS:(1) In the auditory cortex slices, the glutamatergic pyramidal cells and the GABAergic fast-spiking interneurons in layer II/III could be identified according to their morphological features and by their characteristic patterns of current-evoked firing. Following perfusion of NaSal, the threshold current needed to evoke an action potential remained unchanged for pyramidal neurons, but significantly increased for fast-spiking interneurons; The drug perfusion caused no significant change in current-evoked firing rates in pyramidal neurons, but drastically and reversibly depressed the evoked firing in fast-spiking interneurons; When I applied step currents, at any level of depolarization, application of NaSal did not significantly change the firing rates in pyramidal neurons, but significantly depressed the evoked firing in fast-spiking interneurons at any rate. These differential effects of NaSal on pyramidal cells and fast-spiking interneurons, the former being excitatory and the latter inhibitory, suggest raised neural excitability in the auditory cortex and thus a plausible neural basis for NaSal-induced tinnitus.(2) In the MGB slices, NaSal altered the intrinsic properties of MGB neurons decreasing the membrane input resistance, hyperpolarizing the resting membrane potential, suppressing the current-evoked firing rate, changing the shape of the action potential and drastically depressing the rebound depolarization, indicating NaSal decreased membrane excitability of MGB neurons. When I applied electrical pulse to stimulate the brachium of the inferior colliculus and recorded the postsynaptic response in the MGB neuron, it turned out that the peak amplitude as well as the response area of the postsynaptic responses were significantly decreased by NaSal, demonstrating suppressed efficacy of synaptic transmission from the inferior colliculus in MGB neurons. The components mediated by GABAA and NMDA receptors were both suppressed significantly following NaSal but the AMPA receptor-mediated component was not affected. All these results imply that NaSal decrease neural excitability in the MGB, and probably contribute to NaSal-induced tinnitus through raising the possibility of neural synchrony in the auditory cortex.CONCLUSION:Nasal has direct effects on the neural excitability of the central auditory structures. Though altering the neuronal intrinsic membrane excitability and/or synaptic transmission, NaSal could change the neural excitability of the auditory cortex and the MGB in different ways, its effects could probably contribute to NaSal-induced tinnitus.